Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[N:6]=2)[CH2:3][CH2:2]1.[CH2:13]([NH2:15])[CH3:14]>C(O)C>[CH2:13]([NH:15][C:7]1[N:6]=[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:10]=[C:9]([Cl:11])[N:8]=1)[CH3:14]
Reactant: CCN
Reactant: Clc1cc(NC2CC2)nc(Cl)n1
Solvent: CCO
Product: CCNc1nc(Cl)cc(NC2CC2)n1
Yield: 74.9 %

Procedure:
A mixture of 130.5 g (0.64 mol) of 4-cyclopropylamino-2,6-dichloropyrimidine, 576 g (6.4 mols) of ethylamine and 500 ml of ethanol is heated to the reflux temperature for 3 hours. The isomer 6-ethylamino-4-cyclopropylamino-2-chloropyrimidine which crystallises out on cooling is removed by filtration. The filtrate is concentrated to dryness on a rotary evaporator and the residue is recrystallised from methanol. 102 g of colourless crystals of melting point 86°-88° are thus obtained.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-].[Na+].Cl.[C:7]1([C@H:17]([NH:19][CH2:20][CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[C:33]([O:36]CC)(=[O:35])[CH3:34]>>[C:33]([OH:36])(=[O:35])/[CH:34]=[CH:7]/[C:1]([OH:3])=[O:4].[C:7]1([C@H:17]([NH:19][CH2:20][CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Agent: C[C@@H](NCC=Cc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Product: O=C(O)/C=C/C(=O)O
Reaction time: 1 h

Procedure:
Aqueous solution of sodium bicarbonate (5% in water; 30 mL) was added to a solution of N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine hydrochloride (5.0 g) in ethyl acetate (30 mL) at room temperature and stirred for 1 hour. After completion of the reaction, product was extracted with ethyl acetate (50 mL). The organic layer was washed with water (30 mL), passed through hyflo bed and hyflo bed was washed with ethyl acetate (10 mL). The ethyl acetate layer was concentrated to about 30 mL. Fumaric acid (2 g) was added to the concentrated ethyl acetate layer at room temperature and stirred for about one hour to obtain the precipitates of N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine fumarate. The solid was filtered, washed with ethyl acetate twice (2×10 mL) and dried under vacuum.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[NH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([NH:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccncn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccncn1)C(CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
A solution of 3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 88, 152 mg, 0.532 mmol) in methylene chloride (10 mL) was treated with dry N,N-dimethylformamide (3 drops). The reaction mixture was cooled to 0° C. and then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.30 mL, 0.58 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 30 min. The reaction mixture was then treated with N,N-diisopropylethylamine (0.22 mL, 1.26 mmol) followed by a solution of 4-aminopyrimidine (106 mg, 1.12 mmol) in dry tetrahydrofuran (5 mL). The resulting reaction mixture was stirred at 25° C. for 17 h. The reaction mixture was concentrated in vacuo. The resulting residue was adsorbed onto silica gel (Merck Silica gel 60, 230-400 mesh) and then purified via Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-N-pyrimidin-4-yl-2-(3-trifluoromethyl-phenyl)-propionamide (170 mg, 88%) as a white solid: mp 113-115° C.;. EI-HRMS m/e calcd for C19H20F3N3O (M+) 363.1558, found 363.1553.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:21])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:30]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:36][N:35]=1)([CH3:33])([CH3:32])[CH3:31].B(O)O>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([N:36]4[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:38][C:34]([C:30]([CH3:31])([CH3:33])[CH3:32])=[N:35]4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2c(=O)ccc3cc(B(O)O)ccc32)cc1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1-(4-Methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-ylboronic acid (1.8 g, 5.8 mmol) was dissolved in CH2Cl2 (120 mL) and pyridine (10 mL) with molecular sieves (activated, 4 A) and the solution was kept overnight at RT. Commercially available ethyl 3-t-butyl-1H-pyrazole-5-carboxylate (1.2 g, 5.8 mmol), Cu(OAc)2 (1.1 g, 5.8 mmol) and molecular sieves (4 Å activated, powder) were added to the boronic acid solution and the reaction mixture was stirred open to the air at RT for 3 days. The reaction mixture was filtered through a pad of Celite®, and the filtrate was evaporated under reduced pressureand purified by silica gel column chromatography to yield ethyl 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)-3-t-butyl-1H-pyrazole-5-carboxylate (2.5 g, 94% yield). LC-MS (EI) m/z: 460.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][CH2:17][S:16](=[O:21])(=[O:20])[CH2:15]1.[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:16]1(=[O:21])[CH2:17][CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:24]4[CH:25]=[CH:26][S:22][CH:23]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 54.3 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxamide (0.069 g, 0.187 mmol) and 3-thienylboronic acid (0.031 g, 0.242 mmol) was dissolved in a 6:1 solution of 1,4 dioxane (3 mL)/water (0.5 mL) in a 20 mL microwave reaction vessel. Potassium carbonate (0.129 g, 0.933 mmol) was added and the solution was degassed with Nitrogen. PdCl2(dppf)2 (0.023 g, 0.032 mmol) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% NH4OH. The desired fractions were concentrated, giving 0.038 g (54%) of the title compound.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:23](=[O:24])[C:22]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:35])=O)(=[O:4])=[O:3].NS(C1C=CC=CC=1NC(C1C(=O)C(CCCC)(CCCC)C2C(=CC=CC=2)C=1O)=O)(=O)=O>>[O:3]=[S:2]1(=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12]([C:14]2[C:23](=[O:24])[C:22]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])([CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])[C:21]3[C:16]([C:15]=2[OH:35])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:1]1
Reactant: CC(C)CCC1(CCC(C)C)C(=O)C(C(=O)Nc2ccccc2S(N)(=O)=O)=C(O)c2ccccc21
Agent: CCCCC1(CCCC)C(=O)C(C(=O)Nc2ccccc2S(N)(=O)=O)=C(O)c2ccccc21
Product: CC(C)CCC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21

Procedure:
The title compound was prepared according to the procedure of Example 4H, substituting the product of Example 6G for the product of Example 4G. 1H NMR (300 MHz, CDCl3): δ 16.69 (d, J=12.13 Hz, 1H), 14.39, 14.25 (s, 1H), 8.28 (d, J=8.09 Hz, 1 H), 7.99 (d, J=8.09 Hz, 1 H), 7.67 (m, 2 H), 7.48 (q, J=7.72 Hz, 2 H), 7.31 (m, 2 H), 2.29 (m, 2 H), 1.93 (m, 2 H), 1.32 (m, 2 H), 0.82 (m, 14 H), 0.44 (m, 2 H).
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:44])[C:18]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:24][CH2:23]2)=[O:19])=[O:12])=[C:5]([CH3:45])[CH:4]=1)=O.C(O)(=O)C.[NH2:50][CH2:51][C@@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:72])[NH:66]2)[O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CO>[C:57]([Si:54]([CH3:56])([CH3:55])[O:53][C@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:72])[NH:66]2)[CH2:51][NH:50][CH2:1][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:44])[C:18]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:24][CH2:23]2)=[O:19])=[O:12])=[C:5]([CH3:45])[CH:4]=1)([CH3:60])([CH3:59])[CH3:58]
Reactant: Cc1cc(NC(=O)CCCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(NC(=O)CCCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To the stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-formyl-2,5-dimethylphenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (0.748 mmol) in DCM from the previous reaction was added 5-[(R)-2-amino-1-(tert-butyl-dimethylsilanyloxy)ethyl]-8-hydroxy-1H-quinolin-2-one acetic acid salt (0.295 g, 0.748 mmol) in 1:1 MeOH:DCM (3.0 mL). The resulting mixture was stirred at room temperature for 30 min and then sodium triacetoxyborohydride (0.476 g, 2.24 mmol) was added and stirring was continued at room temperature for 4 h. Aqueous NaOH (1 M, 3 mL) and DCM (3 mL) were added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-15% MeOH in DCM) to give the title compound (420 mg, 60% yield) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[O:16]1[CH2:18][CH:17]1[CH2:19][N:20]1[C:28]2[CH2:27][CH2:26][N:25]([C:29](=[O:31])[CH3:30])[CH2:24][C:23]=2[C:22]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[N:21]1>CCO>[NH:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[CH:4]1[CH2:3][CH2:2][N:1]([CH2:18][CH:17]([OH:16])[CH2:19][N:20]2[C:28]3[CH2:27][CH2:26][N:25]([C:29](=[O:31])[CH3:30])[CH2:24][C:23]=3[C:22]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[N:21]2)[CH2:6][CH2:5]1
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(c3nc4ccccc4[nH]3)CC2)C1
Temperature: 60 °C
Yield: 36 %

Procedure:
A solution of 83 mg (0.41 mmol) of 2-piperidin-4-yl-1H-benzoimidazole was dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 55 mg (36%) of a white solid. MS (electrospray): exact mass calculated for C30H33F3N6O2, 566.26. m/z found, 567.3 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers):10.66 (br s, 0.5H), 10.57 (br s, 0.5H), 7.73 (bd, J=8.41 Hz, 1H), 7.72-7.63 (m, 3H), 7.60 (bd, J=8.41 Hz, 1H), 7.39-7.32 (m, 1H), 7.23-7.13 (m, 2H), 7.02 (br s, 1), 4.86 and 4.75 (A and B of AB quartet, J=15.85 Hz, 1.25H), 4.64 (br s, 1H), 4.21-4.06 (m, 2H), 4.06-3.81 (m, 2H), 3.80-3.63 (m, 1H), 3.80-3.69 (m, 1H), 3.00-2.68 (m, 5H), 2.44-2.36 (m, 2H), 2.39-2.23 (m, 2H), 2.19 (s, 1.6H), 2.15 (s, 1.4H), 2.13-2.00 (m, 4H), 2.00-1.80 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:13]([CH2:23][OH:24])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:26]1[C:27]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.ClC1C=C(O)C=NC=1>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@@H:13]([CH2:23][O:24][C:26]2[C:27]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncccc1O
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)C[C@@H]1CO
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using (2R,4R)-tert-butyl 4-(benzyloxymethoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (EXAMPLE 79 Step 2) and ethyl 3-hydroxypicolinate instead of (R)-pyrrolidin-2-ylmethanol and 5-chloropyridin-3-ol.
Reaction SMILES: I[C:2]1[S:3][C:4](I)=[C:5]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8].C([Sn]([C:37]1[CH:41]=[CH:40][S:39][C:38]=1[C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)(CCCC)CCCC)CCC.Cl>CN(C=O)C.[Cu]Cl>[CH2:10]([O:9][P:7]([C:6]1[C:5]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:40]2[S:39][C:38]([C:42]3[S:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][CH:41]=2)[S:3][C:2]=1[C:44]1[S:43][C:42]([C:38]2[S:39][CH:40]=[CH:41][CH:37]=2)=[CH:46][CH:45]=1)([O:12][CH2:13][CH3:14])=[O:8])[CH3:11]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1-c1cccs1
Reactant: CCOP(=O)(OCC)c1c(I)sc(I)c1P(=O)(OCC)OCC
Agent: Cl[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1c(-c2ccc(-c3cccs3)s2)sc(-c2ccc(-c3cccs3)s2)c1P(=O)(OCC)OCC
Temperature: 80 °C
Reaction time: 12 h

Procedure:
In DMF, 0.0971 g (0.159 mmols) of 2,5-diiodo-3,4-bis(diethoxyphosphoryl)thiophene and 0.0346 g (0.349 mmols) of commercially available copper(I) chloride were dissolved, to which 0.1744 g (0.383 mmols) of tributylstannylbithiophene was added at room temperature. Thereafter, the reaction mixture was heated to 80° C. and stirred for 12 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 0.6 M hydrochloric acid aqueous solution was added, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance 1. The results are shown in Table 12.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1.C(#N)C.O>CS(C)=O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:25][CH2:26]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Solvent: CS(C)=O
Solvent: CC#N
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (725 mg, 2.185 mmol) was added DMSO (7 ml), trans-cyclohexane-1,4-diamine (1996 mg, 17.48 mmol) and TEA (0.609 ml, 4.37 mmol) was stirred at about 100° C. for 20 hours. The reaction was monitored by LC/MS. The crude reaction mixture mixture was cooled to room temperature, diluted with 3 ml DMSO, filtered, and purified by prep HPLC. (there is a general HPLC conditions in the general experimental session). The fractions were concentrated, mixed with 500 ml ethyl acetate, and basified with saturated sodium bicarbonate 120 ml. The ethyl acetate layer was separated, and the basic water layer was extracted with 300 ml ethyl acetate. The ethyl acetate layers were combined and washed with water (3×), saturated salt solution (1×), dried with sodium sulfate, filtered and concentrated to yield a solid. The solid was dissolved in (1:1 ACN/water) filtered and lyapholized to yield 755 mg of the title compound as free-base. LCMS (m/z): 426.3 (MH+), retention time=0.59 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.10-1.43 (m, 4 H) 1.90 (d, J=12.01 Hz, 2 H) 2.01 (d, J=12.01 Hz, 2 H) 2.70-2.84 (m, 1 H) 3.47-3.60 (m, 1 H) 4.48 (s, 2 H) 6.44 (d, J=8.50 Hz, 1 H) 6.51 (s, 1 H) 6.71 (d, J=7.33 Hz, 1 H) 6.79-6.91 (m, 1 H) 7.00 (d, J=9.96 Hz, 1 H) 7.05-7.13 (m, 1 H) 7.15-7.27 (m, 1 H) 7.40 (t, J=7.77 Hz, 1 H) 7.85 (s, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:2].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[O:3][CH2:1][CH3:2])[C:8]([OH:10])=[O:9]
Reactant: CCOc1ccc(C(=O)O)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4ethoxybenzoic acid (3.6 g, 0.022 mol) in chloroform (60 ml) was added bromine (1.13 ml, 0.022 mol) in chloroform (20 ml) dropwise. After stirring overnight at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:28])[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCNCC4)cc3)c2n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C(C)C)CC4)cc3)c2n1
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
A solution of Compound 157 (0.350 g, 0.97 mmol) in 1,2-dichloroethane was added with acetone (0.106 mL, 1.46 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.616 g, 2.91 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 161 (0.205 g, 0.51 mmol, 52%).
Reaction SMILES: OC1SC2C=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(C(C)C)CC)(C)C.N1CCCC1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[N:34][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47]([OH:49])=O)[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:36][CH:37]=1>ClCCl>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[N:36][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47]([N:6]4[CH2:5][CH2:7][CH2:8][CH2:9]4)=[O:49])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:34][CH:33]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: Oc1nc2ccccc2s1
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
EDCxHCl (115 mg, 0.60 mmol), hydroxybenzothiazol (82 mg, 0.60 mmol), diisopropylethylamine (0.35 ml, 2.02 mmol) and pyrrolidine (0.05 mL, 0.60 mmol) were added to an ice-cooled suspension of 51e) (200 mg, 0.50 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with dichloromethane (40 mL). The organic phase was successively washed with saturated ammonium chloride solution (2×50 mL), saturated sodium hydrogen carbonate solution (2×30 mL), water (30 mL), and brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography [100-200 mesh silica; 2% methanol in dichloromethane]. White solid. Yield: 65 mg (28% of theory). HPLC-MS (method 5): Rt=3.13 min; m/z [M+H]+=449.1
Reaction SMILES: C(O)(=O)C.Cl.C(OC([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([S:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([NH:30]C(=O)C2C=CC=CC=2)=[N:25][CH:24]=[CH:23]3)[CH2:14]1)=O)(C)(C)C>CO>[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([S:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([NH2:30])=[N:25][CH:24]=[CH:23]3)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Sc2ccc3c(NC(=O)c4ccccc4)nccc3c2)C1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nccc2cc(SC3CCCNC3)ccc12

Procedure:
Glacial acetic acid (2 ml) and 6M hydrochloric acid (4.25 ml) were added to the 3-(1-benzoylaminoisoquinolin-6ylsulfanyl)piperidine-1-carboxylic acid tert-butyl ester (18 mg, 0.039 mmol) and the mixture was refluxed for 24 h. The mixture was then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and then eluted with 2M ammonia in methanol to give 6-(piperidin-3-ylsulfanyl)isoquinolin-1--ylamine which was further purified using prep-HPLC, EIMS: m/z=260.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:10]2[CH2:12][CH2:11]2)=O)[C:3]=1[CH3:13].[Cl-].[CH3:15][O:16][CH2:17][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[CH:15][O:16][CH3:17])[C:3]=1[CH3:13]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(Cl)ccnc1C(=O)C1CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC=C(c1nccc(Cl)c1C)C1CC1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
A yellow suspension of (4-chloro-3-methylpyridin-2-yl) (cyclopropyl) methanone (2.99 g, 15.28 mmol), (Methoxymethyl) triphenylphosphonium chloride (7.84 g, 22.87 mmol) and Potassium tert-butoxide (3.41 g, 30.4 mmol) in toluene (50 mL) was heated to 60° C. and stirred for 3.5 h. The reaction mixture was cooled down to room temperature and an aqueous solution of 4M Hydrochloric acid (50 mL) was added. The reaction mixture was washed with toluene (3×50 mL). The aqueous layer was diluted in ice, and solid sodium bicarbonate was added until pH reaches 7-8. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and evaporated to dryness. The oily residue was purified by flash column chromatography over silica gel using a gradient of ethyl acetate in heptane to yield a 1 to 1 mixture of the isomeric vinyl ethers as yellow oil (2.93 g, 82%).