Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Cl:5][C:6]1[CH:7]=[C:8]([N:16]([C:21]2[C:40]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][C:24]3[C:25]([C:35]([NH:37][CH3:38])=[O:36])=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[O:27][C:23]=3[CH:22]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:10][C:11]=1[C:12]([CH2:14][OH:15])=[CH2:13].CCN(C(C)C)C(C)C>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]([N:16]([C:21]2[C:40]([CH:41]3[CH2:42][CH2:43]3)=[CH:39][C:24]3[C:25]([C:35]([NH:37][CH3:38])=[O:36])=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[O:27][C:23]=3[CH:22]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:10][C:11]=1[C:12]([CH2:14][O:15][CH2:2][O:3][CH3:4])=[CH2:13]
Reactant: COCCl
Reactant: C=C(CO)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(COCOC)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
Methyl chloromethyl ether (0.024 mL, 0.321 mmol) was added to a mixture of 6-(N-(3-chloro-4-(3-hydroxyprop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (83 mg, 0.146 mmol) and DIEA (0.076 mL, 0.438 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine, dried over sodium sulfate and concentrated to give 6-(N-(3-chloro-4-(3-(methoxymethoxy)prop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide as a white foam (76 mg, 85%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.89 (dd, J=8.78, 5.27 Hz, 2H) 7.60 (s, 1H) 7.48 (s, 1H) 7.38 (d, J=2.15 Hz, 1H) 7.26-7.31 (m, 1H) 7.16-7.24 (m, 2H) 5.77-5.94 (m, 1H) 5.56 (s, 1H) 5.31 (s, 1H) 5.22 (s, 1H) 4.65 (s, 2H) 4.34 (s, 2H) 3.33 (s, 3H) 3.27 (s, 3H) 3.00 (d, J=4.88 Hz, 3H) 1.87-2.29 (m, 1H) 0.14-1.47 (m, 4H). LCMS (m/z, ES+)=613 (M+H+).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=3)[C:33]([O:35]CC)=O)[CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH:43]1([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:50]([N:49]([CH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1)[C:33](=[O:35])[C:32]1[CH:38]=[CH:39][CH:40]=[C:30]([N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:7]3([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:42])([F:1])[F:41])[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:13]4[C:8]3=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:25][CH2:26]2)[CH:31]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CCOC(=O)c1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)c1
Reactant: c1ccc(CNC2CCCCC2)cc1
Product: O=C(c1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)c1)N(Cc1ccccc1)C1CCCCC1

Procedure:
Steps (c) and (d) of Example 1 were repeated, except that the compound prepared in step (b) of Example 87 was used and N-cyclohexylbenzylamine was used instead of N-methylbenzylamine. Thus, the title compound was prepared.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccccc4)ncnc32)[C@]1(C)F
Yield: 95.9 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 8 ml) was added benzylamine (about 0.56 ml, 5.19 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 3% methanol in dichloromethane as eluent furnished title compound (0.22 g) as a colorless solid. Yield: 97%; 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 1H), 8.13-7.96 (m, 3H), 7.59-7.57 (m, 1H), 7.49-7.28 (m, 7H), 6.57 (d, 1H, J=23.1 Hz), 6.24 (bs, 1H), 4.89-4.79 (m, 3H), 4.50-4.43 (m, 1H), 2.18 (s, 3H), 1.90 (d, 3H, J=2.1 Hz), 1.47 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 534 (85%), [M+Na]+ 556 (100%). IR cm−: 3385, 1751, 1720, 1619, 1528, 1476, 1369, 1274, 1062, 712; HPLC: 95%.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([OH:6])=[O:5].[CH3:10][CH:11]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C(OC(OCC)C(C[C@@H](C)CCCC(C)C)C(OCC)OCC)C>C(Cl)Cl>[CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([O:6][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:15]=[CH:14][C:13]([CH2:12][CH:11]([CH3:10])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:18][N:17]=2)=[CH:24][CH:23]=1)=[O:5]
Reactant: CC(C)CCCC(C)Cc1cnc(-c2ccc(O)cc2)nc1
Reactant: CC[C@H](C)[C@H](Cl)C(=O)O
Agent: CCOC(OCC)C(C[C@@H](C)CCCC(C)C)C(OCC)OCC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](Cl)C(=O)Oc1ccc(-c2ncc(CC(C)CCCC(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8 g of (S,S)-3-methyl-2-chloropentanoic acid, 16 g of optically active p-[5--(2,6-dimethylheptyl)-pyrimidin-2-yl]phenol [obtainable by condensation, known from the literature, of (S)-1,1,3,3-tetraethoxy-2-(2,6-dimethylheptyl)-propane with 4-hydroxyphenylamidine hydrochloride], 11.6 g of N,N-dicyclohexylcarbodiimide, 0.6 g of 4-N,N-dimethylaminopyridine and 300 ml of methylene chloride is stirred overnight at room temperature. After the urea derivative which has precipitated has been filtered off, the filtrate is washed with dilute hydrochloric acid and H2O and the organic phase is worked up in the customary manner. p-[5-(2,6-Dimethylheptyl)-pyrimidin-2-yl]-phenyl (S,S)-3-methyl-2-chloropentanoate is obtained.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:17][CH2:18][CH3:19])(=[O:3])[CH3:2].[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[Cl:22])[C:5]=1[CH2:17][CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: Clc1ccccc1CBr
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(C(C)=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-acetyl-2-propylindole-6-carboxylate (74 mg) in dimethylformamide (1.4 m ) was added sodium hydride (60%, 15.4 mg). The mixture was stirred at 20° C. for 30 minutes, then 2-chlorobenzyl bromide (0.045 ml) was added. After stirred for 1 hour, the mixture was diluted with ethyl acetate and washed with water and brine. The organic chase was dried over sodium sulfate and evaporated in vacuo to give methyl 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (125 mg) as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][N:8]=2)[N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2ncc(I)cc2n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a solution of 2-chloro-7-iodo-1,5-naphthyridine (D-17) (586 mg, 2.02 mmol, 1.0 eq) in 1,4-dioxane (20 mL), tert-butyl piperazine-1-carboxylate (372 mg, 2.00 mmol, 1.0 eq), cesium carbonate (922 mg, 2.83 mmol, 1.4 eq), tris(benzylideneacetone)dipalladium (37 mg, 0.04 mmol, 0.02 eq) and Xantphos (35 mg, 0.06 mmol, 0.03 eq) were added. The mixture was stirred at reflux for 16 h under an argon atmosphere. After the reaction mixture was cooled to RT, it was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (15% ethyl acetate/petroether) to afford the desired product, tert-butyl 4-(6-chloro-1,5-naphthyridin-3-yl)piperazine-1-carboxylate (D-18) (207 mg, 29.4% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3-d6) δ: 8.79 (d, J=2.7 Hz, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 3.64 (m, 4H), 3.34 (m, 4H), 1.49 (s, 9H); EST-MS m/z: 349.13[M+H]+.
Reaction SMILES: [Br:1]Br.CO[C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9](OC)[C:10]=1OC.C1(C2SC=C(C(C3C=C(OC)C(OC)=C(OC)C=3)=O)N=2)C=CC=CC=1.O>C(O)C>[Br:1][CH2:16][C:15]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=1)=[O:17]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Solvent: O
Solvent: CCO
Product: O=C(CBr)c1ccccc1
Yield: 70 %

Procedure:
Bromine (160 mg, 1 mmol) was added dropwise to a stirred solution of an 1-(3,4,5-trimethoxyphenyl)ethanone (210 mg, 1 mmol) in ethanol (30 mL) and the solution was stirred at 0° C. for 1h and then poured into water to form a precipitate. This was recrystallized from ethanol to give bromoacetophenone (70%) and used directly for next step. A mixture of bromoacetophenone (288 mg, 1 mmol) and benzothioamide (137 mg, 1 mmol) in ethanol was refluxed for 1h. The reaction mixture was concentrated in vacuo and purified with flash column to give 2i (167 mg, 51.1%). 1H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.48-7.44 (m, 3H), 7.41 (s, 1H), 7.22 (s, 2H), 3.97 (s, 6H), 3.89 (s, 3H). MS (ESI) m/z 350.1 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([Cl:14])[CH:3]=1.[C:15]([OH:20])(=[O:19])[C:16]([CH3:18])=O.N12CCN(CC1)CC2>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:4]1[CH:3]=[C:2]2[C:12]([CH:18]=[C:16]([C:15]([OH:20])=[O:19])[NH:1]2)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(=O)C(=O)O
Reactant: CCOC(=O)c1cc(I)c(N)cc1Cl
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 129 %

Procedure:
A solution of ethyl 4-amino-2-chloro-5-iodobenzoate (1.82 g, 5.59 mmol) in N,N-dimethylformamide (18 ml) under argon was admixed with pyruvic acid (1.27 ml, 18.2 mmol) and 1,4-diazabicyclo[2.2.2]octane, evacuated and flushed with argon. Then argon was passed through the solution for 5 min and then palladium(II) acetate (68 mg, 0.30 mmol) was added and the mixture was heated to 100° C. for 2 h. The cooled solution was filterd through Celite and the filtercake was rinsed with ethyl acetate (100 ml). The filtrate (suspension) was washed with hydrochloric acid (2 M; 2×25 ml) and with water (2×25 ml), dried over sodium sulphate and filtered. The filtrate was concentrated to dryness under reduced pressure and gave a red-brown solid (1.93 g, approx. 51% product), which was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Oc1ccccc1Cl
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Clc1ccccc1Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-chloro-phenol to give [1-(2-chloro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[C:10]2[C:11](=O)[O:12]C(=O)[NH:14][C:9]=2[CH:8]=[CH:7][CH:6]=1>O.CCOC(C)=O>[NH2:14][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[C:10]=1[C:11]([NH:2][CH3:1])=[O:12]
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Reactant: CN
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(N)cccc1OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 70.1 %

Procedure:
Phosgene (4.72 ml, 8.97 mmol; 20% in toluene) was added dropwise to a solution of 2-amino-6-methoxybenzoic acid (1 g, 5.98 mmol) in 2N aqueous sodium hydroxide (6.28 ml, 12.56 mmol) and water (15 ml) cooled to 0° C. over a period of 15 minutes, maintaining the temperature at 0-5° C. The resulting suspension was stirred at 0° C. for 15 minutes. The precipitate was collected by filtration, washed with water, followed by a small amount of acetonitrile and ether and dried under vacuum at 40° C. to afford 5-methoxy-1H-3,1-benzoxazine-2,4-dione (0.760 g, 65.8%) as a beige solid. 40% aqueous methylamine (1.57 ml, 18.1 mmol) was added to a stirred suspension of 5-methoxy-1H-3,1-benzoxazine-2,4-dione (700 mg, 3.62 mmol;) in water (5 ml). The resulting solution was stirred at room temperature for 36 hours. The mixture was diluted with EtOAc, washed sequentially with saturated aqueous sodium carbonate, water and brine. The organic layer was dried over MgSO4 and evaporated to afford 2-amino-6-methoxy-N-methylbenzamide (457 mg, 70.0%) as a white solid. 1H NMR spectrum (500 MHz, DMSO): 2.73 (d, 3H), 3.73 (s, 3H), 5.79 (bs, 2H), 6.19 (d, 1H), 6.30 (d, 1H), 6.99 (dd, 1H), 7.98 (q, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[CH:12]([C:18](=[O:30])[NH:19][C:20]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH:21]3[CH:23]=[CH2:24])[CH2:11]2)[CH:6]=[C:5]([O:31][CH3:32])[N:4]=1.[CH3:33][NH:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:28]([O:27][C:25]([C:20]1([NH:19][C:18]([CH:12]2[CH2:11][CH:10]([O:9][C:7]3[CH:6]=[C:5]([O:31][CH3:32])[N:4]=[C:3]([O:2][CH3:1])[N:8]=3)[CH2:14][CH:13]2[C:15](=[O:16])[N:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:33])=[O:30])[CH2:22][CH:21]1[CH:23]=[CH2:24])=[O:26])[CH3:29]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Reactant: CCCCC=CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Yield: 67.9 %

Procedure:
The acid 18d (1.2 g, 2 mmol) was reacted with N-methylhexeneamine (0.34 g, 3.0 mmol), DIEA (1.29 g, 10.0 mmol) and HATU (1.1 g, 3 mmol) in dry DMF (30 ml) according to the procedure described in Example 13 step c. Purification by column chromatography on silica gel gave the title compound (0.74 g, 74%), (M+H)+545.
Reaction SMILES: [O:1]=[C:2]([Cl:8])OC(Cl)(Cl)Cl.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[N:9]1([C:2]([Cl:8])=[O:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)N1CCc2ccccc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
22.5 mmol of diphosgene dissolved in 90 ml of dichloromethane are cooled to 0° C.; there are then added 45 mmol of indoline, and then 67.5 mmol of triethylamine, while maintaining the temperature at 0° C. After 12 hours at ambient temperature, the mixture is filtered and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6](=O)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1.[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[CH3:21][C:4]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][C:2]([CH3:20])([CH3:1])[CH2:6][N:5]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CCOC(=O)[C@@H]1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of (S)-1-tert-butyl 2-ethyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (163D) (10 g, 0.035 mol) in dry THF (60 mL) stirred at −78° C. under nitrogen was added a 1 M solution of lithium hexamethyldisilazide in THF (38.5 mL, 0.038 mol). The mixture was stirred at −78° C. for 30 min, iodomethane (5.4 g, 0.038 mol) in THF (5 mL) was added, and the mixture was then stirred 1 h, warmed up to room temperature and continued stirring for additional 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography (10-20% EtOAc/hexane) to furnish (163E) (8.2 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccc(F)c2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cccc(F)c1

Procedure:
From 2-amino-4-(3-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:26]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH:40]=O)[C:34](=[O:42])[CH:33]=[CH:32]2)([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:40][CH2:39][N:35]4[C:36]5[C:31](=[CH:30][C:29]([CH:26]([CH3:28])[CH3:27])=[CH:38][CH:37]=5)[CH:32]=[CH:33][C:34]4=[O:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)c1ccc2c(ccc(=O)n2CC=O)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(ccc(=O)n2CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Yield: 44 %

Procedure:
To 4 mL of a chloroform solution containing 0.62 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.41 g of (6-isopropyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 40 μL of acetic acid were added, then, to the reaction mixture, 0.57 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.44 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-isopropyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl.[CH2:14](O)[CH3:15]>O1CCOCC1>[CH2:14]([O:8][C:7]([C:6]1[CH:10]=[CH:11][C:3]([B:2]([OH:12])[OH:1])=[CH:4][CH:5]=1)=[O:9])[CH3:15]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(B(O)O)cc1
Reaction time: 1.5 h

Procedure:
A suspension of 4-(dihydroxyboryl)benzoic acid (5.0 g, 30.13 mmol) in ethanol (16.0 mL) was treated with 4N HCl in dioxane (34.0 mL), heated to reflux, stirred for 1.5 hours, and concentrated. The concentrate was partitioned between water (150.0 mL) and diethyl ether (100.0 mL) and the aqueous layer was extracted with diethyl ether (2×100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (APCI) m/e 194 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.07 (m, 2H), 7.81 (m, 211), 4.41 (q, 2H), 1.41 (t, 3H).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[CH3:50][C:51]1[N:52]=[CH:53][C:54]([CH2:57][NH2:58])=[N:55][CH:56]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:58][CH2:57][C:54]4[CH:53]=[N:52][C:51]([CH3:50])=[CH:56][N:55]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)nc2C)cn1
Yield: 38 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a colorless solid in 38% yield: mp 191-193° C.; 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.40 (s, 1H), 7.30-7.27 (m, 2H), 7.07-7.02 (m, 2H), 6.76 (br s, 1H), 4.70 (d, J=3.0 Hz, 2H), 4.47 (s, 2H), 4.09 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.63 (s, 3H), 2.57 (s, 3H); MS (ES+) m/z 441.2 (M+1).