Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:12][C:11]=2[CH3:27])[CH:7]=[CH:8][CH:9]=1)=[O:3].[SiH](CC)(CC)CC.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[C:11]([CH3:27])[CH:12]=1
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)ccc1-c1cccc(C(N)=O)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCN)ccc1-c1cccc(C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl (2-{[3′-(aminocarbonyl)-2-methyl-4-biphenylyl]oxy}ethyl)carbamate (0.090 g; 0.24 mmol; I-VII-2) and Et3SiH (0.1 mL; 0.6 mmol) in CH2Cl2 (5 mL) at room temperature was added TFA (1 mL) in one portion. The mixture was aged 2 h and concentrated in vacuo, affording the title compound as a pale yellow gum which was used without further purification. LC/MS (method A) 1.18 min, m/z 271 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][NH2:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:18]([C:21]1[C:22]([O:34][CH2:35][O:36][CH3:37])=[CH:23][C:24]([O:30][CH2:31][O:32][CH3:33])=[C:25]([CH:29]=1)[C:26](O)=[O:27])([CH3:20])[CH3:19].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C.CN1CCCC1=O>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:17])[NH:15][NH:16][C:26](=[O:27])[C:25]3[CH:29]=[C:21]([CH:18]([CH3:20])[CH3:19])[C:22]([O:34][CH2:35][O:36][CH3:37])=[CH:23][C:24]=3[O:30][CH2:31][O:32][CH3:33])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Reactant: NNC(=O)Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NNC(=O)Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of 4-[4-(morpholin-4-yl)-phenyl]semicarbazide (IM9-O-01:70.9 mg, 0.3 mmol) and 5-isopropyl-2,4-bis(methoxymethoxy)-benzoic acid (IM3-a:85.3 mg, 0.3 mmol) in dimethylformamide (4 mL), were added N-methylpyrrolidone (0.2 mL), 1-hydroxybenzotriazole monohydrate (60.8 mg, 0.45 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (115.0 mg, 0.6 mmol) successively, and the mixture was stirred at room temperature overnight. The reaction mixture was mixed with ethyl acetate (30 mL) and 5% aqueous sodium hydrogencarbonate (20 mL). The aqueous layer was separated, and extracted with ethyl acetate. The combined organic layers thus obtained were dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol=30:1-20:1) to obtain the title compound (IM5-O-a01: colorless syrup, 104.9 mg, 70%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.Cl.CO.[N+:14]([O-])([O-])=O.[NH4+].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[NH2:14][CH:7]1[CH2:8][CH2:9][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6]1
Reactant: O=C1CCN(C2CC2)CC1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [BH3-]C#N
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: NC1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an ice cold solution of 2.8 g. of 1-cyclopropyl-4-piperidone in 300 ml. of absolute methanol is added 0.02 moles of a solution of hydrogen chloride-methanol, 27 g. of ammonium nitrate and 2.4 g. of sodium cyanoborohydride. The solution is stirred for 72 hours at 25° C. and then poured into dilute acetic acid. The acidic solution is washed with ether and then made basic by the addition of ammonium hydroxide. The basic solution is extracted with methylene chloride, and the organic extract dried. Concentration of the extract in vacuo gives 4-amino-1-cyclopropylpiperidine.
Reaction SMILES: [CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]#[C:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cu]I.O>[CH:1]([N:14]1[C:15]2[C:16](=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:22]=[C:23]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)(=[O:29])=[O:28])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)NCCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Product: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)NCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 76.1 %

Procedure:
A mixture of N-{4-[2-(benzhydrylamino)-5-chlorophenyl]but-3-ynyl}-1-(3,4-dichlorophenyl)-methanesulfonamide (1.0 g, 1.71 mmol) and copper (I) iodide (0.30 g, 1.58 mmol) was heated to 120° C. and stirred for 7 h, and then cooled to room temperature. Water (50 mL) was added. The mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4. The solvent was evaporated. The residue was purified by column chromatography, using a mixture of heptane and EtOAc (2:1) as elute to give a white solid (0.76 g, 76%). 1H NMR (CDCl3): δ6.7-7.6 (m, Ph. CHPh2), 6.58 (d, 1H, J=8.9 Hz), 4.20 (m, 1H), 3.99 (s, 2H), 3.10 (dd, 2H, J=6.9, 13.3 Hz), 2.94 (t, 2H, J=6.7 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].O[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(O)C>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]1[CH2:12][C:13](=[O:14])[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:7]1)#[N:2]
Reactant: O=C(CO)c1ccccc1
Reactant: N#Cc1cccc(C=O)c1
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(C2CC(=O)c3ccccc3O2)c1
Yield: 10.6 %

Procedure:
A mixture of 3-cyanobenzaldehyde (25 g, 0.19 mol), 2-hydroxyacetophenone (25.9 g. 0.19 mol), 38.1 g (0.1 mol) of borax, 250 ml of ethanol, and 250 ml of H2O was refluxed for four days. When cool the reaction mixture was diluted with H2O and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous Na2SO4, filtered, and evaporated to give a dark, tarry residue. The residue was chromatographed on 1 kg of silica gel, eluting with benzene. From this was isolated 5 g of 3'-cyano flavanone as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C3C=CC(Cl)=CC=3)[C@@H:10]([O:11]C(=O)C3C=CC(Cl)=CC=3)[CH2:9]2)[C:4](=[O:34])[N:3]=1.NC1N=CN([C@H]2O[C@H](COC(=O)C3C=CC(Cl)=CC=3)[C@@H](OC(=O)C3C=CC(Cl)=CC=3)C2)C(=O)N=1.C[O-].[Na+]>CO>[CH2:9]1[C@H:8]([N:5]2[C:4](=[O:34])[N:3]=[C:2]([NH2:1])[N:7]=[CH:6]2)[O:22][C@H:21]([CH2:23][OH:24])[C@H:10]1[OH:11]
Reactant: Nc1ncn([C@H]2C[C@H](OC(=O)c3ccc(Cl)cc3)[C@@H](COC(=O)c3ccc(Cl)cc3)O2)c(=O)n1
Agent: C[O-]
Agent: Nc1ncn([C@@H]2C[C@H](OC(=O)c3ccc(Cl)cc3)[C@@H](COC(=O)c3ccc(Cl)cc3)O2)c(=O)n1
Agent: [Na+]
Solvent: CO
Product: Nc1ncn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reaction time: 5 h
Yield: 67 %

Procedure:
A mixture of 4-amino-1-[3,5-di-O-(4-chloro-benzoyl)-2-deoxy-β-D-ribofuranosyl]-1H-[1,3,5]triazin-2-one in about 50% HPLC purity and 4-amino-1-[3,5-di-O-(4-chloro-benzoyl)-2-deoxy-α-D-ribofuranosyl]-1H-[1,3,5]triazin-2-one (6.15 Kg, 12.17 mol) and methanol (21.4 Kg) were charged into a suitable reactor at about 25° C. 30% Sodium methoxide in methanol solution (0.61 Kg) was added to the mixture solution and then stirred for 5 hours. The solids were filtered, washed with methanol (3.3 Kg) and dried at 50° C. for 14 hours to obtain 0.927 Kg (4.11 mol) crude decitabine in 97.1% HPLC purity (about 67% yield based on 4-amino-1-[3,5-di-O-(4-chloro-benzoyl)-2-deoxy-β-D-ribofuranosyl]-1H-[1,3,5]triazin-2-one (compound Ib)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[F:13][C:14]([F:50])([F:49])[C:15]1[CH:16]=[C:17]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:18][N:19]([C:36]1[N:37]=[N:38][N:39]([CH3:41])[N:40]=1)[C@H:20]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]2[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:31])=[CH:30][C:21]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:23]2[CH2:24][CH2:25][CH2:26][C@H:20]([N:19]([CH2:18][C:17]3[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=[C:15]([C:14]([F:13])([F:50])[F:49])[CH:16]=3)[C:36]3[N:37]=[N:38][N:39]([CH3:41])[N:40]=3)[C:21]3[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([F:34])([F:33])[F:35])=[CH:27][C:22]2=3)=[CH:6][CH:5]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)cc1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
Add 4-formylbenzoic acid methyl ester (133 mg, 0.815 mmol) to a solution of (S)-(3,5-bis-trifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (Example 3, Step 18) (150 mg, 0.272 mmol) in acetic acid (1 mL) and 1,2-dichloroethane (10 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxy borohydride (231 mg, 1.08 mmol) and stir for 3 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brined (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a white solid (100 mg, 52%): mp 71-74° C. dec; 1H NMR (CDCl3, 300 MHz) δ 1.61-1.65 (m, 2H), 2.02-2.22 (m, 2H), 2.29 (s, 3H), 2.71-2.80 (m, 1H), 3.02-3.11 (m, 1H), 3.89 (s, 3H), 4.18 (s, 3H), 4.22-4.40 (m, 2H), 4.89-5.10 (m, 2H), 5.55-5.60 (m, 1H), 6.90 (s, 1H), 7.21 (s, 1 H), 7.45-7.49 (m, 2H), 7.65-7.70 (m, 2H), 7.75-7.80 (m, 1H), 7.97-7.81 (m, 2H); ESI MS m/z 701 [C32H29F9N6O2+H]+; HPLC 98.3%, tR 19.6 min.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1
Reactant: COCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 82 %

Procedure:
Chloromethyl methyl ether (34.2 ml) was added to a mixture of 4-hydroxybenzaldehyde (50.0 g), potassium carbonate (84.9 g) and N,N-dimethylformaldehyde (150 ml) at 0° C. and stirred at room temperature for 11 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (300 ml) and methanol (50 ml) and sodium borohydride (7.76 g) was added in portions at 0° C. After stirring for 30 minutes, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain 4-methoxymethoxybenzylalcohol (56.7 g, yield 82%) as a colorless oil from an ethyl acetate-hexane (2:3, v/v) eluted fraction.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9]2[N:10]([C@H:21]3[C:24](=[O:25])[NH:23][C@H:22]3[C:26](OC)=O)[C:11](=[O:20])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.OCC1CCN1.CC1C=CC(S(O)(=O)=O)=CC=1.[N-:47]=[N+:48]=[N-:49].[Na+]>>[N:47]([CH2:26][C@H:22]1[C@@H:21]([N:10]2[C:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:11]2=[O:20])[C:24](=[O:25])[NH:23]1)=[N+:48]=[N-:49]
Reactant: COC(=O)[C@@H]1NC(=O)[C@@H]1n1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCC1CCN1
Agent: [BH4-]
Product: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1n1c(-c2ccccc2)c(-c2ccccc2)oc1=O

Procedure:
Sodium borohydride reduction of methyl cis-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine-2-carboxylate as described in Preparation 3, followed by conversion of the 2-hydroxymethylazetidine product to the p-toluenesulfonate derivative and reaction of this derivative with sodium azide as described in Preparation 4 gives the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14].O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[Br:7][C:5]1[N:6]=[C:2]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[S:3][CH:4]=1
Reactant: O=C1CCCCN1
Reactant: Brc1csc(Br)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCCCN1c1nc(Br)cs1
Temperature: 120 °C
Yield: 55.8 %

Procedure:
2,4-dibromothiazole (2.0 g, 8.23 mmol) and piperidine-2-one (0.816 g. 8.23 mmol) were added to seal tube containing 1,4 dioxane (15 ml). Cesium carbonate (4.02 g, 12.35 mmol) and xantphos (027 g, 0.412 mmol) were added, the nitrogen gas was bubbled through reaction mixture for 15 minutes and tris(dibenzylideneacetone)dipalladium(0) (0.151 g, 0.165 mmol) was added under nitrogen and the tube was sealed. The reaction mixture was heated at 120° C. for 3 hr under stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and diluted with water (50 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extract was dried over sodium sulfate filtered and concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 15% ethyl acetate in hexanes as an eluent to obtain the title compound (1.2 g, 55.8%). MS: m/z 262 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[C:21]([CH2:20][Cl:19])=[N:1]2
Reactant: Cc1ccccc1NC(=O)c1c(N)cccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Yield: 37 %

Procedure:
Prepared according to Procedure B with 1j (750 mg, 2.88 mmol) and chloroacetyl chloride (0.69 mL, 8.63 mmol) in acetic acid (15 mL). Purified by chromatography in CH2Cl2, followed by recrystallization from isopropanol to afford 340 mg of a white solid (37%). 1H NMR (CDCl3) δ: 7.69 (d, J=2.1 Hz, 1H); 7.68 (q, J=7.4 Hz, 1H); 7.54 (dd, J=2.2, 7.0 Hz, 1H); 7.35-7.47 (m, 3H); 7.21-7.25 (m, 1H); 4.27 (d, J=12 Hz, 1H); 4.11 (d, J=12 Hz, 1H); 2.18 (s, 3H). MS (ES): m/z 319.0 (M+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3/[C:24](=[CH:32]/[C:33]3[NH:34][CH:35]=[CH:36][CH:37]=3)/[C:25](=[O:31])[NH:26]4)[CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[NH2:7][CH:8]1[CH2:9][CH2:10][CH:11]([C:14]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3/[C:24](=[CH:32]/[C:33]3[NH:34][CH:35]=[CH:36][CH:37]=3)/[C:25](=[O:31])[NH:26]4)[CH:17]=2)=[O:38])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cccc(-c3cccc4c3/C(=C/c3ccc[nH]3)C(=O)N4)c2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(C(=O)Nc2cccc(-c3cccc4c3/C(=C/c3ccc[nH]3)C(=O)N4)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
A solution of the (Z)-[4-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenylcarbamoyl]-cyclohexyl]-carbamic acid tert-butyl ester (51.4 mg, 0.098 mmol) in 3 mL of methylene chloride was then treated with 2 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 h, and the reaction mixture was diluted with 50 mL of ethyl acetate. The organic phase was carefully washed with a saturated aqueous sodium bicarbonate solution (3×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow-brown solid. This crude solid was washed with 70% chloroform-hexanes, and the insoluble solid was collected by suction filtration to provide pure (Z)-4-amino-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]phenyl]cyclohexanecarboxamide (yield: 17 mg, 40%) as a yellow solid (mp 210-212° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.3 %

Procedure:
A mixture of 4-(4-hydroxy-phenyl)-piperazin-1-carboxylic acid tert-butyl ester (278 mg, 1 mmol), bromomethyl-benzene (171 mg, 1 mmol) and K2CO3 (138 mg, 1 mmol) in DMF (3 mL) was stirred at rt for 24 h and then at 50° C. for 6 h, followed by addition of water (150 mL). The resulting solid was collected by filtration and washed with water to yield the desired compound (340 mg, 92%) as a white solid: MS (ESI) m/z 369 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 3.01 (t, J=4.8 Hz, 4H), 3.57 (t, J=4.8 Hz, 4H), 5.02 (s, 2H), 6.87-6.93 (m, 4H), 7.33-7.44 (m, 5H).
Reaction SMILES: CN(C=O)C.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[Cl:23].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(Cl)Cl>O>[O:27]1[CH2:28][CH2:29][N:24]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]3[Cl:23])[CH2:25][CH2:26]1
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 85 %

Procedure:
DMF (3 lt), 6-(3-chloropropoxy)-7-methoxy-4-chloro quinazoline (200 gm) and morpholine (210 gm), were heated to 70-75° C. for 6-8 hours. The reaction mass was cooled to room temperature, and methylene chloride (2.5 lt) and water (2.5 lt) were charged. The layers separated and the aqueous layer extracted with methylene chloride twice (500 ml). The combined methylene chloride layer was washed with water, dried over sodium sulphate (10 gm) and concentrated completely at 35-40° C. to yield the title compound (200 gm, 85% yield).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12](O)=[O:13])=[O:6])#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CO>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][OH:13])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Product: N#CCNC(=O)[C@@H]1CCC[C@H]1CO
Temperature: -78 °C
Reaction time: 2 h

Procedure:
trans-2-{[(Cyanomethyl)amino]carbonyl}cyclopentanecarboxylic acid (860 mg, 4.38 mmol) was placed in a 50 mL round bottom flask. The flask was fitted with a rubber septum and then flushed with nitrogen. Tetrahydrofuran (9 mL) was added and the reaction mixture was cooled to −78° C. 4-Methylmorpholine (0.53 mL, 4.8 mmol) was added, followed by addition of isobutyl chloroformate (0.61 mL, 4.7 mmol). The reaction mixture was warmed to ambient temperature over 1.5 h and then recooled to −78° C. Sodium borohydride (0.28 g, 7.4 mmol) was added and then methanol (3.0 mL). The reaction mixture was stirred at −78° C. for 2 h and then quenched with saturated aqueous ammonium chloride (10 mL). The reaction mixture was warmed to ambient temperature and then poured into 100 mL saturated aqueous sodium chloride solution. The product was extracted into ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. Toluene (5 mL) was added to the residue and the reaction mixture was stirred for 30 min. The solution was removed by decantation and the residue was dried under high vacuum to give trans-N-(cyanomethyl)-2-(hydroxymethyl)-cyclopentanecarboxamide as a colorless solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=O)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CCOCC.O>[OH:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[CH2:8][N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCN(CCCC)C(=O)c1cccc(OC(C)=O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCCN(CCCC)Cc1cccc(O)c1

Procedure:
A mixture of 33.0 g (0.133 m) of 3-acetoxy-N,N-dibutylbenzamide in 400 ml of ether was slowly added over one half hour to a suspension of 5.0 (0.133 m) grams of lithium aluminum hydride (LAH) in 300 ml of ether. The mixture was heated to reflux for 2 hours. The mixture was slowly treated with 5.0 ml of water, 5.0 ml of 15% sodium hydroxide and 15.0 ml of water. Magnesium sulfate was added and stirred well. The mixture was filtered and washed well with ether. The solvent was evaporated off leaving the 3-hydroxy N,N-dibutylbenzylamine product in a yield of 23.3 g. The product was a yellow oil with a refractive index of n(25/D)=1.5172.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:25])[C:18]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([C:18]4[C:17]([Cl:25])=[CH:16][N:15]=[CH:14][C:13]=4[Cl:12])[CH2:20][CH2:21]3)[NH:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2[nH]c(Cl)nc2c1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Product: Clc1ccc2nc(N3CCN(c4c(Cl)cncc4Cl)CC3)[nH]c2c1

Procedure:
The 2,5-dichloro-1H-benzoimidazole (0.37 g, 1.98 mmol, Example 20b) and 1-(3,5-dichloropyridin-4-yl)piperazine (0.46 g, 1.98 mmol, Maybridge) reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 258-260° C. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[C:19]1([CH2:29][CH2:30][NH2:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:29][CH2:30][NH:31][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: NCCc1cccc2ccccc12
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccc4ccccc34)cc2)cn1
Yield: 26.7 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366 g, 0.151 mmol) and 2-naphthalen-1-ylethylamine (0.0285 g, 0.166 mmol) gives the title compound (0.0160 g, 26.7%): TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C25H24N3O2 398.1869 (M+H)+, found 398.1855, time 0.39 min; TLC [silica gel 60 F254, 4% (2.0 M NH3 in methanol) in ethyl acetate] Rf=0.26.