Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][O:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13]>CC(C)=O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:11]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCOCC1CO1
Reactant: CO[SiH](OC)OC
Solvent: CC(C)=O
Product: CO[Si](CCCOCC1CO1)(OC)OC
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
In a 10-liter flask provided with stirrer, reflux condenser, internal thermometer and 2 dropping funnels, one filled with 2.85 kg of allyl glycidyl ether and the other with 3.05 kg of trimethoxysilane, 500 ml of allyl glycidyl ether or gamm-glycidyloxypropyltrimethoxysilane was heated to 130° C. Then 1 ml of an 0.01 molar solution of the mesityl oxide-platinum dichloride complex in acetone was added and the reaction was allowed to take place with rapid stirring and the simultaneous feeding in of the two reactants, within about 20 minutes. The internal temperature was kept between 130° C. and 140° C. by slight external cooling and by regulating the feed. This was followed by vacuum distillation producing 5.4 kg of γ-glycidyloxypropyltrimethoxysilane boiling at BP0.05 81° C. (nD20 : 1.4290, d420 : 1.073).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[O:33]1[CH2:38][CH2:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH2:34]1>>[O:33]1[CH2:38][CH2:37][CH:36]=[C:35]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:7][CH:6]=4)[CH2:34]1
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cccnc1F
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1cnc(C3=CCCOC3)cc12

Procedure:
The titled compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 18B, 2-fluoropyridin-3-ylboronic acid and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: N12CCN(CC1)CC2.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].Cl[C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][NH:37]2>ClCCCl.[Cl-].[Na+].O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:33]3[N:41]=[CH:40][N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][NH:37]4)[CH:21]=2)=[CH:12][C:11]=1[C:28]([F:29])([F:30])[F:31]
Reactant: Clc1ncnc2[nH]cnc12
Reactant: O=C(/C=C/c1cccc(O)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: O=C(/C=C/c1cccc(Oc2ncnc3[nH]cnc23)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 11.2 %

Procedure:
To a mixture of 1,4-diazabicyclo[2.2.2]octane (0.098 g, 0.87 mmol) in DCE (25 mL) was added (2E)-N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(3-hydroxyphenyl)-acrylamide (300 mg, 0.87 mmol) and 6-chloro-9H-purine (1.95 mmol). TEA (366 μL, 2.61 mmol) was added, and the resulting solution was stirred at 60° C. The solution was diluted with brine and extracted with EtOAc. The combined organic solutions were dried over Na2SO4, filtered and concentrated. Purification by column chromatography (SiO2, 10-80% EtOAc in hexanes) provided the title compound as a white solid (45 mg). 1H NMR (400 MHz, d6-DMSO): 813.68 (br s, 1H), 10.67 (s, 1H), 8.55 (bs, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 7.92 (dd, 1H), 7.70 (d, 1H), 7.65 (s, 1H), 7.60 (m, 2H), 7.38 (d, 1H) and 6.80 (d, 1H). LCMS, AA: Rt=1.71 min, [MH+ 460.0].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>CN(C)C=O>[CH2:38]([NH:40][C:41]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:42])[CH3:39]
Reactant: Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
Compound A-09 (4-(3-hydroxyphenyl)-2-(morpholin-4-yl)-7-(pyridin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.09 mmol) obtained in Example 1-A-09 was dissolved in dimethylformamide (1 mL), and diisopropylethylamine (32 μL) and ethyl isocyanate (32 μL) were added, followed by stirring at 60° C. for 12 hours. The reaction mixture was poured onto water, followed by extraction with dichloromethane, and the organic layer was dried over sodium sulfate. After the drying agent was filtered off, followed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol), to obtain the desired compound (colorless powder, 22 mg, 55%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[NH:19][N:18]=1>>[F:27][C:16]([F:15])([F:26])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[N:19]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][C:10]3=[O:14])=[CH:4][CH:3]=2)[N:18]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: O=C1CCCN1Cc1ccc(I)cc1
Product: O=C1CCCN1Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 1-[(4-iodophenyl)methyl]-2-pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 19.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[N:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.Cl>O1CCCC1>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][C:46]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:47])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2)N1CCOCC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 40.4 %

Procedure:
To the solution of the product of Example 345 (0.015 g, 0.032 mmol) in tetrahydrofuran (0.4 mL) was added triethylamine (0.009 mL, 0.064 mmol). The mixture was cooled to 0° C. and 4-morpholinecarbonyl chloride (0.004 mL, 0.035 mmol) was added. The reaction mixture was warmed to 23° C. and stirred for 15 hours. 1 N hydrochloric acid (0.065 mL, 0.064 mmol) was added and the mixture was then concentrated under reduced pressure. The product was washed with diethyl ether and water to give the title compound (7.5 mg, 40%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (500 MHz, DMSO-d6) δ 3.57 (t, 4 H) 4.38 (d, J=4.88 Hz, 2 H) 5.60 (bs, 2 H) 7.11 (m, 2 H) 7.27 (m, 6 H) 7.38 (m, J=7.32, 3.05 Hz, 1 H) 7.49 (m, J=7.32 Hz, 1 H) 7.73 (bs, 1 H) 8.21 (d, J=7.32 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a solution of 4-hydroxy-2-fluoro-benzonitrile (1.0 g, 7.3 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (2.09, 15 mmol) and benzyl bromide (0.87 mL, 7.3 mmol), and the solution was stirred at room temperature for 5 hours. Water and ethyl acetate were added to the reaction solution, which was then extracted, washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (1.5 g, 6.7 mmol, 92%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:12][CH:11]=1.Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.CC(O)C>[CH2:17]([N:14]([CH2:15][CH3:16])[C:13]1[CH:19]=[CH:20][C:10]([NH:9][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(Nc2cc(N)ncn2)cc1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 4-amino-N,N-diethylaniline (0.82 mL, 5 mmol), 2-propanol (5 mL) and HCl conc. (0.225 mL, ˜2.5 mmol) is shaken for 36 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-saturated K2CO3-solution and ethyl acetate. The precipitate thus formed is filtered off, washed with H2O and ethyl acetate and dried in vacuo to afford the title compound. Greyish solid, HPLC: tR=2.37 min (gradient F), ESI-MS: 258.3 [MH]+.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH:24]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)=O>CCO>[C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH2:24])=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCc1cccc(Cl)c1NC(=O)c1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Solvent: CCO
Solvent: O=CO
Product: CC(C)(C)C(=O)OCc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Yield: 87.4 %

Procedure:
A mixture of compound 9a (8.90 g, 14 mmol) and formic acid (15 mL, 96% in H2O) in EtOH (150 mL) was refluxed for 24 h. After cooling, the solution was concentrated in vacuo. The residue was subjected to a short column using EtOAc in hexane (30% to 70%) to give the crude compound 10a which was triturated with 10% EtOAc in hexane to give compound 10a (4.50 g, 87% yield). 1H NMR (500 MHz, CDCl3) δ 1.17 (s, 9H), 5.09 (s, 2H), 7.20-7.39 (m, 5H), 8.01 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[N:15]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:17]3[C:22]=2[CH2:21][CH:20]=[CH:19][CH2:18]3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:23]1([C:16]2[N:15]([CH2:29][C:30]([OH:32])=[O:31])[C:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:22]3[C:17]=2[CH2:18][CH:19]=[CH:20][CH2:21]3)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)Cn1c(-c2ccccc2)c2c(c1-c1ccccc1)CC=CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(-c2ccccc2)c2c(c1-c1ccccc1)CC=CC2

Procedure:
5 ml of trifluoroacetic acid are added at 0° C. to a solution of 5 g of the compound of Step A in 50 ml of anhydrous dichloromethane. After reaction for 12 hours at ambient temperature, the reaction mixture is concentrated in vacuo and the residue obtained is rinsed with ether to allow isolation of the expected product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>CC(C)=O.CCOCC>[NH2:12][C:10]([C@H:9]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15])[CH2:13][CH3:14])=[O:11]
Reactant: CC[C@@H](N)C(N)=O
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC[C@@H](NC(=O)CCCCl)C(N)=O
Temperature: 0 °C
Yield: 86 %

Procedure:
31.1 g (0.225 mole) of ground potassium carbonate are mixed with 12.47 g (0.09 mole) of (R)-2-aminobutanamide hydrochloride in 160 ml of acetone. The reaction mixture is cooled to 0° C. and a solution of 15.23 g (0.108 mole) of 4-chlorobutyryl chloride in 25 ml of acetone is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 100 ml of anhydrous ether for 15 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 30 ml of ether, and dried in vacuo to obtain 16 g of (R)-N-[1-(aminocarbonyl)propyl]-4-chlorobutanamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[C:11]([NH:13][C:14](=[N:17]CCSCC1N=CNC=1)SC)#[N:12]>C(O)C>[C:11]([NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[NH:17])#[N:12]
Reactant: NCCSCc1c[nH]cn1
Reactant: CSC(=NCCSCc1c[nH]cn1)NC#N
Solvent: CCO
Product: N#CNC(=N)NCCSCc1c[nH]cn1

Procedure:
4-((2-Aminoethyl)thiomethyl)imidazole is reacted with dimethyl-N-cyanoimidodithiocarbonate according to the procedure of Example 3(c)(i) and the resultant N-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-S-methylisothiourea treated with ammoniacal ethanol according to the procedure of Example 5 to give the title compound.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.[NH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[CH:27]=[N:26][CH:25]=[C:24]2[Br:29]>C1COCC1.CCOC(C)=O>[Br:29][C:24]1[C:23]2[C:28](=[C:19]([NH:18][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)[CH:20]=[CH:21][CH:22]=2)[CH:27]=[N:26][CH:25]=1
Reactant: Nc1cccc2c(Br)cncc12
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c(Br)cncc12)c1cccnc1
Reaction time: 8 h

Procedure:
Nicotinoyl chloride hydrochloride (356 mg, 2 mmol) and triethylamine (558 μl, 2 mmol) are added to a solution of 8-amino-4-bromoisoquinoline (intermediate 23.2, 446 mg, 0.90 mmol) in anhydrous THF (25 ml). The reaction mixture is stirred overnight, diluted with AcOEt (200 ml) and washed twice with 1N NaOH (100 ml) and then the organic phase is dried over Na2SO4 and evaporated under vacuum. The residue is purified on silica gel, eluting with AcOEt.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.S1C=CC=C1[CH2:23][CH2:24][NH2:25].[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:25][CH:24]([CH3:23])[CH3:26])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NCCc1cccs1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)NC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 2-thiophenethylamine (64 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile] to give an anti-form compound (21 mg) and a syn-form compound (14 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(C)=O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A167) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:14]2[CH:22]=[CH:21][C:17]3[NH:18][CH:19]=[N:20][C:16]=3[CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH:8]1OCC[O:9]1.[OH-].[Na+]>CC(C)=O.O.C(OCC)(=O)C>[NH:18]1[C:17]2[CH:21]=[CH:22][C:14]([O:13][C:4]3[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[CH:3]=3)=[CH:15][C:16]=2[N:20]=[CH:19]1
Reactant: Clc1cc(Oc2ccc3[nH]cnc3c2)ccc1C1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc3[nH]cnc3c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-{[3-Chloro-4-(1,3-dioxolan-2-yl)phenyl]oxy}-1H-benzimidazole (1.41 g) was dissolved in approximately 15 mL of acetone and heated at reflux over 3 days with 25 mg of p-tosic acid. An additional 50 mg of p-tosic acid was added and the reaction was heated at 80 degrees Centigrade for an additional 6 hours. The reaction was allowed to cool to room temperature, diluted with water and ethyl acetate, made basic with 10 N NaOH and extracted twice with ethyl acetate. The organic layer was washed with brine and 1N NaOH, dried over MgSO4 and concentrated. The residue was dissolved and stirred in neat trifluoroacetic acid overnight. The reaction was concentrated and purified by silica gel column chromatography (0-10% gradient of methanolic 2N NH3/CH2Cl2). The fractions were concentrated and the residue was purified by preparative HPLC to give 4-(1H-benzimidazol-5-yloxy)-2-chlorobenzaldehyde, which was ultimately used to prepare Examples Nos. 73 and 74.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[CH2:31][NH2:32].CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:32][CH2:31][C:26]4[N:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: NCc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCc4ncccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), pyrimidin-2-ylmethylamine and DIEA to give 4-ethoxy-6-[4-oxo-2-[(pyrimidin-2-ylmethyl)-amino]-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 417 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17](=[O:18])[CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27]OC)=[CH:22][CH:21]=3)[CH2:15][NH:14][C:13](=[O:30])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:31][C:32]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][C:33]=1/[CH:34]=[C:35]1/[C:36](=[O:53])[N:37]([S:43]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)(=[O:45])=[O:44])[CH2:38][C:39](=[O:42])[NH:40][CH2:41]/1>>[CH3:23][O:26][CH2:27][O:31][C:32]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][C:33]=1/[CH:34]=[C:35]1/[C:36](=[O:53])[N:37]([S:43]([C:46]2[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=2)(=[O:44])=[O:45])[CH2:38][C:39](=[O:42])[NH:40][CH2:41]/1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17](=[O:18])[CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH2:15][NH:14][C:13](=[O:30])[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(/C=C2\CNC(=O)CN(S(=O)(=O)c3ccc(Cl)cc3)C2=O)c1
Reactant: COCOc1ccc(CC2CNC(=O)CN(S(=O)(=O)c3ccc(Cl)cc3)C2=O)cc1
Product: COCOc1ccc(C)cc1/C=C1\CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)cc2)C(=O)C(Cc2ccc(O)cc2)CN1

Procedure:
4-[(4-chlorophenyl)sulfonyl]-6-[4-(methoxymethoxy)benzyl]-1,4-diazepan-2,5-dione, synthesized by using, instead of the starting material of Reference Example 124, that is, the compound S120, the compound S121 for the similar procedure as in Reference Example 124, Example 1, and Example 29, was used instead of the starting material compound of Example 193 that is, (6E)-6-[2-(methoxymethoxy)-5-methylbenzylidene]-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione, for the similar procedure as in Example 193 to obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=O)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])[CH:2]([CH3:4])[CH3:3].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C([BH3-])#N.[Na+].[CH3:41][OH:42]>ClC(Cl)C.CC(O)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH2:24][N:30]2[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]2)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])[CH:2]([CH3:4])[CH3:3].[C:41]([OH:35])([C:26]([F:29])([F:28])[F:27])=[O:42]
Reactant: CC(C)Cc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Reactant: O=C(O)C1CNC1
Reactant: CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Cc1ccc(-c2onc3c2CCc2cc(CN4CC(C(=O)O)C4)ccc2-3)cc1C(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 23D, 0.3 g, 0.751 mmol) in dichloroethane (2 mL) and methanol (2 mL) was added azetidine-3-carboxylic acid (0.091 g, 0.901 mmol) followed by 8 drops of AcOH. The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride was added in one lot. The contents were stirred at room temperature for 30 min., concentrated, dissolved in acetonitrile (1.5 mL) and subjected to prep. HPLC purification PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the product were collected and concentrated. The oily residue was freeze dried to yield 1-((3-(4-isobutyl-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (0.146 g, 0.244 mmol, 32.5% yield) as a tan solid. The compound had an HPLC retention time=3.55 min. (condition C); LC/MS M+1=485.4. 1H NMR (500 MHz, MeOD) δ ppm 7.83-7.94 (m, 3H) 7.50 (d, J=8.32 Hz, 1H) 7.38 (s, 1H) 7.34 (dd, J=8.05, 1.66 Hz, 1H) 4.33 (s, 2H) 4.18-4.28 (m, 3H) 3.58 (qd, J=8.37, 8.18 Hz, 1H) 3.15 (1H, hidden under CD3OD peak) 2.96-3.01 (m, 4H) 2.62 (d, J=6.94 Hz, 2H) 1.85-1.94 (m, 1H) 0.84 (d, J=6.66 Hz, 6H).