Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH2:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH:21][CH2:23][CH2:24][O:25][C:26]2[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:27]=2[C:28]#[N:29])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: NCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCCBr
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCNCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
To a solution of N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)ethane-1,2-diamine {Preparation Sc Step (1), 1.0 g, 3.265 mmol} in DMF (5 mL) was added TEA (0.495 g, 4.89 mmol) followed by 2-(2-bromoethoxy)-4-nitrobenzonitrile (Preparation N, 1.05 g, 3.91 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound in silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 10% methanol in chloroform) to get 2-(2-(2-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)ethylamino)ethoxy)-4-nitrobenzonitrile (0.35 g, 21.7%) as a light yellow solid. LC-MS (M+H)+=497.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.93-7.91 (1H, d, J=6.8 Hz), 7.90 (1H, s), 7.86-7.85 (1H, m), 7.12-7.00 (2H, m), 6.98-6.96 (2H, m), 5.30 (1H, br s), 4.34-4.32 (2H, m), 4.26-4.24 (1H, m), 3.70-3.66 (2H, m), 3.21-3.19 (2H, m), 3.04-3.02 (2H, m), 2.78-2.63 (3H, m), 1.99-1.98 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.N#N.[Si]([C:17]#[N:18])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:17]#[N:18])=[C:4]([Cl:10])[CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: Clc1cc(Br)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CC#N
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
4-Bromo-1-bromomethyl-2-chloro-benzene (3.04 g, 10.7 mmoles) was dissolved into anhydrous CH3CN. To this mixture (under N2 at ambient temp) was added TMSCN (2.1 mL, 15.7 mmoles) followed by 1.0M TBAF (15.7 mL, 15.7 mmoles, soln in THF). The resulting mixture was stirred at ambient temperature for 15 min after which time it was evaporated in vacuo to yield crude residue. The crude residue was purified using flash silica chromatography (0-10% EtOAc/Hexane) to yield (4-bromo-2-chloro-phenyl)-acetonitrile (1.98 g, 80%) as an off-white solid. 1H-NMR (CDCl3): δ 7.60 (d, J=2.0 Hz, 1H), 7.47 (dd, J′=8.1 Hz, J″=1.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.79 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[CH:17]1([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: BrCCCCOC1CCCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCOC1CCCCC1)C(=O)OCC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
15 g of malonic acid diethyl ester are added dropwise at 50° C. to a solution of sodium ethylate, freshly prepared from 1.5 g of sodium and 30 ml of ethanol. This temperature is maintained for 1 hour and 11.7 g of 4-cyclohexyloxybutyl bromide are then added dropwise. When the addition is complete, the mixture is stirred for 3 hours at 60° C. and is concentrated considerably, 100 ml of ice water are added to the residue and the mixture is extracted 3 times with a total of 150 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and the solvent is removed by distillation in vacuo, together with excess malonic acid diethyl ester. This gives 10.5 g of [4-(cyclohexyloxy)-butyl]-malonic acid diethyl ester in the form of a pale yellow oily residue.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N[S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26])(=[O:15])=[O:14])CC>>[CH2:1]([NH:8][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26])(=[O:14])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Product: O=C1Nc2ccc(S(=O)(=O)NCc3ccccc3)cc2C1=O

Procedure:
The title compound was prepared from benzyl amine following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:9][C:10]([C@H:12]1[CH2:17][C:16]([CH3:18])=[CH:15][CH2:14][N:13]1[C:19](=[O:50])[C@H:20]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=1)[NH:21][S:22]([C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][N:31](C(=O)C(F)(F)F)[CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:11])[CH3:8]>O.C(O)C>[CH2:7]([O:9][C:10]([C@H:12]1[CH2:17][C:16]([CH3:18])=[CH:15][CH2:14][N:13]1[C:19](=[O:50])[C@H:20]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=1)[NH:21][S:22]([C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][NH:31][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@H]1CC(C)=CCN1C(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H]1CC(C)=CCN1C(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CNCC2
Reaction time: 20 h
Yield: 79.9 %

Procedure:
A solution of sodium carbonate (2.83 g, 26.7 mmol) in water (20 ml) was added to a stirred solution of 4-methyl-1-[N-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-cyano-(S)-phenylalanyl]-1,2,3,6-tetrahydropyridine-2(R)-carboxylic acid ethyl ester (Preparation 36; 3.38 g, 5.34 mmol) in ethanol (20 ml) and the resulting suspension stirred for 20 hours. The bulk of the ethanol was removed under reduced pressure, the residual mixture diluted with water and extraction with ethyl acetate effected. The organic extract was washed with water, then saturated brine, dried (MgSO4) and evaporated under reduced pressure to afford the title compound (2.29 g) as a foam. Rf 0.42 (SS 9). [α]D25 +14° (c=0.1, CH3OH). Found: C,61.60; H,6.06; N,10.10. C28H32N4O5S; 0.50 H2O requires C,61.63; H,6.09; N,10.26%.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[CH3:54][NH:55][CH3:56].O1CCCC1.C(OCC)(=O)C>O1CCCC1>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][C:1]([N:55]([CH3:56])[CH3:54])=[O:43])=[CH:4][CH:5]=3)(=[O:20])=[O:19])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)N(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate (60 mg) in tetrahydrofuran (0.5 mL) was added 2M dimethylamine/tetrahydrofuran (0.5 mL) and the mixture is was stirred at ambient temperature for 30 min. Ethyl acetate was added and the mixture was washed with saturated sodium bicarbonate/water (4×), dried (sodium sulfate), evaporated, and purified by chromatography (silica gel, hexanes/ethyl acetate, 3:7) to provide the title compound as a solid foam. 1H NMR (DMSO-d6): δ 0.76 (3H, d), 0.82 (3H, d), 1.1-1.2 (1H, m), 1.2 (1H, br quintuplet), 1.9-2.0 (if, m), 2.2 (1H, t), 2.6-2.8 (3H, m), 2.81 (3H, s), 2.9 (3H, s), 3.0 (1H, br s), 3.2-3.3 (2H, m), 3.4-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.0 (1H, br s), 5.5 (1H, d), 6.1 (2H, s), 6.9 (2H, d), 7.0 (1H, d), 7.15 (2H, d), 7.19 (1H, s), 7.22 (2H, br d); MS: 664 (MH+); C31H41N3O11S.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C@H:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=2)[CH2:19][C@H:18]1[O:33][CH3:34]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C@H:17]2[CH2:22][CH2:21][N:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)[CH2:19][C@H:18]2[O:33][CH3:34])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1coc(N2CC[C@H](N)[C@H](OC)C2)n1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1coc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)n1
Yield: 59.5 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (2 mL) and ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-1,3-oxazole-4-carboxylate obtained in Example (103d) (0.3 g, 1.12 mmol). Purification by silica gel column chromatography (elution solvent: ethyl acetate/hexane=4/1, 1/0) gave 0.19 g of the title compound as a brown oily substance (60%).
Reaction SMILES: C[O:2][C:3](=[O:46])[CH2:4][CH2:5][NH:6][C@:7]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:39])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.[OH-].[Na+]>O1CCOCC1>[C:3]([CH2:4][CH2:5][NH:6][C@:7]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:39])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)([OH:46])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 80 °C
Yield: 34.6 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-methoxy-3-oxopropyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.024 mmol) and sodium hydroxide (0.238 mL, 0.238 mmol) in dioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and then filtered, the clear solution was purified by HPLC to provide the title compound as a white solid (5 mg, 33%). LCMS: m/e 602.43 (M+H)+, 2.25 min (method 10). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.9 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.39 (t, J=4.4 Hz, 2H), 3.17-3.02 (m, 1H), 2.98-2.80 (m, 2H), 2.31-1.02 (m, 22H), 1.77 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1C(=O)C(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 6-bromoisatin (CAS#6326-79-0, 4.52 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mind). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered and concentrated to provide 6-bromo-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 6-bromo-1-methyl-1H-indole-2,3-dione (1.0 g, 4.2 mmol) was then treated with hydrazine hydrate (7.0 mL, 225 mmol). The reaction was heated to 130° C. and stirred for 80 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 6-bromo-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 225.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: Fc1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2-fluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 134. LRMS (ES)+: 354.3 (M+H)+.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[CH3:8][C@@H:9]1[N:12]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)[C:11](=[O:18])[C@H:10]1[NH:19][C:20](=[O:59])/[C:21](/[C:34]1[N:35]=[C:36]([NH:39]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:37][CH:38]=1)=[N:22]\[O:23][C:24](C(C)(C)C)([CH2:26]C(O)=O)[CH3:25].ClCCl>C1(C)C=CC=CC=1>[CH3:8][C@@H:9]1[N:12]([C:13]2[NH:14][N:15]=[N:16][N:17]=2)[C:11](=[O:18])[C@H:10]1[NH:19][C:20](=[O:59])/[C:21](/[C:34]1[N:35]=[C:36]([NH2:39])[S:37][CH:38]=1)=[N:22]\[O:23][C:24]([C:3]([OH:5])=[O:4])([CH3:25])[CH3:26]
Reactant: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(CC(=O)O)C(C)(C)C)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)N1c1nnn[nH]1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1c1nnn[nH]1
Reaction time: 1 h
Yield: 16 %

Procedure:
Trifluoroacetic acid (0.50 ml) was added to a -15° solution of 39 (0.047 g, 0.065 mmol) and 0.5 ml dichloromethane. After one hour, the solution was warmed to 23° and stirred for an additional hour before 2 ml toluene was added and volatiles were removed under a stream of nitrogen. Dilution with 10 ml water and washing with 20 ml of 1:1, ethyl acetate: diethyl ether was followed by evaporation under vacuum and chromatography by reverse phase preparative TLC (10% ethanol in water). Elution of a band of Rf 0.9 with 80% acetonitrile in water gave 0.0043 g (16%) 40 as a white solid after lyophilization:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([CH:32]([CH3:34])[CH3:33])=[CH:20][C:10]=1[C:11]([NH:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([CH:32]([CH3:34])[CH3:33])=[CH:20][C:10]=1[C:11]([NH:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[S:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(=S)NN2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-piperidin-1-yl-benzamide (F67-02: 198 mg, 0.43 mmol), toluene (5 mL) and Lawesson's reagent (157 mg, added in two portions) were placed in a test tube and heated for 2.5 hours under reflux. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The foam thus obtained was subjected to the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[OH:23])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[O:23][C:13]([CH2:12][CH2:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:15][C:16]=2[CH:21]=1
Reactant: COc1ccc(CCC(=O)Nc2cc(Cl)ccc2O)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2nc3cc(Cl)ccc3o2)cc1OC
Yield: 64.9 %

Procedure:
N-[3-(3,4-dimethoxyphenyl)propanoyl-2-hydroxy-5-chloro-aniline (2.3 g, 6.3 mmol) in toluene (30 ml) and p-toluenesulfonic acid monohydrate (0.3 g, 1.5 mmol) was heated under reflux for 3 hours. The cooled reaction mixture was decanted from some tar and the toluene was evaporated. The residue was crystallized from t-butyl methyl ether with charcoal to give 1.3 g of the title compound which was recrystallized from t-butyl methyl ether to give pure title compound (1.08 g) mp 102-105° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:2]1=2.[Cl-:11].[C:12]([C:15]1[CH:20]=[CH:19][N+](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])[NH2:13]>CO>[Cl-:11].[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]3[CH:19]=[CH:20][C:15]([C:12](=[O:14])[NH2:13])=[CH:16][CH:17]=3)[C:2]1=2
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: Nc1cccc2c1OCC2
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1cc[n+](-c2cccc3c2OCC3)cc1

Procedure:
A mixture of 2,3-dihydrobenzo[b]furan-7-ylamine (6.8 g prepared in a similar manner to that described in Tetrahedron Letters 1982,23,147), 4-carbamoyl-1-(2,4-dinitrophenyl)pyridinium chloride (14.7 g prepared in a similar manner to that described in Example 2) and methanol (400 ml) was stirred under reflux for 5 hours then allowed to stand at ambient temperature and heated for 16 hours. The solvent was removed in vacuo, and the residue was triturated with hot acetone, cooled and filtered to give 1-(2,3-dihydrobenzo[b]furan-7-yl)-4-carbamoylpyridinium chloride as a yellow solid (11.5 g), m.p. 289°-290° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[NH:4][C:3]1=[O:15].Cl[CH2:18][CH2:19][O:20]C1CCCCO1>>[CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[N:4]([CH2:18][CH2:19][OH:20])[C:3]1=[O:15]
Reactant: ClCCOC1CCCCO1
Reactant: CC1(C)C(=O)Nc2ccc(S(C)(=O)=O)cc21
Product: CC1(C)C(=O)N(CCO)c2ccc(S(C)(=O)=O)cc21

Procedure:
Prepared from 3,3-dimethyl-5-methanesulfonyl-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:29][NH:30]2)=[CH:26][CH:25]=1>>[CH3:36][N:34]([CH2:33][C:28]1[C:27]2[C:31](=[CH:32][C:24]([NH:23][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:3]4[CH:4]=[C:5]([C:8]5[O:9][C:10]([CH3:13])=[N:11][N:12]=5)[CH:6]=[CH:7][C:2]=4[CH3:1])=[CH:15][CH:16]=3)=[O:21])=[CH:25][CH:26]=2)[NH:30][CH:29]=1)[CH3:35]
Reactant: CN(C)Cc1c[nH]c2cc(N)ccc12
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccc5c(CN(C)C)c[nH]c5c4)cc3)c2)o1

Procedure:
N-[3-(Dimethylaminomethyl)indol-6-yl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 6amino-3(dimethylaminomethyl)indole using method I. LCMS; retention time 3.16 min, [M-H·]463.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][C:28]([C:30]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=4)[CH2:4]3)=[O:31])=[N:27][N:26]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Reactant: Cc1cc(OC2CNC2)ccc1CN(C)C
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN(C)C)c(C)c4)C3)o2)cc1
Yield: 74.6 %

Procedure:
Using a similar protocol as described in Example 16 employing 20C (0.16 g, 0.73 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.20 g, 0.80 mmol) as starting materials afforded 0.23 g (74%) of 20 as a solid. 1H NMR (600 MHz, CDCl3): δ 2.21 (s, 6H), 2.33 (s, 3H), 3.30 (s, 2H), 3.87 (s, 3H), 4.27-4.35 (m, 1H), 4.58-4.66 (m, 1H), 4.69-4.76 (m, 1H), 5.00-5.15 (m, 2H), 6.53 (d, 1H), 6.58 (s, 1H), 7.00 (d, 2H), 7.14 (d, 1H), 8.08 (d, 2H), MS (APCI+) m/z 423 [M+H]+, LC purity: 98%.