Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:33]=[CH:32][C:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:25]=4[CH:24]=3)[N:21]=2)[CH:16]=[CH:17][CH:18]=1.Cl[CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38]>>[CH3:40][S:37]([CH2:36][CH2:35][N:29]1[CH2:28][CH2:27][C:26]2[CH:32]=[CH:33][C:23]([NH:22][C:20]3[N:21]=[C:14]4[C:13]([C:4]5[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:18][CH:17]=[CH:16][N:15]4[N:19]=3)=[CH:24][C:25]=2[CH2:31][CH2:30]1)(=[O:39])=[O:38]
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Reactant: CS(=O)(=O)CCCl
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(CCS(C)(=O)=O)CC4)nc12

Procedure:
[3-(2-Methanesulfonyl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-[8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-amine was prepared from [8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.200 g, 0.441 mmol) and 1-chloro-2-methanesulfonyl-ethane (0.126 g, 0.882 mmol) in a manner analogous to Example 320b to give product (0.150 g, 61%). MP=194-196° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.52 (s, 1H), 8.80 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.40 (m, 3H), 7.08 (t, 1H), 7.00 (d, 1H), 3.85 (s, 3H), 3.28 (m, 2H), 3.05 (s, 3H), 2.85 (m, 2H), 2.75 (m, 4H), 2.60 (m, 4H): MS=560 (MH)+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO>ClCCl>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: CNCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CN(Cc1ccccc1)C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 22.9 %

Procedure:
A mixture of intermediate 59 (0.4 g, 0.00109 mol), N-methylbenzylamine (0.42 mL, 0.00326 mol) and MeOH (0.1 mL) is heated at 95° C. for 2 days. The reaction mixture is cooled to RT, dichloromethane is added and the mixture is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (80:20-75:25) gives 110 mg of the product 81. 1H NMR (CDCl3) δ 7.50-7.20 (m, 6H), 7.10-6.90 (m, 7H), 6.90-6.75 (m, 2H), 5.52 (q, 2H), 4.84 (d, 1H), 4.52 (d, 1H), 2.97 (s, 3H), 1.45 (s, 9H); MS: m/z 442 (M++1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:24][C:25]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:22][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[OH:23])=[O:28]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 2,3-dichlorobenzoyl chloride (135 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give the title compound (161 mg, 77%).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:8]=2[C:9](=[O:11])[CH:10]=1)(OC)=[O:2].O.[BH4-].[Na+].CC(C)=O>CO>[OH:2][CH2:1][C:5]1[O:6][C:7]2[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:8]=2[C:9](=[O:11])[CH:10]=1
Reactant: COC(=O)c1cc(=O)c2ccc(S)cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: O=c1cc(CO)oc2cc(S)ccc12
Reaction time: 2 h

Procedure:
The ester from Step 4 (3.0 g) in suspension in methanol (20 ml) and water (40 ml) at 0° was stirred vigorously during the portionwise addition of NaBH4 (1.8 g). The mixture was stirred for 2 hours at 5°. Acetone (1 ml) was added followed by acidification with 1N HCl and extraction with methanolchloroform (1:9, 3×50 ml). The combined extracts were dried (Na2SO4), reduced to dryness in vacuo and the residue was recrystallized from methanolethyl acetate to provide the title compound, m.p. 139°-140°.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])C.[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7][C:6]=1[C:4]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: NCCC(=O)O
Reactant: CCOC(=O)c1ncc2cc(Oc3cccnc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2cc(Oc3cccnc3)ccc2c1O
Yield: 84.4 %

Procedure:
A mixture of 4-hydroxy-7-(pyridin-3-yloxy)-isoquinoline-3-carboxylic acid ethyl ester (26 mg), 3-amino-propionic acid (30 mg) and NaOMe (0.50 mL, 0.5 M solution in MeOH) was microwaved at 130° C. for 1 h; then cooled, concentrated, residue was dissolved in water, acidified with 2 M HCl; solids were collected via filtration, washed with water and air dried to give the desired product (25 mg). LC MS ESI: 354 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](Cl)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].N1([C:24]2[C:25](=[O:43])[N:26]([C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]4=[O:42])=[CH:32][CH:31]=3)[CH2:27][CH2:28][CH:29]=2)CCOCC1.C(N(CC)CC)C.Cl>CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:5]1[C:39]2[CH2:40][CH2:41][N:36]([C:33]3[CH:32]=[CH:31][C:30]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:24][C:25]4=[O:43])=[CH:35][CH:34]=3)[C:37](=[O:42])[C:38]=2[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Reactant: O=C1CCCCN1c1ccc(N2CCC=C(N3CCOCC3)C2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 470 mg, 1.3 mmol) in EtOAc (4 mL) was treated with 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 334 mg, 1.3 mmol, 1.0 equiv) at 0-5° C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 263 mg, 0.33 mL, 2.6 mmol, 2.0 equiv) at 0-5° C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was cooled down to 5-10° C. before being treated dropwise with a 4.0 N aqueous HCl solution (1.7 mL, 6.5 mmol, 5.0 equiv) at 0-5° C. The resulting mixture was stirred at 5-20° C. for 4 h. The resulting slurry was then treated with water (10 mL) and EtOAc (10 mL) before the two layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65, 423 mg, 635 mg theoretical, 67% for two steps) as pale-yellow solids, which solidified upon standing in vacuo at room temperature. For 65, CIMS m/z 489 (M++H, C27H28N4O5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Br.[CH3:16][C:17]1([CH3:24])[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:16][C:17]1([CH3:24])[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CC1(C)CCN=C(N)N1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1(C)CCn2c(nc(-c3ccncc3)cc2=O)N1
Yield: 33 %

Procedure:
A mixture of 7.68 g (39.8 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 7.9 g (37.9 mmol) of 6,6-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrobromide (prepared according to Bull. Soc. Chim. Belg., 1950, 59, 573-587) and 11 g (79.5 mmol) of potassium carbonate in 80 ml of ethanol were heated at reflux temperature during 18 h. The reaction mixture was cooled and the solvent removed by evaporation. The residue obtained was treated with water and the precipitate recovered by filtration to give 3.21 g (33%) of product.
Reaction SMILES: C[O:2][C:3]1[N:4]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)[N:6]=2.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:12][C:9]1[N:8]=[C:7]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][O:16]2)[N:6]=[C:5]2[C:10]=1[NH:11][C:3](=[O:2])[N:4]2[CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: COc1nc2c(N)nc(OCC3CCCO3)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(OCC2CCCO2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
8-(Methoxy)-2-[(tetrahydro-2-furanyl methyl)oxy]-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.1500 g) was dissolved in methanol (10 mL). To this solution was added 4N hydrogen chloride in 1,4-dioxane (2 mL). The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was evaporated under reduced pressure and then water (3 mL) and methanol (3 mL) was added to the residue to give a finely divided suspension. This was neutralised (to pH 7) by the addition of 2N sodium hydroxide and then evaporated under reduced pressure to dryness. Water (3 mL) was then added to the residue and the resultant white suspension of solid was isolated by filtration under suction. The solid was washed with methanol (1 mL) and then air-dried under suction. The solid was then dried further to constant weight under vacuo at 50° C. (˜1 hour). This gave the title compound as a white solid (0.1130 g)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[OH-].[Na+].[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.C([O-])([O-])=O.[Na+].[Na+]>P([O-])(O)(O)=O.[Na+].O>[CH2:21]([O:20][C:14]([C:15]1[C:4]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:3][NH:2][C:16]=1[CH3:18])=[O:19])[CH3:22]
Reactant: NCC(=O)CCCC(=O)O
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Solvent: O
Product: CCOC(=O)c1c(CCCC(=O)O)c[nH]c1C
Temperature: 25 °C
Yield: 70.7 %

Procedure:
6-amino-5-oxohexanoic acid hydrochloride (S1) 22.44 g (0.12 mol) (Lartillot, Serge. et al, Bulletin de la Societe Chimique de France, 1964, 4:783) was solved in about 6.1 L sodium dihydrogen phosphate buffer (300 g sodium dihydrogen phosphate was solved in 6 L water, then Saturated sodium hydroxide aqueous solution was added until a pH of about 6.5 was reached), and ethyl acetoacetate 16.12 g (0.12 mol) was added to the above-mentioned solution. The reaction solution was refluxed for half an hour, cooled to room temperature and Na2CO3 was added until a pH of about 8 was reached. The mixture was extracted with 100 ml CHCl3 and Aqueous phase was acidified with 6 mol/L HCl to pH 1. The brown solid was collected by filtration, washed with water and dried in vacuum condition to give 20.29 g (71%) 4-(4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-3-yl)butanoic acid (S2).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH2:10]1CCN2C(=NCCC2)C[CH2:11]1.C[Si](Cl)(C)C>ClC(Cl)C.CN(C=O)C>[CH3:4][C:3]1([CH3:5])[S:6][CH2:11][CH2:10][NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CC1(C)SCCN[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
To a 0° suspension of 14.92 g (0.10 mmol) of D-penicillamine in 300 mL of dichloroethane and 2.0 mL of DMF was added 22.4 mL of DBU followed by 19.0 mL of trimethylsilyl chloride. The ice bath was removed and the reaction was stirred for 3 h, after which an additional 29.9 mL of DBU was added. The reaction was stirred overnight at room temperature and then 10 mL of methanol was added and the reaction was stirred for 1 h. The resulting white precipitate was filtered off, washed with 10 mL of methanol and dried in vacuo to provide 16 g of (3S)-2,2-dimethyl-3-thiomorpholine carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23](Br)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[N+:43]([O-:45])=[O:44].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[C:29]([N+:43]([O-:45])=[O:44])[CH:30]=3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: COc1cc2nccc(N3CCOc4ccc(Br)cc4C3)c2cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(N3CCOc4ccc(-c5ccc(N)c([N+](=O)[O-])c5)cc4C3)c2cc1OC
Yield: 62.4 %

Procedure:
A mixture 4-[6,7-bis(methyloxy)quinolin-4-yl]-7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine (78 mg, 0.19 mmol), 4-amino-3-nitrophenylboronic acid pinacol ester (59 mg, 0.23 mmol), potassium carbonate (105 mg, 0.76 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (20 mg, 0.02 mmol) in dimethoxyethane (3 mL) was stirred at 80° C. for 3 h. Ethyl acetate (50 mL) was added and the mixture was washed with water (20 mL), and brine (20 mL), dried over sodium sulfate, and concentrated. Column chromatography on silica (dichloromethane:methanol 95:5) gave 4-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-2-nitroaniline (56 mg, 63% yield). MS (EI) for C26H24N4O5: 473 (MH+).
Reaction SMILES: CC([N:5]([C@@:9]([CH3:33])([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]4([CH2:31][O:32][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH2:30][CH2:29]4)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>ClCCl>[C:28]12([C:27]3[C:22]([O:21][C:18]4[N:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@:9]([CH3:33])([CH2:10][CH3:11])[NH2:5])=[CH:20][CH:19]=4)=[CH:23][CH:24]=[CH:25][C:26]=3[O:32][CH2:31]1)[CH2:29][CH2:30]2
Reactant: CC[C@](C)(C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1,1-dimethylethyl[(1R)-1-methyl-1-({[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]amino}carbonyl)propyl]carbamate (Intermediate 92, 106 mg) in dry dichloromethane (2 ml) at 0° C. TFA (0.360 ml, 4.67 mmol) was added. The mixture was stirred at this temperature for 5 minutes, then allowed to warm up at room temperature. After 2 hours UPLC/MS showed the absence of the starting material and the presence of the desired compound: toluene (5 ml) was added and the mixture was concentrated under vacuum. The residue was loaded on a SCX cartridge (1 g), which was eluted with methanol and a 1M NH3 solution in methanol. The basic eluate was concentrated under vacuum to afford the title compound as a brown oil (68 mg) which was used in the following experiment without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1OC.COC1C=CC=[C:18]([O:39][CH3:40])[C:19]=1[C:20]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:40][O:39][CH:18]1[CH2:19][CH:20]1[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)c(OC)c1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(C2CC2OC)cc1
Temperature: 100 °C

Procedure:
To form 2,4-dimethoxy-cyclopropylbenzene (4cc), the general procedure was followed using 1-chloro-2,4-dimethoxybenzene (3b) (173 mg, 1.00 mmol), cyclopropyl MIDA boronate (2h) (236 mg, 1.20 mmol), SPhos (41 mg, 0.10 mmol) and Pd(OAc)2 (11 mg, 0.048 mmol). The reaction temperature was modified so that the reaction mixture was heated to 100° C. for 6 h. Compound 4cc was isolated as a colorless liquid (175 mg, 97%). TLC (hexanes:EtOAc 9:1) Rf=0.65, visualized by UV (254 nm). 1H-NMR (500 MHz, CDCl3w/ TMS) δ 6.77 (d, J=8.5 Hz, 1H), 6.44 (d, J=2.5 Hz, 1H), 6.39 (dd, J=8.5, 2.5 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 2.03 (m, 1H), 0.85 (m, 2H), 0.57 (m, 2H). 13C-NMR (125 MHz, CDCl3) δ 159.2, 158.6, 125.7, 124.2, 103.8, 98.4, 55.5, 55.3, 9.0, 6.9. HRMS (EI+) Calculated for C11H14O2 (M)+: 178.0994, Found: 178.0995. IR (thin film, cm−1) 3080, 3000, 2955, 2940, 2835, 1615, 1585, 1510, 1464, 1439, 1416, 1370, 1319, 1290, 1261, 1209, 1172, 1158, 1117, 1062, 1037, 938, 884, 834, 823, 799.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:38])[CH2:40][CH2:41]1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 50 °C
Reaction time: 17 h
Yield: 96.7 %

Procedure:
To a mixture of (S)-tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate (8.0 g, 26.7 mmol) and cesium carbonate (13.1 g, 37.4 mmol) in DMF (130 ml) was added 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid benzyl ester (12.94 g, 32.1 mmol). The resulting reaction mixture was stirred at 50° C. for 17 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine (×3), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 50% ethyl acetate/iso-hexane to afford the title compound (13.7 g, 93%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1.[CH3:22][S:23]([O-:25])=[O:24].[Na+]>CN1C(=O)CCC1.CCCCCCC.CCOC(C)=O>[NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1
Reactant: CS(=O)[O-]
Reactant: CCOC(=O)Cn1c2c(c3cccc(Br)c31)CC(N)CC2
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c2c(c3cccc(S(C)(=O)=O)c31)CC(N)CC2

Procedure:
A solution of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (0.238 mmol), cuprous iodide (204 mg, 1.073 mmol, 4.5 eq.) and sodium methanesulfinate (129 mg, 1.073 mmol, 4.5 eq.) in degassed NMP (5 ml) is heated under inert atmosphere at 140° C. overnight. Then, the mixture is diluted with heptane (5 ml) and AcOEt (5 ml) and filtered over a pad of silica gel with AcOEt as eluent. The solvent is removed in vaccuo and the residue dissolved in AcOEt and H2O. The phases are separated and the aq. phase is extracted twice with AcOEt. The combined org. phases are washed with brine and H2O, dried over Na2SO4 and concentrated in vacuuo to yield the corresponding ethyl (3-amino-8-methanesulfonyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[NH:19][C:18](=[O:20])[CH2:17][N:16]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:14]=3[CH:27]=2)=[O:9])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[C:10]2[CH:11]=[CH:12][C:13]3[NH:19][C:18](=[O:20])[CH2:17][N:16]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:14]=3[CH:27]=2)=[CH:28][CH:29]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2cc(C(O)c3ccc(Cl)cc3)ccc2N1
Temperature: 0 °C
Yield: 78 %

Procedure:
Sodium tetrahydroborate (2.68 g) was added portionwise at 5° C. to a solution of intermediate (27) (0.0354 mol) in methanol (150 ml). The solution was poured into ice water and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (12.27 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated. The residue was crystallized from methanol, yielding 10.4 g (78%) of (±)-7-[(4-chlorophenyl)hydroxymethyl]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (intermediate 28).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:18][C:17]2[CH:16]=[N:15][C:14]3[N:19](CC4C=CC(OC)=CC=4)[N:20]=[CH:21][C:13]=3[C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH:9]1[CH2:18][C:17]2[CH:16]=[N:15][C:14]3[NH:19][N:20]=[CH:21][C:13]=3[C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([OH:35])([C:32]([F:37])([F:36])[F:31])=[O:34]
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NCc2ccccc2)CC4)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CNC2CCc3c(cnc4[nH]ncc34)C2)cc1
Temperature: 65 °C

Procedure:
To N-benzyl-3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-amine (0.030 g, 0.075 mmol) was added trifluoroacetic acid (3 mL). The reaction mixture was heated at 65° C. for 2 hours. On completion of the reaction, toluene (2 mL) was added and the solvent removed under reduced pressure. The crude product was purified using reverse phase HPLC to give the desired product, N-benzyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-amine as a TFA salt and a white solid (0.015 g, 71%). M.p.>232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.39 (s, 1H), 9.06 (brs, 2H), 8.05 (d, J=1.6 Hz, 1H), 7.99 (s, 1H), 7.56 (m, 2H), 7.46 (m, 3H), 4.31 (s, 2H), 3.61 (m, 1H), 3.43 (m, 1H), 3.08 (m, 3H), 2.43 (m, 1H), 1.97 (m, 1H); LCMS [M+H]: 279.