Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].N1C=CC=CC=1.[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:33])[N:29]2[CH3:32])=[CH:24][CH:23]=1>O>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:33])[N:29]2[CH3:32])=[CH:24][CH:23]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: CN1C(=O)CCc2ccc(N)cc21
Solvent: O
Solvent: c1ccncc1
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3F)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Fluoro-4-(trifluoromethyl)benzoyl chloride was added to a pyridine solution of 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one, followed by stirring at room temperature for 12 hours. Water was added to the reaction liquid, followed by stirring for 30 minutes and then the precipitated crystals were collected by filtration to obtain 2-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[ClH:5].[CH3:6][N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][Cl:11]>C(O)C>[ClH:11].[ClH:5].[CH3:6][N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][S:3][C:2](=[NH:4])[NH2:1]
Reactant: NC(N)=S
Reactant: CN(C)CCCCl
Agent: Cl
Solvent: CCO
Product: CN(C)CCCSC(=N)N

Procedure:
Equimolar quantities of thiourea and 3-(dimethylamino)-1-chloropropane hydrochloride and a little ethanol are heated together at 140° for 3 hours, and the cooled mixture is recrystallised from methanol/isopropanol to give the title product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 2-hydroxy-4-iodobenzoate (22.8 g), benzyl bromide (10.3 ml) and K2CO3 (22.67 g) in DMF (200 ml) was stirred at rt for 72 h. The mixture was partitioned between diethyl ether and water, the organics separated washed with water, dried and evaporated under reduced pressure to give a white solid, 29.5 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.[CH3:47][S:48][C:49]1[C:57]2[C:52](=[CH:53][C:54]([NH2:58])=[CH:55][CH:56]=2)[N:51]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:50]=1>ClCCl>[CH3:47][S:48][C:49]1[C:57]2[C:52](=[CH:53][C:54]([NH:58][C:15](=[O:17])[CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:55][CH:56]=2)[N:51]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:50]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N)ccc12
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)CC3CCCCN3C(=O)OC(C)(C)C)ccc12
Temperature: 15 °C
Reaction time: 0.17 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(1-(tert-butoxycarbonyl)piperidin-2-yl)acetic acid (0.47 mg), 1H-benzo[d][1,2,3]triazol-1-ol (300 mg, 1.96 mmol), EDC.HCl (370 mg, 1.94 mmol), 4-methylmorpholine (590 mg, 5.84 mmol, 2.98 equiv) in dichloromethane (3 mL). The resulting solution was stirred for 10 min at 15° C. A solution of 3-(methylthio)-1-phenyl-1H-indazol-6-amine (500 mg, 1.96 mmol, 1.00 equiv) in dichloromethane (3 mL) was added. The resulting solution was stirred for an additional 2 h at 15° C. The resulting mixture was washed with aq. sodium bicarbonate (1×8 mL) and brine (2×8 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10˜1:3) to yield tert-butyl 2-(2-(3-(methylthio)-1-phenyl-1H-indazol-6-ylamino)-2-oxoethyl)piperidine-1-carboxylate as a white solid. MS: 481 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:49][C@@H:50]2[CH2:54][O:53][C:52](=[O:55])[NH:51]2)(=O)=O)=CC=1>C(#N)C.O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:49][C@H:50]4[CH2:54][O:53][C:52](=[O:55])[NH:51]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2COC(=O)N2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
A solution of N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.5 g) in acetonitrile (10 mL) was treated with potassium carbonate (0.495 g) and (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (0.324 g) under nitrogen. The resulting mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water, and extracted with DCM. The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle compound as a solid (0.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:34]#[N:35])([CH2:20][C:21]([O:23][CH:24]1[CH:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:27][CH:26]([CH3:33])[CH2:25]1)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:38].C(=O)([O-])[O-].[K+].[K+].OO>O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:34](=[O:38])[NH2:35])([CH2:20][C:21]([O:23][CH:24]1[CH:29]([CH:30]([CH3:31])[CH3:32])[CH2:28][CH2:27][CH:26]([CH3:33])[CH2:25]1)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC1CCC(C(C)C)C(OC(=O)CC(C#N)(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)CC(NC(=O)OCc2ccccc2)(C(N)=O)C(=O)OC(C)(C)C)C1
Reaction time: 6 h
Yield: 45.8 %

Procedure:
t-Butyl 2-benzyloxycarbonylamino-2-cyano-3-[(−)-menthyloxycarbonyl]propionate (2.00 g, 4.11 mmol) and acetone (10 ml) were mixed and an aqueous solution of potassium carbonate (566 mg, 5.34 mmol) in water (5.0 ml) was added thereto. Further, 30% aqueous hydrogen peroxide solution (1.6 ml) was added dropwise and the mixture was stirred for about 6 hours. When completion of the reaction was confirmed, water was added and the precipitated crystals were filtered, washed with sprayed water and hexane to give t-butyl 2-benzyloxycarbonylamino-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (950 mg, yield 45.8%) as a pale yellow crystal. Optical purity of (2R)-derivative was 7.4% d.e.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)C(C)C)(C)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:19])[CH3:18]
Reactant: O=C1CNCCN1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCNC(=O)C1
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of piperazin-2-one (2.50 g, 24.9 mmol) and N,N-diisopropylethylamine (4.78 mL, 27.5 mmol) in methylene chloride (50 mL) under an atmosphere of nitrogen, acetic anhydride (2.47 mL, 26.2 mmol) was added and stirred at the temperature for overnight. The resultant solution was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 90:10:1 mixture of chloroform, methanol, and ammonium hydroxide. Collection and concentration of appropriate fractions provided the title product.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1>[Pt].CC(=O)CC>[CH3:9][CH:1]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][CH:5]([CH2:6][CH3:7])[CH3:4])=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH2:2][CH3:3]
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: [Pt]
Solvent: CCC(C)=O
Product: CCC(C)Nc1ccc(Cc2ccc(NC(C)CC)cc2)cc1
Temperature: 120 °C
Yield: 96 %

Procedure:
4,4′-Methylenebis(benzeneamine) (MDA; 1.20 g), Pt(S)/C (1.20 g), and 2-butanone (methyl ethyl ketone, MEK; 50.0 g) were charged to an autoclave. The autoclave was degassed three times with H2 at 22° C. and the mixture was heated to 120° C. under 14 psig (1.98×105 Pa) H2 without stirring. At 120° C., with stirring, the autoclave was pressurized to 85 psig (6.87×105 Pa) with H2 over a period of twelve minutes. The reaction mixture was then cooled to 22° C. GC analysis showed 100% conversion of MDA, and a 96% yield of N,N′-di(2-butyl)-4,4′-methylenebis(benzeneamine).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C:14]1[C:15]2[C:22]([C:23]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([NH2:31])[CH:30]=3)=[O:24])=[CH:21][N:20]([CH:32]([CH3:34])[CH3:33])[C:16]=2[N:17]=[CH:18][N:19]=1>N1C=CC=CC=1>[NH2:13][C:14]1[C:15]2[C:22]([C:23]([C:25]3[CH:30]=[C:29]([NH:31][S:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)(=[O:11])=[O:10])[CH:28]=[N:27][CH:26]=3)=[O:24])=[CH:21][N:20]([CH:32]([CH3:34])[CH3:33])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2c(N)ncnc21
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cncc(NS(=O)(=O)c3cc(F)cc(F)c3)c2)c2c(N)ncnc21
Temperature: 40 °C

Procedure:
3,5-Difluoro-benzenesulfonyl chloride (19.7 mg, 0.093 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (25 mg, 0.084 mmol) in pyridine (0.7 mL). The resulting solution was heated to 40° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue dissolved in DMSO (2 mL) and purified using reverse phase preparative HPLC to furnish the title compound as a white solid. MS: 473.2 (MH+); HPLC Rf: 4.91 min. (HPLC method 4).
Reaction SMILES: [CH:1]1([N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)=[O:20].C(NC(C)C)(C)C>CN(C)C=O>[F:37][C:35]([F:36])([F:38])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:19]([N:15]3[CH2:16][CH2:17][CH:12]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH2:5][C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:13][CH2:14]3)=[O:20])=[CH:23][CH:24]=2)=[N:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: c1cncc(CN(C2CCNCC2)C2CC2)c1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2cccnc2)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-piperidin-4-yl-pyridin-3-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (26%, light brown solid). HPLC-MS m/z=(M+1) 513.3, Rt: 2.64 min.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cc(F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 2,5-difluorophenol (6.50 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.60 mg, 29.3% yield) as a thick oil: 1H NMR δ 7.46 (s, 1H), 7.40–7.32 (m, 4H), 7.31–7.20 (m, 2H) 7.17 (s, 1H), 7.01–6.92 (m, 2H), 6.65–6.42 (m, 2H), 5.27 (m, 1H), 3.13 (m, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.28–1.80 (m, 8H), 1.25 (d, 6H, J=7.1 Hz); ESMS t/e: 493.4 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:19][N:20]([CH2:28][C:29]([F:31])([F:30])[F:32])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][N:26]=1
Reactant: CN(CC(F)(F)F)c1ncc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CN(CC(F)(F)F)c1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyrimidin-5-yl}-amide was prepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-Methyl-N-(2,2,2-trifluoro-ethyl)-pyrimidine-2,5-diamine. LCMS calcd for C18H13F6N5O2 (m/e) 445, obsd 446 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11][C:12]1[C:13]([Li])=[CH:14][O:15][CH:16]=1>>[Br:11][C:12]1[C:13]([C:1]([C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]=2[CH3:10])([OH:3])[CH3:2])=[CH:14][O:15][CH:16]=1
Reactant: CC(=O)c1oc(C)nc1C
Reactant: [Li]c1cocc1Br
Product: Cc1nc(C)c(C(C)(O)c2cocc2Br)o1

Procedure:
Following the general method of Example 1a but using 5-acetyl-2,4-dimethyloxazole and 4-bromo-3-lithiofuran (Liebigs Ann. Chem., 1986, 625-637), the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]2([N+:17]([O-])=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[OH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1>CO.Cl.[Zn]>[NH2:17][C:11]1([CH:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[OH:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])C1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: NC1(C(O)c2cc(Cl)cc(Cl)c2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of (3,5-dichloro-phenyl)-(1-nitro-cyclohexyl)-methanol (5.87 g, 19.3 mmol) in methanol (40 mL) and concentrated HCl (10 mL), cooled to ˜5° C., was added zinc powder. The mixture was stirred at room temperature overnight and filtered through Celite. The filter cake was washed with methanol (2×100 mL) and the filtrate was evaporated to dryness. The residue was treated with 5% aqueous NaOH (100 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over Na2SO4 and evaporated to leave (1-amino-cyclohexyl)-(3,5-dichloro-phenyl)-methanol (4.36 g) as a white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.25 (s, 1H), 7.185 (s, 2H), 4.21 (s, 1H), 1.55 (m, 4H), 1.3 (m, 3H), 1.1 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[BH3-]C#N.[Na+]>CO>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=Cc1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccccc1NCc1ccncc1
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-aminobenzoate (4 g) and 4-pyridylformaldehyde (1.2 eq) and NaBH3CN (2 eq) in methanol stirred overnight. The solvent was evaporated, and EtOAc (100 ml) and H2O (100 ml) were added. The solution was extracted three times with EtOAc and washed with H2O followed by brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give ethyl 2-[(4-pyridylmethyl)-amino]benzoate. The above compound (400 mg) was stirred with acetyl chloride (1.2 eq) and DIEA (1.2 eq) in dichloromethane at RT for two hours. The solution was washed with H2O followed by brine, dried over Na2SO4 and evaporated to give ethyl 2-[N-(4-pyridyl-methyl)acetylamino]benzoate for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:22][CH:21]=3)\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and acetylchloride
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:10][CH2:9]1
Reactant: ClCCN1CCCCC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(CCN4CCCCC4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A mixture of (S)-N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.200 g, 0.595 mmol), 1-(2-chloroethyl)piperidine monohydrochloride (0.131 g, 0.714 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in acetonitrile (12 mL) was heated to reflux for 1.0 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with dichloromethane, the solids filtered off, and the filtrate concentrated in vacuo to give the crude product (0.308 g). This crude material was chromatographed over silica gel (5 g), eluting with 5% and then 10% methanol/chloroform, to afford, after concentration of appropriate fractions, 0.192 g (72%) of the title compound as an off-white solid with mp 169°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30](F)[C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:29].[CH3:35][S:36](C)=O>O>[F:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([S:36][CH3:35])[C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:29]
Reactant: CS(C)=O
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(=O)n(Cc5c(F)cccc5F)c4n3)cc2)CC1
Solvent: O
Product: CSc1cccc(F)c1Cn1c(=O)ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 90 %

Procedure:
8-(2,6-difluorobenzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (23 mg, 0.05 mmol, Example 61) was treated with NaSMe (5 mg, 0.06 mmol) in DMSO (0.2 mL) at 100° C. for 2 h. The reaction mixture was diluted with water, the precipitated product was filtered off, then purified by silica gel column chromatography using dichloromethane:methanol (95:5) to give 8-(2-fluoro-6-(methylthio)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (22 mg, Y=90%). ESMS m/z 491 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>ClCCl>[S:15]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=4)=[CH:19][CH:18]=3)=[O:7])[C:9]=2[CH:17]=[CH:16]1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sccc32)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of 0.30 g of 4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 0.208 ml of triethylamine in 10 ml of dichloromethane is added, under argon, 0.251 g of 3,4-dichlorobenzoyl chloride. The mixture is stirred overnight and concentrated to dryness under vacuum. The residue is dissolved in ethyl acetate and the solution washed with H2O, 2N citric acid, NaHCO3 solution, brine and dried (Na2SO4). The solvent is removed and the residual yellow solid crystallized from ethyl acetate-hexane to give 0.254 g of crystals, m.p. 154°-160° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([C:26]#[C:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=[CH:30][N:29]=1)(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]#[CH:26])=[N:29][CH:30]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 2 h

Procedure:
43.66 g (156.0 mmol) of TBAF was added to a solution of 46.50 g (142.0 mmol) of 2-[(tert-butyldimethylsilanyl)ethynyl]-5-(4-chlorophenyl)pyridine in 1 L of DCM at RT and the mixture was stirred for 2 hours. The organic phase was washed with water, dried over sodium sulfate, and evaporated down in vacuo. The residue was stirred with DIPE, and the precipitate was filtered off and washed with PE. Yield: 26.0 g (86% of theoretical); C13H8ClN (M=213.662); calc.: molpeak (M+H)+: 214/216 (Cl); found: molpeak (M+H)+: 214/216 (Cl); Rf value: 0.30 (silica gel, cyc/EtOAc 4:1).