Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:10]=2[CH3:17])[CH:7]=1.[OH-:28].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH2:16])=[O:28])[CH:12]=[CH:11][C:10]=2[CH3:17])[CH:7]=1
Reactant: [OH-]
Reactant: Cc1ccc(C#N)nc1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(N)=O)nc1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Yield: 81 %

Procedure:
A solution of 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)-methyl]-5-methyl-2-pyridinecarbonitrile (127 mg) in 2M sodium hydroxide solution (0.8 ml) and ethanol (4 ml) was stirred under reflux for 2 hours. Solvent was removed in vacuo and water (5 ml) added. The mixture was extracted with ethyl acetate (3×5 ml) and the combined extracts washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (107 mg, 81%) as a white solid. LC/MS [MH+]=419/421, RT=3.57 min.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][C:22]1[C:23]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:24]([F:37])[C:25](F)=[C:26]([C:28](=[N:34][OH:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:27]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C=O)C>[Si:3]([O:20][CH2:21][C:22]1[C:23]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:24]([F:37])[C:25]2[O:35][N:34]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26]=2[CH:27]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=NO)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Sodium hydride (0.159 g, 3.97 mmol) was suspended in 20 ml of DMF and cooled in an ice bath. Ethyl 2-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-(hydroxyimino)acetate (Intermediate 165, 1.94 g, 3.18 mmol) was dissolved in 20 ml of DMF and added to the reaction flask. The ice bath was removed and the reaction stirred at room temperature for 2 hours. The reaction was quenched with sat NH4Cl (5 ml), diluted with water and extracted three times with ethyl acetate. The organic layers were combined, washed with water and brine 5×, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate to give the title compound (1.250 g, 66.6%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([N:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1)[CH:23]=2)=[O:18])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH:23]=2)=[O:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)c1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(F)cc1NC(=O)c1cnc2cc(N3CCNCC3)ccc2c1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl 4-(3-(2-(tert-butoxycarbonylamino)-5-fluoro-phenyl-carbamoyl)quinolin-7-yl)piperazine-1-carboxylate (100 mg, 0.17 mmol) in DCM (3 mL) was added TFA (1.5 mL). The reaction mixture was stirred at r.t for 1 h and concentrated to give a residue, which was purified by Pre-HPLC to afford compound N-(2-amino-5-fluorophenyl)-7-(piperazin-1-yl)quinoline-3-carboxamide (40 mg, 62%) as a light yellow solid. 1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 9.34 (s, 1H), 9.05 (s, 3H), 8.10 (s, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.24 (s, 1H), 6.96 (s, 2H), 3.71 (s, 4H), 3.31 (s, 4H). LCMS: 1.21 min, m/z=366 (M+H)+
Reaction SMILES: N1C=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:22]=3)[C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14]2)=CC=1.C([Sn](CCCC)(CCCC)C1[N:39]=[CH:40][S:41]C=1)CCC.O.CCOC(C)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:19]1[CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]2[N:39]=[CH:40][S:41][CH:5]=2)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1=[O:32]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=C1CCCCC(c2ccccc2-c2ccncc2)N1Cc1cccc(-c2nccs2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCCC(c2ccccc2-c2cscn2)N1Cc1cccc(-c2nccs2)c1
Temperature: 75 °C

Procedure:
A mixture of 7-(2-bromophenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one (preparation described in example 450; 50 mg; 0.11 mmol), commercially available 4-(tributylstannyl)thiazole (51 mg; 0.13 mmol), and PdCl2(PPh3)2 (8 mg; 0.011 mmol) in THF (1 ml) was heated to 75° C., under nitrogen, for 18 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 446.14 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cccc2ccc(Cl)nc12
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccc2cccc(NCc3cccnc3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.4 %

Procedure:
A mixture of 2-chloroquinolin-8-amine (1.75 g, 9.8 mmol), 3-pyridinecarbaldehyde (2.14 g, 20 mmol) and AcOH (1.2 g, 20 mmol) in MeOH (10 mL) were added NaCNBH3 (1.26 g, 20 mmol) in portions at room temperature, then the reaction mixture was stirred at room temperature for 5 h. The reaction was concentrated in vacuo, and the residue was taken up in CH2Cl2. The solution was washed with water (1×50 mL), dried over Na2SO4, concentrated and purified by silica gel column (20:1 pentane/ethyl acetate) to give 2-chloro-N-(pyridin-3-ylmethyl)quinolin-8-amine as a yellow oil (2.1 g, yield 80%).
Reaction SMILES: CS(OCC[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][O:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48]N)[CH2:43][CH2:42]1>C(N(CC)CC)C>[ClH:31].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:20]2[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][CH:8]=[C:9]([CH2:48][CH2:47][N:44]5[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:42][CH2:43]5)[CH:10]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Reactant: COCCN1CCN(CCN)CC1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2cccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccc(Cl)c(Cl)c3)C4)c2)CC1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanamine and triethylamine as described in general procedure 6 to afford the desired product as hydrochloride salt. M.p.=220-225° C. 1H NMR (DMSO) 400 MHz δ 12.25 (bs, 1H), 11.70 (bs, 1H), 9.67 (s, 1H), 8.34-8.30 (m, 2H), 7.79 (s, 1H), 7.67 (d, J=9.6 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.52-7.41 (m, 3H), 7.28 (t, J=8.0 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.03-6.99 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 4.46 (t, J=6.4 Hz, 1H), 3.90-3.68 (m, 6H), 3.68-3.32 (m, 8H), 3.28 (s, 3H), 3.18-3.12 (m, 2H), 3.11-3.05 (m, 2H). LCMS: 588 m/e [M+H]. Calc. for C33H35Cl2N5.2.60 Hydrochloric acid.1.42 Water.0.03 Ethyl Acetate: C, 55.90; H, 5.76; N, 9.84. Found C, 55.91; H, 5.76; N, 9.84.
Reaction SMILES: [N+]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[CH:6][CH:5]=1)([O-])=O.FC1C=CC(C=C2C3C(=CC=CC=3)N[C:28]2=[O:36])=CC=1.FC(F)(F)C1C=CC(C=C2C3C(=CC=CC=3)N[C:47]2=[O:55])=CC=1.S1C=CC=C1C=C1C2C(=CC=CC=2)NC1=O>>[CH3:47][O:55][C:19]1[CH:20]=[CH:4][C:5]([O:36][CH3:28])=[CH:6][C:7]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18]
Reactant: O=C1Nc2ccccc2C1=Cc1ccc(C(F)(F)F)cc1
Reactant: O=C1Nc2ccccc2C1=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2ccccc2C1=Cc1ccc(F)cc1
Agent: O=C1Nc2ccccc2C1=Cc1cccs1
Product: COc1ccc(OC)c(C=C2C(=O)Nc3ccccc32)c1

Procedure:
3-(4-Nitrobenzylidene)-2-indolinone, 3-(4-Fluorobenzylidene)-2-indolinone, 3-(4-Trifluoromethylbenzylidene)-2-indolinone, and 3-[(Thien-2-yl)methylene]-2-indolinone may also be synthesized according to the above protocol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cc(Cl)ccc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cc(Cl)ccc4Br)oc23)[C@@H]1CO

Procedure:
Compound of example 139 (0.11 g, 0.216 mmol) was subjected to demethylation using pyridine hydrochloride (1.1 g, 9.5 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH:8]1([CH2:14][CH2:15][N:16]2[C:20]3[N:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:19]=3[CH:18]=[C:17]2[CH2:27][N:28]2[C:32](=[O:33])[C:31]3([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:30]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:29]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(OC(=O)C)(=O)C>ClCCl.C(N(CC)CC)C>[C:3]([N:36]1[CH2:37][CH2:38][C:31]2([N:30]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:29][N:28]([CH2:27][C:17]3[N:16]([CH2:15][CH2:14][CH:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:20]4[N:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:19]=4[CH:18]=3)[C:32]2=[O:33])[CH2:34][CH2:35]1)(=[O:4])[CH3:2]
Reactant: N#Cc1ncc2cc(CN3CN(c4ccccc4)C4(CCNCC4)C3=O)n(CCC3CCCCC3)c2n1
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC2(CC1)C(=O)N(Cc1cc3cnc(C#N)nc3n1CCC1CCCCC1)CN2c1ccccc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a solution of 7-(2-cyclohexyl-ethyl)-6-(4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile trifluoroacetic acid salt (142 mg, 0.28 mol) in dichloromethane (2 ml), triethylamine (395 μl) and acetic anhydride (54 μl, 0.57 mmol) are added at 0° C. The reaction mixture is stirred for over night at room temperature, quenched with ice-water and extracted with ethyl acetate. The combined extracts are washed with H2O, brine and dried over sodium sulphate. Chromatography on silica gel gives 90 mg of 6-(8-acetyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 58% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH2:18][CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:18][CH3:19])[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cncc(Br)c1)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a solution of ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 0.051 g, 0.182 mmol) in DMF (3 mL) cooled at 0° C. with an ice bath was added 60% NaH in mineral oil (0.011 g, 0.274 mmol) and the mixture was stirred at room temperature for 20 min. Then, iodoethane (0.045 g, 0.292 mmol) was added and the reaction mixture was stirred for 3 h before being quenched with water (5 mL). The aqueous solution was extracted with EtOAc (2×15 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.051 g, 82%) as orange oil which was used with no further purification. MS: 307.1 and 309.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:23])[NH2:22])=[CH:19][C:18]([N+:24]([O-])=O)=[CH:17][C:16]=2[C:27](=[O:29])[NH2:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:16]([C:27](=[O:29])[NH2:28])=[CH:17][C:18]([NH2:24])=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(C(N)=O)cc([N+](=O)[O-])cc2C(N)=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C(N)=O)cc(N)cc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3,5-dicarbamoylnitrobenzene (3.0 g) in methanol (60 ml) was added palladium on carbon (0.3 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the desired compound (2.8 g, yield quantitative) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](SC)[C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].O[O:13][S:14]([O-:16])=O.[K+].S([O-])(O)=O.[C:22](=O)(O)[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:14]([CH3:22])(=[O:16])=[O:13])[C:5]([NH2:9])=[N:6][C:7]=1[CH3:8]
Reactant: CSc1cc(Cl)c(C)nc1N
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(N)c(S(C)(=O)=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
5-Chloro-6-methyl-3-methylsulfanyl-pyridin-2-ylamine (160 mg, 848 μmol, Eq: 1.00) and oxone (1.56 g, 2.54 mmol, Eq: 3) were combined in methanol (15 ml) to give an off-white suspension. The mixture was cooled to 0° C., and water (30 ml) was added dropwise, followed by 39% hydrogen sulfite (1.5 ml) and saturated sodium bicarbonate solution (6 ml). The mixture was stirred for 10 min and then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The product (88 mg, 47%) was obtained as a white solid by chromatography (SiO2, ethyl acetate/n-heptane). MS: m/z=221.2 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[N:12])[C:8]([N+:13]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]([C:11]#[N:12])[C:8]([NH2:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N#Cc1nc(N)c(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1nc(N)c(C(=O)O)cc1N
Reaction time: 15 h
Yield: 44.1 %

Procedure:
A mixture of the compound prepared in Example 239 (0.063 g) and 10% Pd on charcoal (0.0161 g) in ethyl acetate (2 mL) and ethanol (0.5 mL) was placed under hydrogen for 15 hours. The reaction mixture was filtered and concentrated to obtain the title compound (0.0238 g) having the following physical data. 1H NMR (d6-DMSO): δ 9.4-8.2 (br m, 3H), 7.78 (s, 1H), 5.40 (br s, 2H).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([N:22]4[C:30](=[O:31])[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:32]#[N:33])[CH:28]=5)[CH2:23]4)=[CH:20][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C(Cl)Cl.CO>[NH2:33][CH2:32][C:27]1[CH:28]=[C:29]2[C:24]([CH2:23][N:22]([C:21]3[C:15]4[C:16](=[N:17][CH:18]=[C:13]([C:10]5[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=5)[N:14]=4)[NH:19][CH:20]=3)[C:30]2=[O:31])=[CH:25][CH:26]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4ccc(C#N)cc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5ccc(CN)cc5C4=O)c3n2)cc1
Reaction time: 2 h

Procedure:
2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]-3-oxo-isoindoline-5-carbonitrile (130 mg, 0.1858 mmol) dissolved in a mixture of DCM (10 mL) and MeOH (5 mL) under N2. CoCl2 (48.25 mg, 0.3716 mmol) added then the reaction mixture cooled in an ice bath. NaBH4 (70 mg, 1.858 mmol) added in one portion. Ice bath removed and mixture stirred for 2 h then cooled in an ice bath and water (˜5 mL) added. Mixture diluted with DCM (˜20 mL) and stirred vigorously for 20 mins. Layers separated and aqueous extracted with DCM. Aqueous phase basified by addition of sat NaHCO3 solution and extracted with DCM (×2). Combined organics dried and concentrated to a brown foam. This material deprotected using Method E Step 2 to give the title compound after purification by hplc; 1H NMR (400 MHz, DMSO) δ 1.21 (6H, d), 3.50 (1H, sep), 3.88 (2H, s), 5.49 (2H, s), 7.65 (1H, d), 7.71 (1H, d), 7.84 (1H, s), 8.00 (2H, d), 8.51-8.53 (3H, m), 9.09 (1H, s) ppm; MS (ES+) 462.0.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][OH:13].C[O-].[Na+].O>CO>[CH3:12][O:13][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 18.7 %

Procedure:
2-Chloromethylbenzimidazole (1.67 g, 10 mmol) was suspended in methanol (34 mL), 28% sodium methoxide methanol solution (9.6 mL, 50 mmol) and water (50 mL) were added, and the mixture was stirred at room temperature for 20 min. The precipitated solid was collected by filtration, and purified by silica gel column chromatography (chloroform/methanol=100/0 to 93/7) to give the title compound (303 mg, 19%).
Reaction SMILES: [C:1]([C:3]1([N:15]2[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:8][CH2:7][N:6]([S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH2:5][CH2:4]1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:21][N:18]1[CH2:17][CH2:16][N:15]([C:3]2([CH2:1][NH2:2])[CH2:8][CH2:7][N:6]([S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH2:5][CH2:4]2)[CH2:20][CH2:19]1
Reactant: CCCS(=O)(=O)N1CCC(C#N)(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCS(=O)(=O)N1CCC(CN)(N2CCN(C)CC2)CC1

Procedure:
tert-Butyl 4-[4-cyano-1-(propylsulfonyl)piperidin-4-yl]piperazine-1-carboxylate was reacted with lithium aluminium hydride as in Scheme 5 to give {[4-(4-methylpiperazin-1-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}amine as a clear oil. m/z (M++H) 319.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C@@H:11]1[C@@H:16]([NH2:17])[CH2:15][C@@H:14]2[CH2:18][C@H:12]1[C:13]2([CH3:20])[CH3:19].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[CH3:10][C@@H:11]1[C@@H:16]([NH:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][C@@H:14]2[CH2:18][C@H:12]1[C:13]2([CH3:19])[CH3:20]
Reactant: N#Cc1ccccc1F
Reactant: C[C@H]1[C@H]2C[C@@H](C[C@@H]1N)C2(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@@H](Nc2ccccc2C#N)C[C@@H]2C[C@H]1C2(C)C
Temperature: 130 °C

Procedure:
2-Fluorobenzonitrile (100 mg), (1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (380 mg), triethylamine (1.5 mL) were dissolved in anhydrous dimethylsulfoxide (5 mL) and heated at 130° C. overnight. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column purification with 0-5% methanol/dichloromethane to afford the title compound.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([Cl:21])=[CH:15][C:16]=2[CH3:20])[NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([NH:7][C:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([Cl:21])=[CH:15][C:16]=2[CH3:20])[N:11]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)n1[nH]c2nc(Cl)cc(C)c2c1=O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)n1c(=O)c2c(C)cc(Cl)nc2n1Cc1ccccc1

Procedure:
In analogy to example 2, 50 mg (0.16 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydro-pyrazolo[3,4-b]pyridin-2-carboxylic acid hexylamide were reacted with 33 mg (0.19 mmol) of bromomethylbenzene in DMF with triethylamine. Yield: 20 mg (31%), M+H+: 401.16.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[NH2:20]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2cc(C)nc(-c3ccccn3)n2)cc1OC

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 3,4-dimethoxyaniline (61.2 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (108 mg, 84%). 1H NMR (CDCl3): 8.63 (d, J=4.2 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.65 (t, J=1.5 Hz, 1H), 7.18 (m, 2H), 6.7 (s, 1H), 6.71 (s, 2H), 6.28 (s, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:12]=1.C(Cl)(Cl)[Cl:32]>>[ClH:32].[ClH:32].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:26][CH2:27][N:28]([C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:29][CH2:30]2)[CH:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2nc(N3CCNCC3)cc(N)c2cc1OC
Reactant: ClC(Cl)Cl
Product: COc1cc2nc(N3CCN(C(=O)Nc4ccccc4)CC3)cc(N)c2cc1OC
Product: Cl
Reaction time: 4 h

Procedure:
Phenylisocyanate (1.1 g) was added to a stirred suspension of 4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (0.72 g) in chloroform (25 ml) at room temperature and the reaction mixture was stirred for 4 hours. The mixture was evaporated in vacuo, the residue taken up in methanol-chloroform and treated with ethereal hydrogen chloride. The crude product was purified by chromatography on silica gel eluting with methylene chloride followed by chloroform/methanol and then recrystallised from methanol/ether to give 4-amino-6,7-dimethoxy-2-[4-(N-phenylcarbamoyl)piperazin-1-yl]quinoline dihydrochloride (0.18 g), m.p. 235°.