Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl.[CH3:19]N(C=O)C.[SH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CCN(CC)CC>[S:24]1[C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]=2[CH:19]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: CCOC(=O)CS
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2

Procedure:
5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from tert-butyl-1-piperidinecarboxylate (9.9 g, 50 mmol), POCl3 (6.3 g, 40 mmol) and DMF (3.8 g, 50 mmol). The chloroformyl intermediate was reacted with ethyl mercaptoacetate (6.0 g, 50 mmol) and Et3N. The product was purified by SiO2 column chromatography by eluting it with 3:1 hexane; ethylacetate. Yield: 8.7 g, 56%; White liquid. (M+H) 312.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8](=O)[C@H:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH3:22].[C:23]([O-])(=O)[CH3:24].[NH4+].ClCC=O>>[C:16]([O:15][C:13]([NH:12][C@@H:9]([C:8]1[NH:22][CH:23]=[CH:24][C:7]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[CH2:10][CH3:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CC(=O)OC(C)(C)C
Reactant: N
Agent: O=CCCl
Agent: [NH4+]
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1[nH]ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
(R)-tert-butyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (505a, 7.41 g, 24.59 mmol) was treated with ammonia (2M in MeOH, 123 mL, 246 mmol) and ammonium acetate (14.21 g, 184 mmol) at RT. The resulting mixture was stirred for at 50° C. for 30 min, then treated with chloroacetaldehyde (50 wt % in water, 15.82 mL, 123 mmol) and stirred at 50° C. for 2 h. The reaction mixture was then stirred at RT overnight. The reaction mixture was concentrated to remove most of MeOH and partitioned between sat'd NaHCO3 (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organics were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a brown residue. It was purified on an ISCO Combiflash RF (160 g Thomson SingleStep column, 0-10% EtOAc in DCM) affording (R)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)propyl)-1H-pyrrole-3-carboxylate (505b, 4.58 g, 14.12 mmol, 57.4% yield) as a light yellow viscous oil. m/z (ESI, +ve) 347.1 (M+Na)+
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:12]5[CH:13]=[CH:14][N:15]=[CH:10][N:11]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](Nc1nccc(-n2cnc3cc(Nc4ccncn4)ccc32)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.6 %

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (14.0 mg) was dissolved in 2 mL MeOH, 10%Pd/C (20.3 mg) added, the system fitted with a balloon of hydrogen, purging the system twice and leaving the reaction stirring at room temperature for 23 h. The mixture was then filtered through Celite®, washing thoroughly with methanol, and the solvent removed in vacuo. The residue was purified on silica gel (2-5%(2M NH3 in MeOH)/CH2Cl2) to yield 5.5 mg of the title compound. Mass spectrum (ESI) 409.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O)=[O:14].[O:24]([CH2:31][CH2:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[CH3:42])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OC(=O)C)(=O)C.[OH-].[NH4+]>C1(C)C=CC=CC=1.C(O)(C)C>[O:24]([CH2:31][CH2:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:13]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[CH:7][C:2]=3[CH3:1])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[O:14]2)=[C:34]1[CH3:42])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: Cc1cc2ccccc2n1CCOc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CCOc4ccccc4)c4ccccc34)OC(=O)c3ccccc32)c(C)c1
Temperature: 70 °C
Yield: 93.2 %

Procedure:
A mixture of 14.0 g of 2-(2-methyl-4-diethylaminophenyl)carbonylbenzoic acid, 10.0 g of 1-(2-phenoxyethyl)-2-methylindole and 500.0 ml of acetic anhydride was maintained at approximately 70° C. for approximately four hours. The reaction solution was cooled to ambient temperature and 25.0 ml of isopropyl alcohol was added. The resulting solution was poured slowly into a mixture of 500.0 ml of toluene and 50.0 ml of 5 percent aqueous ammonium hydroxide. The toluene layer was separated, washed with water and then with saturated aqueous sodium chloride solution. The toluene layer was evaporated to dryness. The residue was recrystallized in 150.0 ml of isopropyl alcohol and dried to obtain 20.2 g of 3-[1-(2-phenoxyethyl)-2-methylindol-3-yl]-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula I: R=C6H5OC2H4 ; R1 =R2 =CH3 ; R3 =R4 =C2H5 ; X=Y=H), a white-colored solid which melted at 182°-183° C. Significant infrared maxima appeared at 1750 (C=O;s) and 1130 (C--O;s)cm-1. The nuclear magnetic resonance spectrum was in accord with the assigned structure. A toluene solution of the product spotted on an acidic clay or a phenolic resin coated paper developed a cyan-colored image.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](S)N2N=CC=C2N=1.CC(OC[C:17]1[CH2:26]S[C@@H]2[C@H](N)C(=O)N2[C:18]=1[C:27]([OH:29])=[O:28])=O.B(F)(F)F.[C:34](#N)C>>[CH3:34][C:18]([C:27]([OH:29])=[O:28])=[CH:17][CH2:26][CH2:1][CH2:2][CH2:7][CH3:6]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC#N
Reactant: Cc1cc(S)n2nccc2n1
Agent: FB(F)F
Product: CCCCCC=C(C)C(=O)O

Procedure:
1.1 g of 5-methylpyrazolo[1,5-a]pyrimidine-7-thiol and 1.80 g of (7R)-7-aminocephalosporanic acid were stirred for 1 hour in 18 ml of a 20 percent solution of boron trifluoride in acetonitrile. The reaction mixture was concentrated, the residue was taken up in 15 ml of water, and the pH was adjusted to 2.5 with 2N sodium hydroxide solution. The precipitated product was filtered off under suction and dried. There was obtained (6R,7R)-7-amino-3-[[(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[OH:28])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2O)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 30, 13.5 mg, 0.03 mmol) in ethanol (0.32 mL) cooled to 0° C. was treated with sodium borohydride (1.2 mg, 0.03 mmol). The reaction mixture was stirred at 0° C. for 20 min. At this time, the reaction was diluted with water (25 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate 3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-hydroxy-cyclopentyl)-N-pyrazin-2-yl-propionamide (10.1 mg, 75.5%) as a white foam: EIHRMS m/e calcd for C19H22ClN3O4S (M+Na)+ 446.0912. found 446.0916.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[N:29]([CH3:31])[CH3:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].C(=O)(O)[O-].[Na+].[C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)#[N:38]>C(OCC)(=O)C>[C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([NH:1][C:2]2[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=2[N:29]([CH3:31])[CH3:30])[C:5]([NH:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:19])[F:17])=[CH:10][C:9]=2[CH3:25])=[O:6])=[O:44])=[CH:41][CH:40]=1)#[N:38]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c(NC(=O)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
3-Amino-4-dimethylamino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (200 mg, 0.44 mmol) (see Example I9) was dissolved in a biphasic mixture of ethyl acetate (4 ml) and aqueous sodium bicarbonate (1N) (4 ml). 4-Cyano-benzoyl chloride (75 mg, 0.44 mmol) was added under vigorous stirring. The reaction mixture was stirred for 18 hours at ambient temperature. The phases were separated, the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography over silica gel (eluent:cyclohexane/ethyl acetate ratio 1:1) gave Compound No. A16 of Table A below (244 mg, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CS)cc1
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Na]
Product: Fc1ccc(C(/C=C\c2ccc(Cl)cc2)SC(/C=C\c2ccc(Cl)cc2)c2ccc(F)cc2)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-chlorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 82% yield following oxidation. 1HNMR (CDC13) δ4.60 (2H, s), 6.70 (1H, d, JH,H=11.78), 7.18-7.60 (8H aromatic+1H ethylenic).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:31][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCCC[C@H]1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 54 mg, 1.34 mmol) in DMF (1 mL) was added Intermediate A (88 mg, 0.54 mmol) and the reaction mixture was stirred for 20 min. A solution of Intermediate 120b (105 mg, 0.45 mmol) in DMF (1 mL) was added and the reaction mixture was heated at 60° C. for 90 min. After cooling, the reaction mixture was quenched by careful addition of MeOH and then loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (77 mg, 45%). 1H NMR (400 MHz, CDCl3): 1.38-1.51 (1H, m), 1.52-1.90 (6H, m), 1.90-2.05 (1H, m), 2.03 (3H, s), 2.04-2.15 (1H, m), 2.15-2.22 (1H, m), 2.33-2.44 (1H, m), 2.99-3.06 (1H, m), 3.82 (1H, dd, J=11.3, 3.2 Hz), 3.99 (1H, dd, J=7.9, 5.1 Hz), 5.23 (1H, t, J=4.5 Hz), 7.11 (1H, dd, J=9.9, 2.2 Hz), 7.23-7.30 (1H, m), 7.34-7.41 (2H, m), 7.60 (1H, d, J=7.7 Hz), 7.65 (1H, dd, J=9.9, 0.7 Hz), 8.42 (1H, d, J=2.2 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C@@H:23]([CH2:28][CH3:29])[CH2:24][C:25](O)=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:22][C@@H:23]([CH2:28][CH3:29])[CH2:24][C:25]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[CH:20][CH:19]=1)=[O:26]
Reactant: CC[C@H](C)CC(=O)O
Reactant: Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)CC(=O)Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
{circle around (1)}: A mixture comprising 2.8 g of 4-(4′-benzyloxyphenyl)phenol, 1.2 g of (S)-2-methylbutylcarboxylic acid, 3.09 g of DCC and 15 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, followed by distilling off dichloromethane from the filtrate. The resultant residue was purified by means of silica gel column chromatography, whereby 3.5 g of (S)-4-[4′-(2″-methylbutylcarbonyloxy)phenyl]-1-benzyloxybenzene was obtained in the form of a colorless crystal.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH2:19])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:11]=2.[OH-].[Na+]>CO.C(O)(C(F)(F)F)=O.O>[CH3:5][N:6]1[CH:18]2[CH:13]([CH2:14][C@H:15]([NH2:19])[CH2:16][CH2:17]2)[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:11]=2
Reactant: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C[C@H](N)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CN1c2ccc(S(=O)(=O)c3ccccc3)cc2C2C[C@H](N)CCC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
A freshly prepared solution of sodium cyanoborohydride (0.91 g, 14.48 mmol) in CH3OH (3.0 mL) was added dropwise to a 0° C. solution of (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (1.02 g, 2.99 mmol) in TFA (7.5 mL), then stirred at room temperature for 3 hours. The reaction was diluted with H2O (40 mL) cooled to 0° C. and made basic by the addition of 50% NaOH. The reaction mixture was extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo to give a colorless foam which was recrystallized from CH3OH/EtOAc to give 0.19 g (19%) of (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine as a colorless as a mixture of cis and trans isomers: mp 217.0-219.3° C.; MS m/z 343.2 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([N:8]([CH2:10][CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])=[O:7])=[C:4]([O:23]C)[CH:3]=1.B(Cl)(Cl)Cl.CO.N>ClCCl>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[O:7])=[C:4]([OH:23])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N(C)CCO[Si](C)(C)C(C)(C)C
Agent: ClB(Cl)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CN(CCO)C(=O)c1cc(Cl)c(N)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
4-Amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-2-methoxy-N-methylbenzamide (2.0 g, 5.3 mmol) was stirred in dichloromethane (100 mL) at −10° C. under an atmosphere of nitrogen and a 1M solution of boron trichloride in dichloromethane (10.68 mL, 10.7 mmol) was added dropwise. The reaction was allowed to warm to room temperature then left to stir at this temperature for 18 h. The reaction was cooled to −10° C. and a further 1 equivalent of boron trichloride solution was added dropwise, then the reaction was allowed to warm to room temperature and stirred for 3 h. After this time analysis by LCMS indicated that the reaction was complete. The reaction was cooled in a ice bath and methanol (20 mL) was added drop-wise to the reaction followed by 7N methanolic ammonia solution (17 mL) and then a further portion of MeOH (˜80 mL) until all the solids had dissolved. The solution was stirred for 1 h at room temperature then concentrated. The resulting residue was stirred with saturated aqueous NaHCO3 (150 mL) for 30 min then the aqueous phase was extracted with ethyl acetate. The combined extracts were washed with brine then passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford a green gum (1.00 g, 77%). This material was taken through to the next step with no further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C:11]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=[O:12].[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>O1CCOCC1.O>[CH3:38][C:37]1[CH:39]=[CH:40][C:34]([S:31]([NH:7][CH2:8][CH:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:10][C:11]([NH:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])(=[O:33])=[O:32])=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CC(CN)c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Potassium carbonate (0.325 g, 2.35 mmol) was added to a solution of 51 (0.128 g, 0.392 mmol) in 1,4-dioxane/H2O 1:1 (5 mL) and followed by tosyl chloride (0.074 g, 0.392 mmol) at room temperature. After stirring for 2 h at room temperature, the resulting mixture was evaporated in vacuo to dryness. Water (10 ml) was added and the resulting white solid was separated by filtration and dried in vacuo. Pure 55 was obtained as an off-white solid (0.122 g, 0.254 mmol, 65%) without further purification, mp 135-137° C. 1H NMR (400 MHz, CD3OD) 1.36 (3H, t, J 7.2 Hz), 2.39 (3H, s), 2.63 (1H, dd, J 8.6, 14.6 Hz), 2.85 (1H, dd, J 6.2, 15.0 Hz), 3.05 (1H, dd, J 7.4, 13.0 Hz), 3.12 (1H, dd, J 6.8, 11.8 Hz), 4.32 (2H, q, J 7.2 Hz), 7.17-7.19 (3H, m), 7.23-7.27 (2H, m), 7.31 (2H, d, J 8.0 Hz), 7.54 (2H, d, J 8.4 Hz), 7.65 (2H, d, J 8.4 Hz), 7.90 (2H, d, J 8.8 Hz). 13C NMR (100 MHz, CDCl3) 14.57, 21.73, 40.65, 42.04, 47.77, 61.07, 119.15, 127.14, 127.75, 127.77, 129.29, 130.07, 130.94, 136.79, 140.74, 142.12, 143.97, 166.36, 170.24. νmax (solid)/(cm−1) 3324, 3191, 1707, 1675, 1597, 1534, 1270, 1157, 1105. MS (API-ES): m/z 481 [M+H]+ (100%), HRMS (API-ES) m/z found 481.1801 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1.[CH3:33][C:34]([CH3:36])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:34]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[CH:9]=1)([CH3:36])[CH3:33]
Reactant: CC(C)=O
Reactant: CC(Nc1cc(-c2cc(N3CC4CC3CN4)c3ccccc3n2)ccn1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1cc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)nc2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 60 mg (0.14 mmol) {4-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-quinolin-2-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.15 mL (2mmol) acetone, 120 mg (2 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as a yellow solid. MS (ES+): 464 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CCO.O>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:4]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH3:2])[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: Cc1ccc(NN)c(C)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)c(C)c1
Yield: 36 %

Procedure:
To a heated solution of 2,4-dimethylphenylhydrazine hydrochloride (1.38 g, 8 mmol) in EtOH/water/1M NaOH (20 mL/12 mL/8 mL) at 50° C., 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8 mmol) was added and the reaction heated until finished by LC-MS. The solution was partitioned between EtOAc and water, and extracted twice. The extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated. Purification using silica gel chromatography eluting with an EtOAC/hexane gradient (5-20%) gave 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-amine (700 mg, 36% yield). 1H NMR (300 MHz, DMSO d6) δ 1.09 (s, 9H), 1.98 (s, 3H), 2.32 (s, 3H), 4.76 (s, 2H), 5.26 (s, 1H), 7.11 (m, 3H). LC-MS (ESI) m/z 244 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.[C:20](N1C=CN=C1)([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[S:21].Cl>C1COCC1>[N:22]1([C:20]([N:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:3]([O:2][CH3:1])[CH2:4]2)=[S:21])[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=S)n2ccnc2)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
Benzyl cis(±)-4-(3-methoxypiperidin-4-yl)-carbamate obtained by the method described in Example (40b) (735 mg, 1.37 mmol) was dissolved in THF (8 mL). 1,1′-Thiocarbonyldiimidazole (270 mg, 1.36 mmol) was added, and the mixture was stirred for 1.5 hours. 0.5 M hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.