Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:5](Br)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[NH3:20]>CO>[CH3:1][O:2][N:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:5]([NH2:20])[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CON=C(c1ccc(Cl)cc1)C(Br)CC1CCCC1
Reactant: N
Solvent: CO
Product: CON=C(c1ccc(Cl)cc1)C(N)CC1CCCC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
The 2-bromo-1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (1.16 g, 2.901 mmol) was dissolved in a solution of ammonia in methanol (30 mL, ˜7 N). The reaction flask was sealed with a Teflon stopper, and the reaction mixture was stirred at 55–60° C. for 2 d. It was cooled to 0° C. then the stopper was removed. The reaction mixture was concentrated to remove ammonia and methanol. The residue was partitioned between water and diethyl ether. The product was extracted with diethyl ether (2×20 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 50–100% ethyl acetate+0.1% triethylamine in hexanes yielded 2-amino-1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (423 mg, 45%) as yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: C1COCCN1
Product: O=Cc1c(N2CCOCC2)n(-c2ccccc2)c2ccccc12

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with morpholine as described in Step 2 of Example 29 to afford 2-(morpholin-4-yl)-1-phenyl-1H-indole-3-carboxaldehyde (885 yield) as a fluffy, creamy solid. ESI/MS 307 (M+H); RT=2.99 min; NMR 10.15 (1H, s); 8.14 (1H, d, J=6 Hz); 7.69 (5H, m); 7.22 (2H, m); 6.94 (1H, d, J=9 Hz); 3.45 (4H, m); 3.28 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[C:16](=[O:21])[CH2:17]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CBr)cc3)CC2=O)CC1
Yield: 49 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (500 mg) in ethyl acetate (15 ml) and sodium bicarbonate solution (10 ml) was added at 0° C. 4-(bromomethyl)benzenesulfonyl chloride (453 mg), and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:3) to give colorless crystals of 4-[4-(bromomethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (437 mg).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C2C=CC=C(C(Cl)=O)C=2C=CC=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]([CH3:36])=[C:34]([CH3:37])[S:33][C:32]1=[NH:38].CCN(CC)CC>C1COCC1>[CH3:27][O:28][CH2:29][CH2:30][N:31]1[C:35]([CH3:36])=[C:34]([CH3:37])[S:33]/[C:32]/1=[N:38]\[C:11]([C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: O=C(O)c1cccc2ncccc12
Reactant: COCCn1c(C)c(C)sc1=N
Agent: O=C(Cl)c1cccc2ncccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2ncccc12
Yield: 48.2 %

Procedure:
The quinoline-5-carboxylic acid (Lancaster, 0.25 g, 1.4 mmol) was converted to quinoline-5-carbonyl chloride using 5 mL SOCl2 using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and quinoline-5-carbonyl chloride in 30 mL THF were processed as in Example 134B to afford the title compound (0.18 g, 0.53 mmol, 49% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.30 (d, J=0.7 Hz, 3H), 2.34 (s, 3H), 3.31 (s, 3H), 3.80 (t, J=5.1 Hz, 2H), 4.49 (t, J=5.3 Hz, 2H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.83 (dd, J=8.5, 7.1 Hz, 1H), 8.15 (dt, J=8.5, 1.0 Hz, 1H), 8.40 (dd, J=7.3, 1.2 Hz, 1H), 8.87 (dd, J=4.1, 1.7 Hz, 1H), 9.55 (ddd, J=8.8, 1.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 342 (M+H)+; Anal. calculated for C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31. Found: C, 63.44; H, 5.05; N, 12.10.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[O:19].Cl>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]([S:25]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[O:19]
Reactant: O[C@H]1CCNC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)N2CC[C@H](O)C2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine (2.0 g, 22.9 mmol) in THF (40 mL) was added diisopropylethylamine (12.0 mL, 68.9 mmol) and 5-chlorosulfonyl-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (6.0 g, 25.3 mmol). The resulting solution was stirred at room temperature for 2 h. Upon completion, as determined by HPLC, the reaction was acidified with 3N HCl and partitioned between H2O (100 mL) and Ethyl acetate (100 mL). The layers were cut and the aqueous layer was extracted with Ethyl acetate (3×100 mL) and EtOAc:THF (1:1, 2×100 mL). The combined organic cuts were washed with a 50% aqueous brine solution (1×100 mL) and brine (1×100 mL), dried over Na2SO4, and concentrated under reduced pressure. Silica gel chromatography (Ethyl acetate:hexanes, 4:1) afforded 6.31 g (95%) of (S)-5-(3-hydroxy-pyrrolidine-1-sulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a white solid, mp 108-109° C. 1H-NMR (400 MHz, CDCl3): δ 7.25 (d, 1H, J=2.4 Hz), 7.17 (d, 1H, J=2.4 Hz), 4.40 (brs, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.33-3.40 (m, 3H), 3.20-3.23 (m, 1H), 1.93-2.02 (m, 1H), 1.82-1.89 (m, 1H), 1.79 (brs, 1H). Anal. Calcd. for C11H16N2O5S, C, 45.82; H, 5.59; N, 9.72; S, 11.12. Found: C, 45.92; H, 5.63; N, 9.61; S, 11.24.
Reaction SMILES: [CH2:1]([C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[CH2:11]1[O:14][CH:12]1[CH3:13]>Cl.[Cl-].[Li+].CN(C)C=O>[OH:14][CH:12]([CH3:11])[CH2:13][N:7]1[C:3]([CH2:1][CH3:2])([CH3:10])[C:4](=[O:9])[N:5]([CH2:11][CH:12]([OH:14])[CH3:13])[C:6]1=[O:8]
Reactant: CCC1(C)NC(=O)NC1=O
Reactant: CC1CO1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC1(C)C(=O)N(CC(C)O)C(=O)N1CC(C)O
Temperature: 50 °C
Yield: 99.7 %

Procedure:
A mixture of 256.3 g of 5ethyl-5-methylhydantoin (1.805 mols), 675 ml of dimethylformamide and 4.51 g of lithium chloride is stirred at 50° C. 288.0 g of propene oxide (4.96 mols) are slowly added dropwise over the course of 2 hours. Thereafter the temperature is gradually raised to 90° C. over the course of 10 hours. The reaction mixture is brought to pH = 7 with 4 drops of 2 N hydrochloric acid, filtered and concentrated on a rotational evaporator at 90° C. bath temperature, under a waterpumpvacuum. It is then treated at 90° C. under 0.1 mm Hg until the weight remains constant. 465 g of a clear pale yellow product (99.5% of theory) are obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cccc(N)n1
Solvent: O=CO
Product: COC(=O)c1cccc(NC=O)n1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A mixture of formic acid (559.3 g.) and acetic anhydride (1033.4 g.) was stirred for 30 minutes at 40° to 50° C. and thereto was added methyl 6-amino-2-pyridinecarboxylate (616 g.) at 40° C., and then the mixture was stirred for 1 hour at 80° C. After the removal of the solvent from the reaction mixture, the residue was dissolved in a mixture of benzene and n-hexane and then filtered. Thus obtained precipitates were recrystallized from benzene (2 l.) to give methyl 6-formamido-2-pyridinecarboxylate (647.8 g.), mp. 134° to 136° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:18]2)[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(N2CCC(NC(=O)OC(C)(C)C)C2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-(tert-butoxycarbonylamino)pyrrolidine (1.68 g) and potassium carbonate (1.49 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 16 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water five times and brine, dried over sodium sulfate and evaporated under reduced pressure to give 1-(4-methylpyridin-2-yl)-3-(tert-butoxycarbonylamino)pyrrolidine (1.36 g).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]4[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=4[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[C:29]4[CH2:30][CH2:31][CH2:32][CH2:33][C:28]=4[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Reactant: NCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester, m.p. 198° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([N+:25]([O-])=O)=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13])C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>FC(F)(F)C(O)=O>[NH2:25][C:10]1[C:9]([OH:8])=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 40 °C
Yield: 89.6 %

Procedure:
To 7.44 g of 3-benzyloxy-N-(5-chloro-2-pyridyl)-2-nitrobenzamide were added 40 ml of trifluoroacetic acid and 3.72 g of pentamethylbenzene and the mixture was stirred at 40° C. for one night. The reaction solution was concentrated in vacuo, to the residue was added a saturated aqueous solution of sodium hydrogen carbonate to such an extent that the residue did not become alkaline and the mixture was extracted with chloroform. The organic layer was extracted with 1N aqueous solution of sodium hydroxide, the aqueous layer was made acidic by addition of hydrochloric acid thereto and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and to the resulting residue were added 200 ml of suspension of Raney nickel in ethanol. This was stirred for 6 hours in a hydrogen atmosphere, N,N-dimethylformamide was added thereto and the insoluble matter was filtered off. The solvent was evaporated in vacuo and water was added to the resulting residue. The resulting precipitate was collected by filtration and dried in vacuo to give 4.58 g of 2-amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([CH:7]1[CH2:13][C:12]2[S:14][CH:15]=[CH:16][C:11]=2[C:10](=O)[CH2:9][N:8]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:6].[Br:23]NC(=O)CCC(N)=O>C(Cl)Cl>[Br:23][C:15]1[S:14][C:12]2[CH2:13][CH:7]([CH2:5][CH3:6])[N:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][C:11]=2[CH:16]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCOC(=O)N1CC(=O)c2ccsc2CC1CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)N1CCc2cc(Br)sc2CC1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.1 %

Procedure:
Aluminum chloride (972.2 mg, 7.291 mmol) was added to DCM (60 mL) at 0° C., followed by addition of borane-tert-butylamine complex (1.268 g, 14.58 mmol). To the mixture was added a solution of Compound 1037 (650 mg, 2.431 mmol) in DCM (5 mL). The reaction was allowed to warm up to RT and stirred for 18 hours, followed by quenching the reaction with 2N HCl solution until gas evolution ceased. The mixture was extracted with DCM, dried over Na2SO4, and the volatiles removed under reduced pressure. The resulting residue (Compound 1038) was dissolved in acetonitrile and N-Bromosuccinamide (432.7 mg, 2.431 mmol) was added dropwise. The reaction mixture was stirred at RT for 1 hour, then concentrated under vacuum. The residue was purified by silica gel chromatography, using a 0-20% EtOAC/hexanes gradient as eluant, to give ethyl 2-bromo-7-ethyl-7,8-dihydro-4H-thieno[2,3-d]azepine-6(5H)-carboxylate (Compound 1039, 300 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2C=C[CH:49]=[C:50]([NH:51][C:52]([NH:54][N:55]([CH3:57])[CH3:56])=[O:53])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.CCO[CH2:62][CH3:63].CO.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:50]([NH:51][C:52]([NH:54][N:55]([CH3:56])[CH3:57])=[O:53])[CH:49]=[CH:62][C:63]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOCC
Reactant: CCCCc1nc2c(NC(=O)NN(C)C)cccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)NN(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 58b from 4'-[(2-n-butyl-4-dimethylaminoaminocarbonylamino-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and hydrochloric acid in ether/methanol/methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CNCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(C)CCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (337 mg, 0.80 mmol) obtained in Example 12 in methylene chloride (8 ml), 2-(methylamino)ethanol (0.077 ml, 0.96 mmol), 1-hydroxybenzotriazole (130 mg, 0.96 mmol), 4-methylmorpholine (0.194 ml, 1.76 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) were added at room temperature. After stirring for 24 hours at room temperature, the reaction mixture was washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with ethyl acetate was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (328 mg, 0.69 mmol, 85%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:27][CH:23]5[CH2:24][NH:25][CH2:26][CH:22]5[CH2:21]4)[C:16]([CH3:28])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:27][CH:23]5[CH2:24][N:25]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:26][CH:22]5[CH2:21]4)[C:16]([CH3:28])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CNCC2C1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CN(C(=O)CC#N)CC2C1
Temperature: 45 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-5-methyl-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (86.9 mg, 0.23 mmol) and 2-cyanoacetic acid (31.3 mg, 0.37 mmol) in a mixture of DCM (8 mL) and DMF (2 mL) were added HOAT (65.5 mg, 0.48 mmol) and EDCI (77.6 mg, 0.40 mmol). After addition, the reaction mixture was stirred at 45° C. for 1 h, and then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (69.8 mg, 68.2%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]([CH2:9]Br)=[CH2:8]>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:8]=[C:7]([Br:6])[CH3:9])[CH3:2]
Reactant: CCNCC
Reactant: C=C(Br)CBr
Product: CCN(C=C(C)Br)CC

Procedure:
Compound 6b is preferably synthesized by reacting diethylamine with 2,3-dibromopropene to produce 1-diethylamino-2-bromo-propene. Copper iodide is then added with THF and the mixture is cooled to below about -78° C. The solution is stirred and allowed to gradually rise to room temperature. The mixture may then be opened to air and poured into a solution of saturated ammonium chloride. Compound 6a may then be extracted with, e.g., ether, and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O[CH2:9][C:10]#[N:11]>O>[NH2:11][CH2:10][CH2:9][NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCO
Reactant: Nc1cccnc1
Solvent: O
Product: NCCNc1cccnc1
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
3-aminopyridine(1.88 g) and hydroxyacetonitrile(2.49 g) were refluxed in water(20 ml) with stirring for 1.5 hours and then the reaction mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. The solution of the residue in tetrahydrofuran(30ml) was dropped into the suspension of lithium aluminium hydride(1.13 g) in tetrahydrofuran (40ml) while being cooled with ice and the mixture was stirred at room temperature for 30 minutes. A small amount of water was added to the reaction mixture and then the resulting deposit was filtrated out. The filtrate was concentrated under a vacuum, thereby yielding 2.24 g of the aimed compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([C:10](=[O:15])[C:11]([O:13]C)=[O:12])=[CH:2]1.C([O-])([O-])=O.[K+:20].[K+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([C:10](=[O:15])[C:11]([O-:13])=[O:12])=[CH:2]1.[K+:20]
Reactant: COC(=O)C(=O)c1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C([O-])C(=O)c1c[nH]c2ncccc12
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Compound 2a (43 g, 0.21 mol) and K2CO3 (56.9 g, 0.41 mol) were dissolved in MeOH (200 ml) and H2O (200 ml). After 8 hours, product 3a precipitated out from the solution. Filtration afforded 43 g of compound 3a as a white solid in 90.4% yield.
Reaction SMILES: C(O[C:4]([C:6]1[N:18]=[C:17]([CH3:19])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[C:7]=1[OH:26])=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[OH:26][C:7]1[C:8]2[N:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]=2[C:17]([CH3:19])=[N:18][C:6]=1[C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5]
Reactant: CCOC(=O)c1nc(C)c2c3ccccc3n(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c1c1ccccc1n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 1(e) from 4-hydroxy-1-methyl-5-phenyl-5H-pyrido[4,3-b]indole-3-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 376 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=2[S:5][CH:4]=1.[N:14]1([NH:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:18]=[CH:17][N:16]=[CH:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.[I-].[K+]>[N:14]1([N:19]([C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[CH2:2][C:3]2[C:7]3[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=3[S:5][CH:4]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: N#Cc1ccc(Nn2ccnc2)cc1
Reactant: COc1ccc2c(CCl)csc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(CN(c3ccc(C#N)cc3)n3ccnc3)csc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
3-Chloromethyl-6-methoxy-benzothiophene (12.35 g, 58.06 mmol) was added to a mixture of 4[N-(1H-imidazol-1-yl)amino]benzonitrile (9.72 g, 52.78 mmol), K2CO3 (14.60 g, 105.56 mmol) and potassium iodide (0.10 g, 0.60 mmol) in dry DMF (70 ml) at room temperature. The mixture was then stirred at room temperature overnight and after poured into water and extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product as solid (14.30 g). Flash chromatography on silica gel (toluene/dioxan: 6/4) yielded the expected product (10.50 g, 55%, powder).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]O)[CH3:2].[Br:10]P(Br)Br>ClCCl>[Br:10][CH2:8][C:7]1[S:6][CH:5]=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: BrP(Br)Br
Reactant: CCc1ncsc1CO
Solvent: ClCCl
Product: CCc1ncsc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-ethyl-1,3-thiazol-5-yl)methanol (1.0 g, 7.0 mmol) in anhydrous dichloromethane (50 mL) was added tribromophosphane (725 μL, 7.6 mmol). The mixture was stirred at room temperature for 2 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 5-(bromomethyl)-4-ethyl-1,3-thiazole. The crude product was used without further purification.