Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]C=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:7][CH2:6][CH:5]3[CH2:3][CH2:2][NH:1][CH2:9][CH2:4]3)=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: Clc1ccc2[nH]c3c(OCCC4CCNCC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-(+)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol. 1H-NMR (400 MHz, CD3OD) δ ppm 8.44 (s, 1H), 8.11 (d, J=2.0 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.29 (dd, J=8.4, 2.4 Hz, 2H), 4.36 (t, J=7.2 Hz, 2H), 3.09-3.01 (m, 2H), 2.62 (td, J=12.4, 2.4 Hz, 2H), 1.96-1.87 (m, 2H), 1.83-1.70 (m, 3H), 1.33-1.18 (m, 2H); MS (ESI) m/z 450.2 (M−H)−; MS (ESI) m/z 452.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]([S:6][C:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[N:12](=[C:14]1[CH2:19][S:18][CH2:17][CH2:16][S:15]1)[OH:13].C(N(CC)CC)C>O1CCOCC1.O>[CH3:1][N:2]([S:6][C:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])[C:3]([O:13][N:12]=[C:14]1[CH2:19][S:18][CH2:17][CH2:16][S:15]1)=[O:4]
Reactant: ON=C1CSCCS1
Reactant: CN(SC(C)(C)CCl)C(=O)Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SC(C)(C)CCl)C(=O)ON=C1CSCCS1
Reaction time: 16 h

Procedure:
To a solution of 1.4 g of N-methyl-N-(2-chloromethyl-2-propanesulfenyl)carbamoyl chloride and 0.966 g of 2-oximino-1,4-dithiane in 50 ml of dioxane, was added dropwise with stirring 0.76 g of triethylamine. After allowing the reaction mixture to stand at ambient temperature for 16 hours it was diluted with water and extracted into ethylacetate. The organic extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The product was crystallized from isopropyl ether-methylene chloride solution. The weight of first crop was 1.0 g. m.p. 116°-117° C.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([CH:19]([CH3:21])[CH3:20])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26](Cl)=[O:27]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26]([C:11]1[C:12]2[C:13]([CH:19]([CH3:20])[CH3:21])=[CH:14][C:15]([F:18])=[CH:16][C:17]=2[N:9]2[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=12)=[O:27]
Reactant: CC(C)c1cc(F)cc2c1cc1n2CCC1C(C)C(=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1ccc(Cl)c(Cl)c1)c1n2CCC1CC(=O)O

Procedure:
Starting from methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 44, Step 2) and 3,4-dichlorobenzoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][N:19](C=O)[C@@H:9]([C@@H:10]3[CH2:11][CH2:12][C:13]([O:22]C)=[CH:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl>CO>[CH3:1][O:2][C:3]1[C:16]2[C@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@@H:10]3[CH2:11][CH2:12][C:13](=[O:22])[CH2:14]4)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC1=C[C@]23CCN(C=O)[C@H](Cc4cccc(OC)c42)[C@@H]3CC1
Agent: Cl
Solvent: CO
Product: COc1cccc2c1[C@]13CCN[C@H](C2)[C@@H]1CCC(=O)C3
Yield: 86.8 %

Procedure:
600 mg (1.91 mmol) 5,6-didehydro-4,6-dimethoxy-N-formylmorphinan were dissolved in 13.5 ml methanol and 1.5 ml 37% hydrochloric acid were added. This mixture was heated at reflux for 17 h, then the solvent was removed in vacuo, the oily residue dissolved in water and rendered alkaline with 30% NH4OH. After extraction with CHCl3, the organic layer was washed with brine, dried and evaporated to give an oil, which was crystallized with ether to yield 450 mg (81%) 4-methoxymorphinan-6-one. 1 H2O m.p. 136°-138°, [α]D26 -75.7° (c=0.88, CHCl3).
Reaction SMILES: [C:1](=[NH:14])([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.Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+]>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].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
An oven-dried test tube was charged with tris(dibenzylideneacetone)dipalladium (4.6 mg, 0.005 mmol) and bis(2-(diphenylphosphino)phenyl)ether [DPE-phos] (8.2 mg, 0.015 mmol), capped with a rubber septum, evacuated and refilled with argon. Benzophenone imine (190 mg, 1.05 mmol), 4-bromoanisole (187 mg, 1.0 mmol) and toluene (2 mL) were added via syringe. The resulting solution was stirred at rt for 5 minutes. The tube was opened and sodium tert-butoxide (135 mg, 1.4 mmol) was added. The tube was again capped with the septum, and additional toluene (2 mL) was added via syringe to wash the solid from the test tube wall into the solution. The solution was stirred at room temperature with a gentle argon purge for 5 minutes, then heated at 80° C. for 4 hours and 30 minutes. The reaction mixture was cooled to room temperature, washed with saturated aqueous sodium chloride (2 mL), and the organic layer was concentrated in vacuo. The product was isolated as a yellow oil (238 mg, 83%) by flash chromatography on silica gel using 5% ethyl acetate in hexanes as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:37]1[C:42](C)=CC=C[C:38]=1C.Cl.CNC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](=[O:23])[N:37]([CH3:42])[CH3:38])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, dimethylamine hydrochloride (20 mg, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-dimethylcarbamoylmethyl-1H-pyrazol-3-yl)-propionamide (64 mg, 60%) as a white solid: ESI-LRMS m/e calcd for C22H29ClN4O4S [M+] 480.2, found 481.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.22 (m, 2H, CH2), 1.41-1.93 (m, 8H, 4×CH2), 2.18-2.27 (m, 1H, CH), 2.97 (s, 3H, NCH3), 3.03 (s, 3H, NCH3), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.5 Hz, 1H, CH), 4.81 (s, 2H, NCH2), 6.71 (d, J=2.3 Hz, 1H, Ar), 7.34 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.8 Hz, 1H, Ar), 7.57 (d, Jm=1.8 Hz, 1H, Ar), 7.96 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[C:18]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:19]([Cl:24])=[CH:20][C:21]=2[O:22][CH3:23])=[O:15])[CH:10]([CH2:33][OH:34])[CH2:9]1)=O)(C)(C)C.[C:35]([OH:39])(=O)[CH:36]=[CH2:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>Cl.CO.CN(C=O)C.O>[OH:34][CH2:33][CH:10]1[N:11]([C:14]([C:16]2[CH:17]=[C:18]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:19]([Cl:24])=[CH:20][C:21]=2[O:22][CH3:23])=[O:15])[CH2:12][CH2:13][N:8]([C:35](=[O:39])[CH:36]=[CH2:37])[CH2:9]1
Reactant: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1CO
Reactant: C=CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC(=O)N1CCN(C(=O)c2cc(-c3cc(Cl)ccc3Cl)c(Cl)cc2OC)C(CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
tert-butyl3-(hydroxymethyl)-4-(2′,5′,6-trichloro-4-methoxy-[1,1′-biphenyl]-3-carbonyl)piperazine-1-carboxylate (420 mg, 0.79 mmol) was stirred in HCl in MeOH (2.85N). The solvent was removed under reduced pressure to yield the crude reside which was dissolved in DMF (20 mL), acrylic acid (57 mg, 0.79 mmol), BOP (421 mg, 0.95 mmol) and DIEA (409 mg, 3.17 mmol) were added. The reaction was stirred at room temperature for 1 h. The resulting mixture was poured into water, extracted with ethyl acetate and washed with water and brine. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=60:1) to afford the desired product (92 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ: 7.64-7.20 (m, 5H), 6.83-6.70 (m, 1H), 6.16-6.11 (d, 1H), 5.74-5.71 (d, 1H), 6.91 (s, 1H), 5.08-4.01 (m, 3H), 3.90-3.86 (d, 3H), 3.49-3.22 (m, 2H), 2.93-2.74 (m, 2H), 2.89-2.67 (m, 2H). ESI-MS m/z: 451.2 [M−H]−.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]2[CH2:30][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=4)[N:22]=[CH:21][C:20]=3[O:19][CH:18]2[O:33]C(=O)C)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.ClCCl>C(O)C.CO>[C:3]([O:7][C:8](=[O:9])[NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH:17]([CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=3)[N:22]=[CH:21][C:20]=2[OH:19])[CH2:18][OH:33])[CH2:15][CH2:16]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(OC(C)=O)O3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(O)c(CC(CO)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (920 mg, 24.2 mmol, 6.0 eq) is added at room temperature to a stirred solution of acetic acid 3-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-2-yl ester (1.90 g, 4.04 mmol, 1.0 eq) in ethanol (120 mL). After 1 hour stirring at room temperature, the reaction mixture is acidified with a 1N hydrochloric acid aqueous solution to pH 4. Solvent is evaporated and the residue is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 25:1 to 15:1, v/v) to afford {trans-4-[2-hydroxy-1-(3-hydroxy-6-methoxy-quinolin-4-ylmethyl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (1.26 g, 65% yield).
Reaction SMILES: C(O)(=O)C.Br.[CH2:6]([O:13][C:14](=[O:40])[C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20](=[O:39])[C@H:21]([CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)[NH:22]C(OCC1C=CC=CC=1)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH2:6]([O:13][C:14](=[O:40])[C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20](=[O:39])[C@H:21]([CH2:33][C:34]1[N:38]=[CH:37][NH:36][CH:35]=1)[NH2:22])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 145 %

Procedure:
After ice-cooling 20 ml of an acetic acid solution of 25% hydrobromic acid, 1.91 g of compound (6) was added to the solution followed by reaction for 2 hours at 5°-10° C. The reaction mixture was added to 200 ml of dry ether and after quickly removing the precipitates thus formed by filtration and then the reaction mixture was dried overnight in a desiccator with potassium hydroxide, to provide 1.99 g of L-histidyl-L-proline benzyl ester.2-hydrobromide (7).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]2[N:16]=[N:17][N:18]=[C:8]2[C:7]=1[N+:19]([O-])=O)([CH3:4])[CH3:3]>[Pt].C(O)C>[CH3:4][C:2]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]2[N:16]=[N:17][N:18]=[C:8]2[C:7]=1[NH2:19])([CH3:1])[CH3:3]
Reactant: CC(C)(C)Nc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Agent: [Pt]
Solvent: CCO
Product: CC(C)(C)Nc1c(N)c2nnnn2c2ccccc12

Procedure:
N-(1,1-dimethylethyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine (4.2 g, Example 18), ethanol (100 mL) and Pt/C (0.5 g) were placed in a Paar apparatus. The mixture was hydrogenated. The reaction mixture was filtered to remove catalyst then concentrated to dryness under vacuum. The residue was recrystallized from ethyl acetate/dichloromethane to provide N5-(1,1-dimethylethyl)tetrazolo[1,5-a]quinoline-4,5-diamine as a pale blue crystalline solid.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@@H:19]1[CH2:23][O:22][C@@H:21]([CH2:24][O:25][C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:27])[CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C.[Br:40][CH2:41][C:42](Cl)=[O:43]>>[Br:40][CH2:41][C:42]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:26]([O:25][CH2:24][C@H:21]1[CH2:20][C@H:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:23][O:22]1)=[O:27])=[O:43]
Reactant: O=C(Cl)CBr
Reactant: CCCCCCCCCCCCCCCCOC[C@@H]1CO[C@@H](COC(=O)NCc2ccccn2)C1
Solvent: CC(=O)Cl
Product: CCCCCCCCCCCCCCCCOC[C@@H]1CO[C@@H](COC(=O)N(Cc2ccccn2)C(=O)CBr)C1

Procedure:
Following the procedure described in example 24, and using instead of the compound prepared in example 23, the compound prepared in example 9, and instead of acetyl chloride, bromoacetyl chloride, the title compound of this example was obtained as a white solid (57% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:25]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14]([CH3:24])[C:15](=[O:23])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:8][CH2:7]2.[H][H]>[Pd]>[NH2:25][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[N:10]([CH2:12][CH2:13][N:14]([CH3:24])[C:15](=[O:23])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: CN(CCN1CCCc2cc([N+](=O)[O-])cc(F)c21)C(=O)Oc1ccccc1
Agent: [Pd]
Product: CN(CCN1CCCc2cc(N)cc(F)c21)C(=O)Oc1ccccc1
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a stirred solution of phenyl 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (560 mg, 1.500 mmol) was added palladium on activated carbon, 10 wt % (160 mg, 0.150 mmol). The resulting suspension was stirred at room temperature in a balloon pressure atmosphere of hydrogen. After 3 h, most of the starting material was consumed, and the reaction was stopped due to the presence of a minor impurity. The reaction mixture was filtered through a pad of celite, then concentrated to give a brown oil. The residue was dried and use directly in the subsequent reaction. Crude product obtained was phenyl 2-(6-amino-8-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (449 mg, 1.308 mmol, 87% yield). 1 H NMR (DMSO-d6) δ 7.40-7.35 (m, 2H); 7.23-7.17 (m, 1H); 7.10-7.05 (m, 2H); 6.19 (d, J=14 Hz, 1H); 6.06 (s, 1H); 4.85-4.72 (m, 2H); 3.57-3.53 (m, 1H); 3.46-3.42 (m, 1H); 3.13-2.93 (m, 4H); 3.07, 2.95 (2s, 3H); 2.57 (t, J=6.3 Hz, 1H); 1.74-1.65 (m, 2H). ESI-MS (m/z, %): 344 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[N:17]=[C:16]([O:24][CH:25]=[O:26])[CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH2:29]>C(O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([NH:29][CH3:28])[N:17]=[C:16]([O:24][CH:25]=[O:26])[CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cc(OC=O)nc(Cl)c2[N+](=O)[O-])C1
Solvent: CCO
Product: CNc1nc(OC=O)cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c1[N+](=O)[O-]
Reaction time: 48 h
Yield: 75.9 %

Procedure:
In a dry reaction bottle, 16 g (R)-1-[2-formyloxy-5-nitro-6-chloropyridin-4-yl]piperidine-3-carbamic acid tert-butyl ester (40 mmol) was added and dissolved in 50 mL ethanol. 31 g 40% methylamine aqueous solution (400 mmol) was added. The stirring was continued for 2 days at 60° C. The reaction solution was extracted with dichloromethane, dried, and evaporated to dryness to afford a crude product as yellow solid, which was purified through a column chromatography (ethyl acetate:petroleum ether=1:1) to afford 12 g titled product with a yield of 75.9%.
Reaction SMILES: [Se](=O)=O.O.C([C:8]1([Cl:14])[CH2:12][CH:11]=[C:10]([Cl:13])[S:9]1)(=O)C.[O:15]1CC[O:18][CH2:17][CH2:16]1>>[Cl:13][C:10]1[S:9][C:8]([Cl:14])=[CH:12][C:11]=1[C:17](=[O:18])[CH:16]=[O:15]
Reactant: C1COCCO1
Reactant: CC(=O)C1(Cl)CC=C(Cl)S1
Agent: O=[Se]=O
Solvent: O
Product: O=CC(=O)c1cc(Cl)sc1Cl
Temperature: 60 °C

Procedure:
A 31.4 g portion of selenium dioxide was added to a solution of 75 ml of dioxane and 10 ml of water and warmed to 60° C. with stirring. A 50 g portion of 2-acetyl-2,5-dichlorothiophene was added and the mixture was stirred at reflux for 7 hours. The mixture was diluted with dioxane, filtered and evaporated to dryness. Ether was added, then heptane and the mixture refrigerated. The solid was collected, giving 30.1 g of 2,5-dichloro-α-oxo-3-thiopheneacetaldehyde.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:27])=[N:14][C:15]([NH:16][C@@H:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18]O)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:1]1([N:7]2[C:11]3[N:12]=[C:13]([Cl:27])[N:14]4[CH2:18][C@H:17]([CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:16]=[C:15]4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H](Cc1ccccc1)Nc1nc(Cl)nc2c1cnn2-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: ClC1=Nc2c(cnn2-c2ccccc2)C2=N[C@@H](Cc3ccccc3)CN12
Reaction time: 8 h
Yield: 56 %

Procedure:
1.037 g of the above product (S)-β-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol was then dissolved in 25 ml CHCl3. Next, 1.38 ml thionyl chloride was added and the reaction was allowed to stir overnight. It was then placed in a freezer at -28° C. After 5 hours the precipitate was filtered and collected washing with cold CHCl3. The white solid was dried in a vacuum oven at 70° C. for 24 hours to yield 550 mg of (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5-chloro-3H-imidazo[1,2-c]pyrazolo-[4,3-e]pyrimidine (56%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].CO>>[ClH:19].[CH3:16][N:15]([CH3:17])[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:18]
Reactant: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)C1CCNCC1
Yield: 99.9 %

Procedure:
A solution of 4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (66) (220 mg, 0.85 mmol) in 4N HCl/MeOH (20 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give the product piperidine-4-carboxylic acid dimethylamide hydrochloride (67) (163 mg, 0.85 mmol, yield 99.9%).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][CH2:9][N:4]2[C:3](=[O:10])[O:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[CH:15]=[N:14][N:13]=1>CN(C=O)C>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([N:7]1[CH2:8][CH2:9][N:4]3[C:3](=[O:10])[O:2][CH2:1][C@@H:5]3[CH2:6]1)=[N:13][N:14]=[CH:15]2
Reactant: O=C1OC[C@@H]2CNCCN12
Reactant: Clc1ccc2c(Cl)nncc2c1
Solvent: CN(C)C=O
Product: O=C1OC[C@@H]2CN(c3nncc4cc(Cl)ccc34)CCN12
Temperature: 135 °C
Yield: 82.2 %

Procedure:
A mixture of (S)-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (1.42 g, 10.000 mmol), 1,6-dichlorophthalazine (1.47 g, 7.39 mmol) and N,N-DIPEA (5.00 mL, 30.0 mmol) in 12 mL DMF was heated at 135° C. The crude material was purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→3:97) to give 1.85 g of a brown oil. MS m/z: 305.1, 307.1 [M+1].
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:39]([NH:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=3)=[O:40])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: COc1cccc(N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Nc3cccc(OC)c3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 25 mg (0.17 mmol, 1.1 eq.) of 3-methoxyphenyl isocyanate were reacted according to General Method 4. Yield: 46 mg (67% of theory)
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[O:15].C1COCC1>C1C=CC=CC=1>[F:10][C:11]([F:17])([F:16])[CH2:12][NH:13][C:14]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:15]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C=NCC(F)(F)F
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)NCC(F)(F)F
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a stirred solution of tert-butyl hydrazinecarboxylate (1.0 g, 8 mmol) in anhydrous benzene (10.0 mL) was added 1,1,1-trifluoro-2-isocyanatoethane (1.06 g, 8 mmol) neat via syringe to give a gelatin like mixture. Anhydrous THF was added to give a clear solution which was stirred for 10 minutes, after which time the reaction mixture was evaporated to afford the title compound as a white solid (1.62 g, 79%): 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.40 (d, J=2.2 Hz, 1H), 5.84 (s, 1H), 3.88 (qd, J=9.0, 6.6 Hz, 2H), 1.48 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −73.20. This material is used without further purification.