Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.C(C[CH2:19][N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)#N>>[OH:25][C@H:22]1[CH2:23][CH2:24][N:20]([CH2:19][CH2:15][C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)[CH2:21]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1CC[C@H](O)C1
Product: Cc1cccc2c(=O)[nH]c(CCN3CC[C@H](O)C3)cc12
Yield: 7.3 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (4.07 g) and (S)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (1.6 g), (S)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (0.228 g) was obtained.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:20][N:21]([CH3:30])[C:22]1[CH:27]=[CH:26][C:25]([N:28]([OH:29])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)c1ccc(N=O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CN(C)c1ccc(N(O)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), N,N-dimethyl-4-nitrosobenzenamine (150 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[S:17]1[C:21]2[CH:22]=[CH:23][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:20]=2[CH:19]=[CH:18]1.N.[C:36]([C:40]([OH:42])=[O:41])([F:39])([F:38])[F:37]>>[F:37][C:36]([F:39])([F:38])[C:40]([OH:42])=[O:41].[S:17]1[CH:18]=[CH:19][C:20]2[CH:25]=[C:24]([C:2]3[N:7]=[N:6][C:5]([O:8][C@@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)[CH:23]=[CH:22][C:21]1=2
Reactant: CC1(C)OB(c2ccc3sccc3c2)OC1(C)C
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2s1

Procedure:
The product of Example 9A (120 mg, 0.5 mmol) was coupled with 2-(1-benzothiophen-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Maybridge, 260 mg, 1.0 mmol) according to the procedure of Example 26B. The title product was purified by preparative HPLC (column: Xterra™ RP-18, 5 μm, 30×100 mm. eluting solvent, MeCN/H2O (with 0.1% v. TFA), (v. 90/10 to 10/90 over 20 min.) flow rate, 40 mL/min., uv, 254 nm) to provide a solid (157.3 mg, yield, 70%). 1H NMR (300 MHz, CD3OD) δ 1.92-2.25 (m, 3H) 2.35-2.49 (m, 1H) 2.63-2.71 (m, 1H) 3.35-3.56 (m, 5H) 3.95-4.06 (m, 1H) 5.55-5.62 (m, 1H) 7.37 (d, J=9.16 Hz, 1H) 7.50 (dd, J=5.43, 0.68 Hz, 1H) 7.68 (d, J=5.43 Hz, 1H) 7.96-8.02 (m, 1H) 8.05-8.10 (m, 1H) 8.22 (d, J=9.49 Hz, 1H) 8.45 (d, J=1.70 Hz, 1H) ppm. MS (DCI/NH3) m/z 338 (M+H)+. Anal. Calculated for C19H19N3OS.CF3CO2H: C, 55.87; H, 4.47; N, 9.31. Found: C, 55.51; H, 4.28; N, 9.12.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: O=C(Cl)OCCCCCl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)OCCCCCl)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 82 μl (2 molar equivalents) of 4-chlorobutyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 119 mg of the desired product (formula shown hereinabove) were isolated as an orange powder (yield=85%) which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[Cu](C#N)[C:14]#[N:15]>CN1CCCC1=O.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1)[C:14]#[N:15]
Reactant: N#C[Cu]C#N
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)nc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
2-Chloro-4-iodo-6-(trifluoromethyl)pyridine (0.50 g, 1.5 mmol, prepared according to the method described in European Journal of Organic Chemistry, (18) 3793-3798; 2004) and copper cyanide (0.52 g, 5.8 mmol) were mixed in N-methylpyrrolidinone (2 mL). The reaction vial was sealed and heated in the microwave to 120° C. for 10 minutes. The mixture was diluted with water and EtOAc and was filtered. The organic layer was washed with water (3×), followed by brine, dried over sodium sulfate and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a colorless oil (0.24 g, 64%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:31]([NH:35][S:36](Cl)(=[O:38])=[O:37])([CH3:34])([CH3:33])[CH3:32]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([O:11][S:36](=[O:38])(=[O:37])[NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OS(=O)(=O)NC(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added 1.10 g (3.20 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR), Et2O (50 mL), and 0.90 mL (6.40 mmol) of NEt3, in that order. The solution was cooled to 0° C. To this solution was rapidly added a solution of 1.10 g (6.40 mmol) of (tert-butyl amino)sulfonyl chloride (Matler, W. L., Comer, W. T., and Deitchman, D., Journal of Medicinal Chemistry, 1972, 15 (5), 538-541) in Et2O (10 mL). A precipitate ensued and the reaction was allowed to stir for 30 minutes. Another two equivalents of (tert-butyl amino)sulfonyl chloride (1.10 g, 6.40 mmol) in Et2O (10 mL) and NEt3 (0.90 mL, 6.40 mmol) were added, and the reaction mixture was stirred for another 30 minutes. The reaction was quenched with brine and the organics extracted with Et2O. The organics were dried (MgSO4) and concentrated. The residue was submitted to flash chromatography (EtOAc:CHCl3 1:9) to yield the title compound. 1H NMR (CDCl3) δ 1.23 (s, 9 H), 1.46 (s, 9 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 4.63 (br s, 1 H), 7.23 (s, 1 H), 7.26 (s, obscured by CDCl3, 1 H), 7.42 (d, 2 H), 7.46 (d, 2 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].O1CCCC1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.[H-].[Na+]>CCOCC>[Cl:30][C:29]1[C:24]([O:1][CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[CH:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[O:6][CH3:7])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(c1cc(C)no1)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(c1cc(C)no1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a mixture of 0.21 g (0.9 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylisoxazole, 3 ml of tetrahydrofuran and 0.29 g (1.35 mmol) of 2,3-dichloro-5-trifluoromethylpyridine was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at room temperature for 2 hours. After completion of the reaction, 100 ml of ether was added and washed with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)-α-methoxybenzyl]-3-methylisoxazole (0.32 g, 86.1%) as colorless oil.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[C:11]([F:12])=[C:10]([N:13]2C(=O)C3=CC=CC=C3C2=O)[C:9]([Cl:24])=[C:8]([F:25])[N:7]=1.N>CO>[NH2:13][C:10]1[C:9]([Cl:24])=[C:8]([F:25])[N:7]=[C:6]([Cl:5])[C:11]=1[F:12]
Reactant: O=C1c2ccccc2C(=O)N1c1c(F)c(Cl)nc(F)c1Cl
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1c(F)c(Cl)nc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a mixed solution of 100 ml chloroform and 40 ml methanol was added 16.2 g of N-(2,5-dichloro-3,6-difluoropyridine-4-yl)phthalimide together with 20 ml of 25% aqueous solution of ammonia, and the mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and after adding 150 ml of chloroform to the residue, the mixture was washed with 20 ml of 15% aqueous solution of ammonia, and then, with 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4.55 g of the title compound as a colorless powder.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:35])=[C:18]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (170 mg, 0.94 mmol) and N,N-dimethylformamide (73 μL, 0.94 mmol) was stirred at room temperature for 10 minutes and then a solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (190 mg, 0.628 mmol) in methylene chloride (4 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, then filtered and concentrated. The resultant crude product was used directly in the next step without further purification (110 mg, 55%). LCMS calculated for C16H15Cl2N2O (M+H)+: m/z=321.0; Found: 321.0
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:13]1[S:12][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:10])[F:9])[O:5][N:4]=2)=[CH:15][CH:14]=1)=[O:21]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Product: COc1ccccc1C(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1
Yield: 54 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 2-methoxybenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (15 then 25%) as eluant to afford product as a yellow-tinted oil (100 mg, 54%). 1H NMR (CDCl3) 2.39 (d, J=1.3, 3 H), 3.82 (s, 3 H), 7.01-7.08 (m, 2 H), 7.27-7.54 (m, 4 H). 13C NMR 8.0, 55.9, 111.9, 115.9 (q, J=151), 120.7, 128.2, 129.0, 129.6, 132.7, 135.0, 136.3, 147.1, 155.4 (q, J=41), 157.3, 158.0, 188.2. 19F NMR −63.1. LC/MS 7.50 min, [M+1]+ 368.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]2[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC.C1COCC1.CCOC(C)=O.[Cu]Br>[CH:15]([N:16]1[CH2:19][CH:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:17]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Br[Mg]c1ccccc1
Agent: [Cu]Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27 %

Procedure:
Under nitrogen mix copper (I) bromide (1.1 g, 7.6 mmol) and anhydrous THF (20 mL). Add a 3.0 M solution of phenylmagnesium bromide in ether slowly (2.5 mL, 7.6 mmol). Stir at RT for 90 min. Dissolve 1-(diphenylmethyl)-3-(methanesulphonyloxy)azetidine (2.0 g, 6.3 mmol) in anhydrous THF (10 mL) and transfer to the reaction mixture. Heat at 50° C. then stir at RT for 16 h. Dilute with EtOAc and wash with saturated aqueous sodium bicarbonate solution. Separate organic layer, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting 10:90 EtOAc:hexanes) to give the title compound (515 mg, 27%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[N:18]=2)[CH2:4][CH2:3]1.IC.[CH2:29](N(C(C)C)C(C)C)C>C(Cl)Cl>[O:26]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH2:17][CH2:16][N:15]([CH3:29])[CH2:14][CH2:13][C:12]=3[N:18]=2)[CH2:6][CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCNCC3)cc1
Solvent: ClCCl
Solvent: CI
Product: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (0.060 g, 0.00016 mol), iodomethane (0.015 mL, 0.00016 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.056 mL, 0.00032 mol) in DCM (2 mL) was stirred at rt for 3 h. The mixture was diluted with DCM and washed with water (3×) and satd. aq. NaCl. The separated organic layer was dried and concentrated. The residue was purified by FCC [7 N NH3/MeOH)/DCM] to give 0.010 g (16%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCC(CC(=O)O)C(F)(F)F
Product: CCCCC(CC(=O)Cl)C(F)(F)F
Yield: 83.1 %

Procedure:
2.0 g (10 mmol) of 3-trifluoromethylheptanoic acid and 6 ml (about 80 mmol) of thionyl chloride were reacted for 2 hours under heat-refluxing, followed by distillation to obtain 1.8 g of 3-trifluoromethylheptanoic acid chloride (b.p.: 72.2°-75.0° C./25 mmHg). The acid chloride was dissolved in 10 ml of diethyl ether and added dropwise to a preliminarily ice-cooled ether solution of diazomethane, followed by stirring overnight at room temperature. After distilling off the solvent, the remainder was suspended in 15 ml of dioxane and then added to an aqueous solution at 70° C. of 1.1 g of silver oxide and 2.7 g of sodium thiosulfate (penta-hydrate), followed by stirring for 70 min. After the reaction, potassium hydroxide aqueous solution was added thereto and the mixture was filtered. 5N-nitric acid was added to the filtrate to provide an acidity as judged by Congo Red, followed by extraction with diethyl ether. The resultant ether layer was dried with anhydrous sodium sulfate, followed by distilling-off of the solvent and distillation of the product to obtain 0.42 g of objective 4-trifluoromethyloctanoic acid (b.p.: 130°-135° C./26 mmHg).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH2:11]([O:13][C:14](=[O:45])[CH2:15][C:16]1([CH2:19][CH2:20][C:21]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=2)(C(OCC=C)=O)[C:22]([O:24]CC=C)=[O:23])[CH2:18][CH2:17]1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:13][C:14](=[O:45])[CH2:15][C:16]1([CH2:19][CH2:20][CH:21]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:40]=2)[C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)[CH3:12]
Reactant: C=CCOC(=O)C(CCC1(CC(=O)OCC)CC1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1(CCC(Cc2ccc(C(=O)OC)cc2)C(=O)O)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
At room temperature, a solution of 4.33 ml (31.06 mmol) of triethylamine and 0.89 ml (23.53 mmol) of formic acid in 20 ml of dioxane is added to a solution of 4.58 g (9.41 mmol) of diallyl {2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}[4-(methoxycarbonyl)benzyl]malonate, 173 mg (0.66 mmol) of triphenylphosphine and 42 mg (0.19 mmol) of palladium acetate in 60 ml dioxane. The reaction mixture is then stirred at 100° C. for 2 hours. After complete conversion, the reaction solution is cooled and the solvent is removed under reduced pressure. The residue is then taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted three more times with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated under reduced pressure. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1). This gives 2.68 g (73% of theory, 95% purity) of a colorless solid.
Reaction SMILES: [CH:1]([N:4]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:5](=[O:23])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20])([CH3:3])[CH3:2].[C:32]1([NH:38][N:39]=[C:40]([C:44](Cl)=[O:45])[C:41](Cl)=[O:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[O:45]=[C:44]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[O:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])[C:41](=[O:42])[C:40]1=[N:39][NH:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2c(C)nn(C)c2C)C(C)C)cc1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3c(C)nn(C)c3C)c3ccccc32)C(C)C)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 192.2 %

Procedure:
A solution of N-Isopropyl-N-(4-methoxy-phenyl)-2-[2-(1,3,5-trimethyl-1H-pyrazol-ylamino)-phenylamino]-acetamide (3.0 g, 7.1 mmol) in THF (70 mL) and a solution of 2-(phenyl-hydrazono)-propanedioyl dichloride (1.75 g, 7.1 mmol) in THF (70 mL) were simultaneously added to THF (35 mL) cooled to 0° C. The solution stirred at RT for 15 h and was subsequently concentrated in vacuo to yield the title compound (8.1 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=4)[N:21]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1(c2ccc(Cl)nc2)CCNCC1
Product: OC1(c2ccc(Cl)nc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 80 %

Procedure:
A mixture of 4-(6-chloropyridin-3-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(6-chloropyridin-3-yl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 80% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)(C#N)S(=O)(=O)c1ccccc1Br
Product: CC(C)(C#N)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile. MS (ESI): mass calcd. for C20H17FN4O2S, 396.11; m/z found, 397.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.18 (d, J=8.0, 1H), 8.12 (d, J=1.2, 1H), 7.94 (m, 1H), 7.88-7.82 (m, 2H), 7.54 (d, J=7.6, 1H), 7.37 (dd, J=12.4, 1.4, 1H), 7.29 (dd, J=8.1, 1.6, 1H), 1.50 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:24]([O-:26])=O)=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1.[NH4+].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:24]([NH:42][CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:26])=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: O=C([O-])c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Reactant: NCCN1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCCN1CCCCC1)c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.2 %

Procedure:
To a suspension of the compound of Example 14 (90 mg, 0.23 mmol) in DCM (2 mL) was added EDC (60 mg, 0.30 mmol) and HOBT (41 mg, 0.30 mmol) and the mixture stirred at r.t. for 15 minutes. A solution 1-(2-aminoethyl)piperidine (45 mg, 0.35 mmol) in DCM (0.5 mL) was added and the reaction stirred at r.t. for 18 h. The reaction mixture was diluted with DCM (10 mL), washed with water (2×5 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (0-20% THF in DCM) to give the title compound as an off-white solid (23 mg). δH (CDCl3) 8.61 (1H, s), 7.61-7.43 (3H, m), 7.40-7.27 (2H, m), 7.25-7.13 (3H, m), 7.00-6.89 (3H, m), 6.50 (1H, bs), 6.33 (1H, d, J 9.7 Hz), 3.43-3.25 (2H, m), 2.47-2.32 (2H, m), 2.31-2.11 (4H, m), 1.50-1.40 (4H, m), 1.39-1.25 (2H, m). LCMS (ES+) RT 2.40 minutes, 473 (M+H)+.