Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([CH2:35][NH:36]C(=O)C)[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:17]([NH:28][CH2:29][CH3:30])=[N:18][C:19]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)(=O)C.CC(N(C(C)C)CC1C=CC=CC=1)C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH3:72][S:73](Cl)(=[O:75])=[O:74]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:72][S:73]([O:4][C:5]1[N:6]=[C:7]([CH2:35][NH:36][S:73]([CH3:72])(=[O:75])=[O:74])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:17]([NH:28][CH2:29][CH3:30])=[N:18][C:19]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)(=[O:75])=[O:74]
Reactant: CCNc1nc2ccc(OC)cc2cc1Cc1c(OC(C)=O)nc(CNC(C)=O)c2cc(OC)c(OC)cc12
Reactant: CS(=O)(=O)Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)N(Cc1ccccc1)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(OS(C)(=O)=O)nc(CNS(C)(=O)=O)c2cc(OC)c(OC)cc12
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
The other portion of the residue CCH 42006-2 (see preparation of compound 56) was transferred in a 5 mL microwave vial equipped with a magnetic stirrer before addition of diisopropylaminomethyl-polystyrene resin (3 mmol/g, 86 mg, 258 μmol), DMAP (2 mg, 16 μmol) and methanesulfonyl chloride (25 μL, 323 μmol) and the reaction mixture was stirred for 20 min at 100° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (30 mL), filtered through cotton wool, then washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methylsulfonamidomethyl)isoquinolin-3-yl methanesulfonate as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:27](O)[CH3:28]>S(=O)(=O)(O)O>[CH2:27]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[F:11])[CH3:28]
Reactant: O=C(O)c1cc(Br)cc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)cc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: 25 °C
Yield: 92 %

Procedure:
Dissolve 5-bromo-3-dibenzylamino-2-fluorobenzoic acid (1.53 g, 3.69 mmol) in ethanol (40 mL). Add concentrated sulfuric acid (0.2 mL) as a catalyst and heat to at reflux for 1 day. Cool to room temperature and concentrate. Dissolve the residue in diethyl ether (30 mL) and wash with 10% aqueous potassium carbonate solution (10 mL) and water (10 mL). Dry (magnesium sulfate) and concentrate to give the title compound as an oil (1.50 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:35][CH2:34][NH:33][CH2:32]2)=[CH:27][CH:26]=1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH2:35][CH:31]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][NH:23][CH3:22])=[CH:26][CH:27]=3)[CH2:32]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: CNCc1ccc(C2CCNC2)cc1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: CNCc1ccc(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)cc1
Yield: 51 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.89 g, 3.0 mmol) and N-methyl-4-(3-pyrrolidinyl) benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (0.71 g, 51%) as a yellow solid, mp 201°-205° C.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9][NH:8][CH:7]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([N:8]1[CH2:9][CH2:10][CH2:11][N:1]2[CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: C1=CN2CCCNC2CCC1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCCN3CCCCCC32)cc1
Reaction time: 0.17 h
Yield: 127.9 %

Procedure:
A mixture of 34.0 g (0.2 mol) 1,8-diazabicylo[5.4.0]undecene and 200 mL toluene was mixed with 34.2 g (0.2 mol) benzyl bromide. An insoluble oil formed and then changed to a white solid as the temperature rose to 57° C. over 10 minutes. After 4 hours, the solid was filtered and dried to provide 62.5 g of 8-benzyl-1,8-diazabicyclo[5.4.0]undecane (the 8-benzyl salt of DBU, which was soluble in water). NaBH4 solution (1.58 g, 5.1 mmol, 4.4M NaBH4 in 14M NaOH solution, obtained from Alfa Aesar, Ward Hill, Mass.) was diluted with 10 mL water. Then, 15 mL t-butyl methyl ether (t-BuOMe) was added to the diluted solution, and the resulting mixture was magnetically stirred and cooled to 3° C. To the cooled mixture was added 3.23 g of the 8-benzyl salt of DBU prepared as described above. After 2 hours, the resulting cold mixture was phase split, the resulting aqueous layer was extracted with t-BuOMe, and the resulting t-BuOMe solutions were combined, dried, and stripped to yield 0.86 g of a product (photolatent catalyst mixture). Gas-liquid chromatographic (GLC) analysis of the product indicated that it contained 39 percent 8-benzyl-1,8-diazabicyclo[5.4.0]undecane (GLC area response with a thermal conductivity detector; identified by gas chromatography/mass spectrometry (GC/MS) analysis), 13 percent of N-3-benzylaminopropylazepine (identified by GC/MS and nuclear magnetic resonance (NMR) analysis), and 48 percent of what was believed to be N-(3-benzylaminopropyl)azepin-2-one (GC/MS mass of 262).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.N1C(C)=CC(C)=CC=1C.[CH2:25]([S:32](Cl)(=[O:34])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C(OCC)(=O)C>[CH2:25]([S:32]([NH:1][C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:34])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOC(=O)Cn1c(C)ccc(N)c1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)Cn1c(C)ccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of ethyl (3-amino-6-methyl-2-oxo-1,2-dihydropyridyl)acetate (0.55 g, 2.6 mmole) and 2,4,6-collidine (1.2 mL, 5.2 mmole) in tetrahydrofuran (10 mL) is cooled in an ice bath. A solution of benzylsulfonyl chloride (0.50 g, 2.6 mmole) in tetrahydrofuran (10 mL) is added over a 15 minute period. After addition is complete, the solution is stirred for 30 minutes at 0° C. The reaction mixture is diluted with ethyl acetate (100 mL), washed with 1.0N HCl (until aqueous layer is pH 1), water (10 mL), saturated sodium bicarbonate (10 mL), and brine (2×10 mL). The organic layer is dried over anhydrous magnesium sulfate, and the solvent is removed. The residue is chromatographed through silica gel using 0:100-20:80 ethyl acetate:dichloromethane as eluent to afford the title compound.
Reaction SMILES: [CH:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:22]=[O:23].S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:15]1([CH3:21])[C:16]([CH:22]=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=O
Reactant: Cc1ccccc1
Agent: CCC(C)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccccc1C=O

Procedure:
To a mixture of 19.4 parts of 5-sec-butylsalicylic acid, 18.4 parts of toluene, 3.8 parts of 87% paraformaldehyde and 30 parts of acetic acid was added 2.0 parts of 95% sulfuric acid (catalyst). After being heated under reflux for 4 hours, the reaction mixture was washed with water, and unreacted toluene and water were removed by vacuum distillation to give 31 parts of 5-sec-butylsalicylic acid-toluene-formaldehyde co-condensation product. 10 parts of the co-condensation product was added to 14 parts of aqueous 10% sodium hydroxide solution and dissolved at 80° C. The resulting solution was cooled to 40° C., and 2.4 parts of zinc chloride was added thereto. After the reaction had been allowed to proceed at 40° C. for 1 hour, precipitates formed were collected by filtration, washed with water and dried to give 11.5 parts of zinc salt of 5-sec-butylsalicylic acid-toluene-formaldehyde co-condensation product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[CH2:18]([O:17][C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)NC1CCNCC1

Procedure:
16 g (61 mmol) of 1-benzyl-4-ethoxycarbonylaminopiperidine were hydrogenated in 240 ml of methanol and 80 ml of 10% strength methanolic hydrochloric acid on 4 g of palladium-on-charcoal (10%) at 45° C. in a shaking vessel for 90 minutes. The catalyst was filtered off with suction, the solvent was evaporated off, the residue was dissolved in 400 ml of ethanol and the solution was neutralized with ethanolic NaOH. The NaCl which had precipitated out was filtered off and the filtrate was concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:15][NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:16]([CH3:15])[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:6]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 57 %

Procedure:
3-Fluoro-5-trifluoromethylbenzoyl chloride (92 mg, 0.41 mmol, CAS RN 171243-30-4) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (40 mg, 0.20 mmol, example 1, intermediate a) and DIPEA (70 μL, 0.40 mmol) in THF (1 mL). After 2 h, an additional 25 μL of acyl chloride was added. The reaction mixture was stirred overnight, filtered and all volatiles removed. The resulting oil was purified by flash chromatography on silica gel eluting with 33-50% EtOAc in n-hexane to yield the product as a waxy solid (45 mg, 57%). MS (ESI): m/z=470.0 [M+H]+.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[OH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:39]5[CH2:40][CH2:41][C@@H:37]([OH:36])[CH2:38]5)[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: O[C@@H]1CCNC1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CC[C@@H](O)C1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(((R)-3-hydroxypyrrolidin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and (R)-3-hydroxypyrrolidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30](Br)[CH3:31])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:40][C:41]([F:50])([F:49])[C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([O:48][C:45]2[CH:46]=[CH:47][C:42]([C:41]([F:40])([F:49])[F:50])=[CH:43][CH:44]=2)[CH3:31])=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(Br)COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
The bromide 48.1 (80 mg, 0.16 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (200 mg, 0.62 mmol) and 4-trifluoromethylphenol (100 mg, 0.62 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL) and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc: hexanes) to obtain 48.2 (39 mg). MS ESI (pos.): m/e 595.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: CCCn1c(N)cc(=O)n(C)c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(N)c(N=O)c(=O)n(C)c1=O
Yield: 81.7 %

Procedure:
6-Amino-3-methyl-1-n-propyluracil (10.46 g, 57.8 mmol) was dissolved in 10 ml of acetic acid at 90° C. Then, with stirring, a solution of sodium nitrite (4.19 g, 60.8 mmol) in 100 ml of water was added in 10 ml portions over 5 minutes. A purple color formed immediately followed by a purple precipitate. The mixture was cooled in the freezer for 20 minutes and then the precipitate was collected by vacuum filtration, washed with water (2×30 ml) and acetone (2×10 ml), and air-dried to give 6-amino-3-methyl-5-nitroso-1-n-propyluracil as purple needles (10.02 g, 83%). 1H NMR (DMSO-d6 +D2O) δ0.89 (t, J=8 Hz, 3 H), 1.55 (sextet, J=8 Hz, 2 H), 3.27 (s, 3 H), 3.80 (t, J=8 Hz, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)Cc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ncccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 2-(pyrimidin-2-yl)acetate (Example 31b, 410 mg. 2.47 mmol) in ethanol (5 mL) was added 2N NaOH (2 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 72 hours, then concentrated under reduced pressure. The residue was triturated with ethanol and concentrated under reduced pressure to give the title compound, which was carried onto the next step without further purification. MS139 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)=[O:24])=[CH:4][CH2:3]1.[CH3:33][NH:34][CH3:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:33][N:34]([CH3:35])[CH:17]1[CH2:18][CH2:19][C:14]([C:12]2[CH:11]=[CH:10][C:9]([NH:22][C:23]([C:25]3[NH:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)=[O:24])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:1])([CH3:32])[CH2:3][CH:4]=3)[CH:13]=2)([OH:21])[CH2:15][CH2:16]1
Reactant: CC1(C)CC=C(c2cc(C3(O)CCC(=O)CC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(C)C1CCC(O)(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-4-oxo-cyclohexyl)-phenyl]-amide (as prepared in Example 21) and dimethylamine (solution in THF) using NaBH(OAc)3 according to literature procedure (J. Org. Chem., 61, 3849-62 (1996)).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]#[C:11][CH2:12][OH:13])[N:5]=1)([O-])=O.CO.NN>C(OCC)(=O)C.[Ni].O>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[N:5]=1
Reactant: O=[N+]([O-])c1ccn(CC#CCO)n1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccn(CCCCO)n1
Yield: 96.7 %

Procedure:
The 4-(3-nitro-pyrazol-1-yl)-but-2-yn-1-ol (prepared in example 52, 113 mg, 0.62 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. While stirring, a 50% slurry of raney nickel in water (1.3 mL) was added followed by hydrazine (400 μL). Immediate effervescence was observed. The reaction continued to stir and bubble for 25 min. The reaction was passed through a plug of celite and concentrated in vacuo to afford 4-(3-amino-pyrazol-1-yl)-butan-1-ol (93 mg, 98%) as a clear oil: ESI-LRMS m/e calcd for C7H13N3O [M+] 155.11, found 156.32 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22]([OH:24])=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC.C1COCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22](=[O:24])[N:27]([CH3:28])[CH3:25])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccccc23)C1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
The 2-t-butoxycarbonyl-9-carboxymethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.65 g, 5.0 mmol) obtained in the above step (1) was dissolved in methylene chloride (30 ml), and the solution was mixed with carbonyldiimidazole (0.81 g, 5.0 mmol), stirred at room temperature for 30 minutes, mixed with 2 M dimethylamine-THF solution (3 ml, 6.0 mmol) and further subjected to 1 hour of the reaction. The reaction solution was concentrated, the resulting residue was dissolved in ethyl acetate (50 ml), washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure. By adding diisopropyl ether (30 ml) to the resulting residue, 1.71 g of the thus precipitated title compound (4.8 mmol, 96% in yield) was obtained as crystals.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](Br)=[N:4][OH:5].[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].[O-]CC.[Na+]>CCO>[NH2:10][C:9]1[O:5][N:4]=[C:3]([C:2]([F:8])([F:7])[F:1])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: N#CCC(N)=O
Reactant: ON=C(Br)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1c(C(F)(F)F)noc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A solution of trifluoroacetohydroximoyl bromide etherate (17.6 g, 91.6 mmol) in 20 mL of EtOH was added to a solution of 2-cyano-acetamide (7.7 g, 91.6 mmol) and sodium ethoxide (6.2 g, 91.6 mmol) in ethanol (300 mL). After stirring at room temperature for 3 h, the solvent was removed. The residue was diluted with EtOAc and washed with water, brine, and dried over MgSO4. The organic phase was filtered and concentrated to give a brown oil. The product was purified by a flash chromatography on SiO2 eluting with hexanes:EtOAc (3:1) to give 7 as a light yellow solid (11 g, 40%); MS (ESI): 196 (M+H)+. Ref: J. Heterocyclic Chem. 1535 (1986).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1c[nH]c(C(N)=O)c1-c1ccc(N)cc1
Yield: 99.2 %

Procedure:
To a suspension of 0.024 g (0.222 mmol) of 10% palladium-on-charcoal in 63 cm3 of methanol is added, at a temperature in the region of 20° C., 0.331 g (0.956 mmol) of 4-tert-butyloxycarbonylamino-3-(4-nitrophenyl)-1H-pyrrole-2-carboxamide. After hydrogenating for 5 hours in an autoclave under 4 bar of hydrogen, at a temperature in the region of 40° C., the reaction mixture is filtered. The catalyst is rinsed with twice 15 cm3 of methanol and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.3 g of 4-tert-butyloxycarbonylamino-3-(4-aminophenyl)-1H-pyrrole-2-carboxamide in the form of a white solid melting at about 142° C.; EI: m/z=316 M+; m/z=260 [M-tBu]+; m/z=243 [M-OtBu]+; m/z=199 [243-CONH2]+; m/z=57: [tBu]+ base peak.
Reaction SMILES: CC(C([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:10]1)C([O-])=O)(C)C.Cl.[C:33](NN)([CH3:36])([CH3:35])[CH3:34]>>[CH3:34][C:33]([N:10]1[C:11]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:12][CH:13]=[N:9]1)([CH3:36])[CH3:35]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)C(C(=O)[O-])n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Product: CC(C)(C)n1nccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the major isomer (80%). ESMS (M−C(CH3)3+2H): 190.0; 1HNMR (400 MHz, d6-DMSO)8.32 (d, 2H), 7.7 (d, 2H), 7.48(d, 1H), 6.25 (d, 1H), 1.42 (s, 9H)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][S:4][C:5]1[NH:9][N:8]=[N:7][C:6]=1[C:10]([O:12]CC)=[O:11]>[OH-].[Na+]>[F:16][C:2]([F:1])([F:15])[CH2:3][S:4][C:5]1[NH:9][N:8]=[N:7][C:6]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1nn[nH]c1SCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nn[nH]c1SCC(F)(F)F
Temperature: 70 °C
Yield: 104.5 %

Procedure:
Ethyl 5-[(2,2,2-trifluoroethyl)thio]-1H-1,2,3-triazole-4-carboxylate (0.086 g) was suspended in 1N aqueous sodium hydroxide solution and heated at 70° C. for 3 h. The reaction mixture was filtered and then acidified with concentrated hydrochloric acid. Concentration in vacuo afforded a colourless solid which was washed with ice cold water to afford the subtitle compound (0.080 g)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:34][CH3:35]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([N:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:34][CH3:35])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 28).