Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[N:11]=[CH:10]2)[CH:4]=1.[NH:19]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([N:19]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]3)=[O:16])[N:11]=[CH:10]2)[CH:4]=1
Reactant: O=C(O)c1cn(-c2cc(C(F)(F)F)ccn2)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)c2cn(-c3cc(C(F)(F)F)ccn3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylic acid (120 mg, 0.47 mmol) and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (87 mg, 0.47 mmol) in DMF (3 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (210 mg, 0.47 mmol) followed by triethylamine (0.20 mL, 1.4 mmol). The reaction was stirred at room temperature overnight and purified by HPLC to give the title compound. MS (M+H) 426.3.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:7][C:8]=2[NH:9][C:10](=[O:12])[CH:11]=1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[N:7]=[C:8]3[C:3]([C:2]([CH3:1])=[CH:11][C:10](=[O:12])[NH:9]3)=[CH:4][CH:5]=2)[CH2:30][CH2:29]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: Cc1cc(=O)[nH]c2nc(OCCCC=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(=O)[nH]c2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
The crude 4-(5-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde from the previous reaction in 1,2-dichloroethane (30 mL) is treated with 1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.144 g, 4.20 mmol), followed by triethylamine (0.90 mL, 6.46 mmol) and sodium triacetoxyborohydride (0.955 g, 4.50 mmol). The cloudy yellow solution is stirred at room temperature for 1 hour. The mixture is quenched with H2O and saturated NaHCO3 solution and extracted with CH2Cl2. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to a yellow oil. The oil is purified by column chromatography (5:95 methano/vethyl acetate) to afford the title compound (0.97 g, 63% over 2 steps) as a white solid. mp 181–182° C. 1H NMR (CDCl3, 400 MHz): δ 7.57 (br s, 1H), 7.40 (d, 1H), 7.18–7.12 (m, 2H), 7.00–6.94 (m, 1H), 6.38 (d, 1H), 4.23 (t, 2H), 3.16–3.00 (m, 5H), 2.77–2.68 (m, 4H), 2.75–2.56 (m, 1H), 2.52–2.36 (m, 3H), 1.86–1.75 (m, 2H), 1.75–1.64 (m, 2H), 1.28 (d, 3H). MS ES: m/z=460.70, 462.58.
Reaction SMILES: [CH3:1][C:2](=[CH:5]N(C)C)[CH:3]=O.[NH:9]([C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[NH2:10].O.Cl>CO>[CH3:5][C:2]1[CH:1]=[N:10][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:3]=1
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Reactant: CC(C=O)=CN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cnn(-c2nc3ccccc3c(=O)[nH]2)c1
Reaction time: 1.5 h

Procedure:
149.2 g (1.32 moles) of 2-methyl-3-dimethylaminoacrolein are added all at once to a mixture, stirred at 40° C., of 211.2 g (1.2 moles) of 2-hydrazino-4(3H)-quinazolinone, 1.5 litres of water, 540 ml of methanol and 220 ml of concentrated hydrochloric acid. The suspension is stirred at 40° for a total of 4.5 hours and at 60° for 1.5 hours. The crude 2-(4-methyl-1H-pyrazol-1-yl)-4(3H)-quinazolinone isolated at room temperature is obtained in an amount of 245 g of melting point 169°-71°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[N:5]([CH3:15])[C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][C:9]([CH3:14])=[CH:8][CH:7]=2)=[O:3].[Na].[C:17](OCC)(=O)[C:18]([O:20]CC)=[O:19].[Na][Na]>C(O)C>[CH3:15][N:5]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][C:11]=2[C:12]2[O:13][C:17]([C:18]([OH:20])=[O:19])=[CH:1][C:2](=[O:3])[C:4]1=2
Reactant: CC(=O)c1c(O)c2cc(C)ccc2n1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Agent: [Na][Na]
Solvent: CCO
Product: Cc1ccc2c(c1)c1oc(C(=O)O)cc(=O)c1n2C

Procedure:
In a manner analogous to that of Example 14, 8.2 g (0.040 mole) of 1,5-dimethyl-3-hydroxy-1H-indol-2-yl methyl ketone (Example 12) was reacted with sodium metal (3.7 g, 0.16 mole) and diethyl oxalate (21.5g, 0.20 mole) in 200 ml absolute ethanol. The red disodium salt intermediate was then converted to the title compound as described in Example 17. Two recrystallization of the final product from DMF-water yielded yellow needles of mpt. 290°.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]([O:25][CH3:26])=[N:23][C:22]3[C:17]2=[N:18][C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:20][C:21]=3[NH2:27])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClC[C:42]1[CH:49]=[CH:48][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:27][C:21]1[N:20]=[C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])[N:18]=[C:17]2[C:22]=1[N:23]=[C:24]([O:25][CH3:26])[N:16]2[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][C:42]2[CH:49]=[CH:48][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=2)[CH2:13][CH2:12]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Reactant: OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(CO)cc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
To the compound (0.84 g, 1.86 mmol) obtained in Example 9, Step (i) was added trifluoroacetic acid (12 ml), and the mixture was stirred at room temperature for 20 minutes. Trifluoroacetic acid was evaporated by an evaporator, and DMF (15 ml), 4-(chloromethyl)benzyl alcohol (0.32 g, 2.04 mmol), and potassium carbonate (1.28 g, 9.30 mmol) were added thereto, and the mixture was stirred at room temperature for 18 hours. The carbonate was removed by filtration, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted three times with chloroform/ethanol=3/1. The resultant was dried over magnesium sulfate, concentrated, and purified by silica gel column (chloroform/methanol=20/1) to give the subtitle compound (0.52 g, 1.11 mmol) as a white solid. Yield: 60%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][OH:20])[CH:17]=2)=[CH:9][C:8]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:20][CH2:19][CH2:18][N:16]1[CH:17]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([NH2:6])=[C:8]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[CH:9]=2)[CH:14]=[N:15]1)(=[O:4])=[O:3]
Reactant: Nc1ncc(-c2cnn(CCO)c2)cc1-c1nc2ccccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonyl chloride (0.072 ml) was added to 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethanol (150 mg, Example 28), triethylamine (0.130 ml) dissolved dichloromethane (5 ml) at 0° C. The resulting suspension was stirred at 0° C. for 2 hours. The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 1 to 4% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethyl methanesulphonate (150 mg) as a solid. NMR Spectrum: (CDCl3) 3.11 (s, 3H), 4.49 (t, 2H), 4.62 (t, 2H), 7.41-7.49 (m, 2H), 7.68 (bs, 2H), 7.78-7.82 (m, 1H), 7.83-7.87 m, 1H), 8.01 (d, 1H), 8.31 (d, 1H), 8.43 (d, 1H), 8.53 (d, 1H); Mass spectrum: M+H+ 400.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:17]=[C:7]1[C:6]2[CH:18]=[C:2]([O:1][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:3]=[CH:4][C:5]=2[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), tert-butyl bromoacetate (0.88 g, 4.5 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.44 g, 87%)
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][CH:9]([CH:17]([CH3:19])[CH3:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([F:22])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:25]I>CN(C=O)C>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([CH3:25])[CH:9]([CH:17]([CH3:18])[CH3:19])[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:5]([F:22])[CH:4]=1)#[N:2]
Reactant: CI
Reactant: CC(C)C(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)OC(C)(C)C)N(C)Cc1ccc(C#N)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 2-[(4-cyano-2-fluorobenzyl)amino]-3-methylbutanoate (7.2 g, 0.023 mol) in DMF (20 mL) was added dropwise to a stirred suspension of sodium hydride (2.2 g, 0.047 mol) in dry DMF (10 mL) at 00° C. The resulting mixture was stirred for 20 min at RT. Methyl iodide (6 mL, 0.094 mol) was then added dropwise at 0° C. and the mixture was allowed to stir for 3 hr at RT. The reaction mixture was quenched in ice water and extracted with ethyl acetate (250 mL). The organic layer was washed with water (3×100 mL) and dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using petroleum ether and ethyl acetate as eluent, affording the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.80 (d, J=10 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.60 (t, J=7.4 Hz, 1H), 3.79 (d, J=15 Hz, 1H), 3.64 (d, J=15 Hz, 1H), 2.65 (d, J=10.7 Hz, 1H), 2.18 (s, 3H), 1.44 (s, 9H), 0.92-0.83 (m, 6H).
Reaction SMILES: ClC1N=[C:4]([NH:18][C:19]2[C:24]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]([CH3:31])=[CH:21][N:20]=2)[C:5](=[O:17])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH:7]=[C:26]([Si:27]([CH3:30])([CH3:29])[CH3:28])[C:25]3[C:24]4[C:19]([NH:18][C:4]=3[C:5]2=[O:17])=[N:20][CH:21]=[C:22]([CH3:31])[CH:23]=4)=[CH:10][CH:11]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3C#C[Si](C)(C)C)c2=O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Temperature: 130 °C
Reaction time: 94 h
Yield: 89.9 %

Procedure:
In a 2 L round bottom flask, 5-chloro-1-(4-methoxybenzyl)-3-(5-methyl-3-((trimethylsilyl)ethynyl)pyridin-2-ylamino)pyrazin-2(1H)-one (35.2 g, 77.85 mmol) was taken up with anhydrous toluene (880 mL), attached a reflux condenser and transferred to an oil bath that was heated to 130° C. The reaction was stirred in the oil bath for 94 h and concentrated in vacuo to afford a brown solid. The crude was suspended in ethyl acetate (200 mL) and heated to a mild boil. The solids were collected by filtration, washed with additional ethyl acetate, diethyl ether and dried in vacuo to provide the title compound as a pale yellow powder (27.4 g, 89%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.43 (s, 9H) 2.56 (s, 3H) 3.80 (s, 3H) 5.30 (s, 2H) 6.89 (d, J=8.59 Hz, 2H) 7.11 (s, 1H) 7.35 (d, J=8.84 Hz, 2H) 8.22 (s, 1H) 8.52 (d, J=1.52 Hz, 1H). ESI-MS: m/z 392.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][C:3]=1[CH3:25].C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:31]4[CH:36]=[CH:35][N:34]=[N:33][CH:32]=4)=[C:3]([CH3:25])[CH:4]=3)=[N:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Cc1cc(CC(=O)Nc2ccc(-c3cccc(F)c3)cn2)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cccc(F)c3)cn2)cnc1-c1ccnnc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a reaction tube containing 2-(6-chloro-5-methylpyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 74-5 (54 mg, 0.15 mmol), 4-(tributylstannyl)pyridazine (55 mg, 0.15 mmol) and Pd(PPh3)4 (16 mg, 0.015 mmol) under Argon was added DMF (0.8 mL). The mixture was stirred at 120° C. for 10 hours. The crude product was purified by reverse phase HPLC to give N-(5-(3-fluorophenyl)pyridin-2-yl)-2-(5-methyl-6-(pyridazin-4-yl)pyridin-3-yl)acetamide 74 as white solid. MS m/z 400.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 9.42 (dd, 1H, J1=4.8 Hz, J2=1.2 Hz), 9.29 (dd, 1H, J1=10.4 Hz, J2=1.2 Hz), 8.56 (d, 1H, J=1.6 Hz), 8.46 (d, 1H, J=1.6 Hz), 8.28 (d, 1H, J=8.8 Hz), 7.90 (dd, 1H, J1=17.6 Hz, J2=2.4 Hz), 7.72 (d, 1H, J=1.6 Hz), 7.70 (dd, 1H, J1=10.8 Hz, J2=2.0 Hz), 7.44-7.39 (m, 1H), 7.32-7.30 (m, 1H), 7.25-7.21 (m, 1H), 7.09-7.04 (m, 1H), 3.82 (s, 2H), 2.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:5]2[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:8][C:4]=2[C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>CC(C)=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:5]2[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[NH:8][C:4]=2[C:3]=1[S:17]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Reactant: CCNCC
Solvent: CC(C)=O
Product: CCN(CC)S(=O)(=O)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Reaction time: 2 h

Procedure:
5,6,7-Trichloro-2-(trifluoromethyl)-4-benzimidazolesulphonyl chloride (22 parts) in dry acetone (80 parts) was added dropwise to a solution of diethylamine (12 parts) in dry acetone (16 parts). The temperature was kept below 30° and the reaction mixture stirred for 2 hours. The solvent was evaporated and the residue treated with 6N hydrochloric acid. The solid product was collected, washed with water and dried (23 parts). Recrystallisation from toluene (charcoal) gave the required product as pale coloured needles (21.6 parts; m.p.[melting point] 152°-154°; 89.7%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][N:36]([C@H:37]1[CH2:38][CH2:39][C@H:40]([CH3:43])[CH2:41][CH2:42]1)[C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:4]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1cccc(C(F)(F)F)c1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.3 g of 3-trifluoromethylcinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.25 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-trifluoromethylcinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[CH:10]=[C:9](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)[N:8]=[N:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>>[C:38]([S:40][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:9]1[N:8]=[N:7][N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]=1)(=[O:41])[CH3:39]
Reactant: CC(O)=S
Reactant: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)nn1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Product: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)nn1

Procedure:
Following a procedure similar to that described in Example 160-(e), (E)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (4.7 g) was treated with thioacetic acid and N,N-dimethylformamide dineopentyl acetal. After extraction, the obtained substance was purified by silica gel chromatography to afford (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-(triphenylmethyl)piperidine (2.6 g). This compound was similarly treated with trifluoroacetic acid in dichloromethane and the residue obtained by concentration of the reaction mixture was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.026 N aqueous trifluoroacetic acid solution, 18/82, v/v) to afford the title compound (550 mg, yield: 14%) as a yellow amorphous solid.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])C.[CH2:33]([OH:37])[CH:34]([CH3:36])[CH3:35].Cl.O1CCOCC1>>[CH2:33]([O:37][C:4](=[O:3])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:22][CH:23]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)CO
Reactant: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.9 %

Procedure:
(R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (1.5 g, 3.3 mmol) was dissolved in isobutyl alcohol (20 mL, 200 mmol) and 4 M HCl in dioxane (10 mL, 40 mmol) was added. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated, dissolved in water/MeCNe/MeOH, and purified (Interchim C18 reverse phase chromatography column, 25-75% MeCN in water for 22 minutes). The clean fractions were combined and lyophilized to yield the title compound (948 mg; purity 99%). MS m/z [M+H]+ calc'd for C24H26ClN3O6, 488.15. found 488.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][CH3:13])[CH3:2].ClC1C=C(C=CC=1OCC)C=[O:19]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]([OH:19])=[O:9])=[CH:6][C:5]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1ccc(C=O)cc1Cl
Reactant: CCOc1ccc(C=O)cc1OC
Product: CCOc1ccc(C(=O)O)cc1OC
Yield: 89 %

Procedure:
When the product of Step A was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49 Step A the identical process afforded the title compound in 89% yield. 1H-NMR CDCl3) 1.4 (tr, 3H, J=6.95 Hz); 3.83 (s, 3H); 4.07 (q, 2H, J=6.96, 13.9, Hz); 6.79 (d, 1H, J=8.4 Hz); 7.47 (s, 1H); 7.58 (d, 1H, J=8.33 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[N:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[N:19]3)[CH:12]=[C:7]12.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([C:20]2[N:21]=[CH:22][N:18]([C:13]3[CH:12]=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][CH:9]=5)[N:19]=2)[CH2:24][CH2:25]1
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=C1CN=C(n2cnc(C3CC3)n2)C=C2c3cccc(Br)c3CCN12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C1CN=C(n2cnc(C3CC3)n2)C=C2c3cccc(-c4ccc(F)nc4)c3CCN12
Temperature: 85 °C
Reaction time: 0.05 h
Yield: 99.7 %

Procedure:
Example 95-2. 9-bromo-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (5.7 g, 14.31 mmol), (6-fluoropyridin-3-yl)boronic acid (4.03 g, 28.6 mmol) and a solution of Na2CO3 (7.58 g, 71.6 mmol) in water (28 mL) was treated with DME (114 mL). The suspension was degassed, Pd(PPh3)4 (2.48 g, 2.15 mmol) was added and the mixture was heated at 85° C. for 2 h. The mixture was allowed to warm to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 70% AcOEt in heptane for 3 min, then from 70% AcOEt in heptane to 100% AcOEt in heptane in 50 min, 100% AcOEt in heptane for 10 min) to yield a beige foam (5.91 g). The residue was dissolved in DCM (100 mL) and MP-TMT resin (4.0 g, 0.71 mmol/g) was added and the mixture was stirred for 2.5 h. The resin was filtered off and the solvent was removed under reduced pressure to yield a yellow foam. The foam was crystallized from hot n-butanol (50 mL) to afford the title compound as white crystals (4.8 g). UPLC-MS: MS 415.4 (M+H+); UPLC rt 1.02 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.87 (m, 2 H), 0.89-0.99 (m, 2 H), 1.98-2.07 (m, 1 H), 2.87 (t, J=6.11 Hz, 2 H), 3.72 (t, J=6.11 Hz, 2 H), 4.30 (s, 2 H), 7.05 (s, 1 H), 7.31 (dd, J=8.44, 2.57 Hz, 1 H), 7.47-7.56 (m, 2 H), 7.89-7.97 (m, 1 H), 8.07 (td, J=8.13, 2.57 Hz, 1 H), 8.30 (d, J=2.45 Hz, 1 H), 9.00 (s, 1 H).