Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[CH3:20][S:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:25])[N:11]3[CH2:26][CH2:27][NH:8][CH2:9][C@H:10]32)=[C:14]([C:21]([F:23])([F:22])[F:24])[CH:15]=1
Reactant: CSc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CSc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methylthio-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (34 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to yield 21 mg of a white solid. MS (ESI) 303 (M−Cl).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[O:1][CH2:16][CH2:15][CH2:14]1
Reactant: BrCCCBr
Reactant: COC(=O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c1OCCCO2

Procedure:
Methyl 2,3-dihydroxybenzoate (1.870 g, 11.12 mmol), 1,3-dibromopropane (2.25 g, 11.1 mmol) and potassium carbonate (6.15 g, 44.5 mmol) were stirred in N,N-dimethylformamide (20 ml) overnight at 60° C. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([O-:33])(=[S:32])[CH3:31].[K+].C(OCC)(=O)C.Cl>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:32][C:30](=[O:33])[CH3:31])[CH2:10][C@H:9]1[CH2:18][N:19]1[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]2[C:23]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 74.2 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (3 g) in dimethylformamide (30 ml), potassium thioacetate (1.65 g) is added. The mixture is stirred at 60° C. for 3.5 hours. The reaction mixture is poured into a mixture of ethyl acetate and dilute hydrochloric acid. The organic layer is taken, washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4S)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (2.12 g). Yield: 74%. Orange colored syrup.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[Cl:8][C:9]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:24]([O-:26])=[O:25])=[C:16]([CH:23]=1)[C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18].C(N(CC)CC)C>CCOCC>[Cl:8][C:9]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:24]([O-:26])=[O:25])=[C:16]([CH:23]=1)[C:17]([O:19][CH2:20][CH2:21][O:22][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])=[O:18]
Reactant: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C)S(=O)(=O)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 23.4 %

Procedure:
Dimethylsulfamoyl chloride (7.2 g, 0.05 mole) was added dropwise to a solution of 2-hydroxyethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (10 g, 0.025 mole), triethylamine (10 ml) and ethyl ether (200 ml). The mixture was heated to and held at reflux for 5 hrs., cooled, added 200 ml of ether and washed three times with water. The ethereal solution was dried over MgSO4, concentrated to 13.9 g of yellow gum. The gummy material was run through a silica gel with 30% acetone-70% cyclohexane as eluent to afford 3.0 g of pure 2-(N,N-dimethylsulfamoyloxy)ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate as colorless gum; nmr (CDCl3) 2.96 (S, 6H), 3.84 (m, 2H), 4.52 (m, 2H), 6.88-8.24 (m, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=2)[CH2:3]1.C([Si](C)(C)O[CH:20]1[CH:25]([O:26][CH3:27])[CH:24]([O:28][CH3:29])[CH:23]([O:30][CH3:31])[CH:22]([CH3:32])[O:21]1)(C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:27][O:26][C@@H:25]1[C@H:24]([O:28][CH3:29])[C@@H:23]([O:30][CH3:31])[C@H:22]([CH3:32])[O:21][C@H:20]1[O:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=2)[CH2:3]1
Reactant: CC(=O)c1ccc2c(c1)CC(O)C2
Reactant: COC1C(C)OC(O[Si](C)(C)C(C)(C)C)C(OC)C1OC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC2Cc3ccc(C(C)=O)cc3C2)[C@@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution at 0-5° C. of 1-(2-hydroxy-indan-5-yl)-ethanone (Compound E-25; 440 mg, 2.50 mmol) and 92% w/w of tert-butyl-dimethyl-(3,4,5-trimethoxy-6-methyl-tetrahydro-pyran-2-yloxy)-silane (Compound E-23; 1.00 g, 2.87 mmol) in CH2Cl2 (6 mL) was added via syringe trimethylsilyl triflate (0.12 mL, 146 mg, 0.66 mmol). The contents were allowed to gradually warm to room temperature and were stirred overnight. The solution was diluted with CH2Cl2 and was washed once with saturated sodium bicarbonate (NaHCO3). The aqueous phase was extracted once with CH2Cl2, and the combined organics were dried (MgSO4). Concentration gave a pale green oil (783 mg, 86%): 1H NMR (CDCl3) δ 7.79 (m, 2H), 7.29 (d, J=7.6 Hz, 1H), 4.97 (s, 1H), 4.64 (m, 1H), 3.67-3.40 (m, 3H), 3.55 (s, 3H), 3.50 (s, 3H), 3.45 (s, 3H), 3.21-2.97 (m, 5H), 2.59 (s, 3H), 1.30 (d, J=6.3 Hz, H); IR (neat) 1683 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]CC3C=CC=CC=3)[CH:9]=2)[N:4]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:3]=1
Reactant: Cc1cn(Nc2ccncc2)c2ccc(OCc3ccccc3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(Nc2ccncc2)c2ccc(O)cc12

Procedure:
3-Methyl-5-phenylmethoxy-1-(4-pyridinylamino)-1H-indole (2.20 g) was subjected to hydrogenolysis in absolute ethanol (80 ml) with 10% Pd-C (0.26 g) at 50 psig hydrogen at 50° C. for 2 hours. The catalyst was removed by filtration through a pad of celite and the solids washed with methanol. Concentration and recrystallization from methanol afforded 0.50 g of highly crystalline product, m.p. 239°-241° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[C:32]([C:37]([NH:39][CH3:40])=[O:38])=[N:33][CH:34]=[CH:35][CH:36]=1.C(O)(C(F)(F)F)=O>O>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[C:32]([C:37](=[O:38])[NH:39][CH3:40])=[N:33][CH:34]=[CH:35][CH:36]=3)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1ncccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccnc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (30.0 mg, 0.0661 mmol) and 3-amino-N-methylpyridine-2-carboxamide (Compound 231C, 15.0 mg, 0.0992 mmol) were taken up in TFE (2.7 mL, 37 mmol) and treated with TFA (15.3 uL, 0.198 mmol). This mixture was irradiated on the CEM for 120 min at 100° C. R×n mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified on an ISCO CombiFlash system (eluting with 0-4% MeOH/DCM) to isolate, after concentrating the relevant fractions and drying in vacuo, the desired product as 20.8 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) δ1.19 (t, J=7.07 Hz, 6H), 2.81 (d, J=4.80 Hz, 3H), 3.28 (d, J=20.50 Hz, 2H), 3.74 (s, 3H), 3.94-4.04 (m, 4H), 6.90 (dt, J=8.15, 1.99 Hz, 1H), 7.05 (s, 1H), 7.33-7.51 (m, 2H), 8.21 (d, J=3.54 Hz, 1H), 8.41 (s, 1H), 9.08 (br. s., 1H), 9.11 (q, J=4.21 Hz, 1H), 12.45 (s, 1H). MS (ES+): m/z=569.10 (100) [M+1]. HPLC: tR=1.52 min (UPLC TOF, polar—3 min).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(Cl)CCl.[C:17]([O:21][C:22]([N:24]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32](O)=[O:33])[S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32]([O:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:33])[S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1ccc(C(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of benzyl 2-hydroxyacetate (0.234 g, 1.410 mmol), EDC (0.541 g, 2.82 mmol) and DMAP (0.086 g, 0.705 mmol) in DCM (25 ml), 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoic acid (0.487 g, 1.410 mmol) was added, and the reaction was stirred at RT for 1 hour. The mixture was washed with HCl 1N and with NaHCO3 5%; the organic phase was dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=80:20 to 70:30) to give 2-(benzyloxy)-2-oxoethyl 3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-4-methoxybenzoate (0.508 g, 1.029 mmol, 73.0% yield, MS/ESI+ 515.9 [MNa]+).
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.Br[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:28]=3)[CH2:21][CH2:22]2)=[O:16])[N:6]=1
Reactant: O=C(CBr)N1CCN(c2ncccn2)CC1
Reactant: Brc1nc(-c2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Cn1nc(Br)nc1-c1ccccc1)N1CCN(c2ncccn2)CC1
Yield: 7.3 %

Procedure:
11 g 5-bromo-3-phenyl-1H-(1,2,4)triazole, 13.2 g 2-bromo-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanon and 28.2 g potassiumcarbonat in 300 mL acetone was stirred overnight at RT. The reaction was filtered and the filtrate was evaporated. The residue was purified by HPLC to give 1.45 g of the desired product. Rt: 1.08 min (method B), (M+H)+: 428/430
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:29]([O:28][C:26]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1)=[CH2:27])[CH3:30]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Yield: 77.1 %

Procedure:
To a solution of 1,1-dimethylethyl {(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}carbamate (20 g, 58 mmol) in dioxane (500 mL) was added tributyl[1-(ethyloxy)ethenyl]stannane (39 mL, 116 mmol) and PdCl2(PPh3)2. The resulting solution was heated at 100° C. for 5 h. The reaction was then concentrated and the residue purified by flash chromatography (47.5% EtOAc, 47.5% hexanes, 5% triethylamine) to give 15 g (77%) of 1,1-dimethylethyl [(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamate as a brown solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([NH2:19])=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([CH2:17][NH2:19])[CH2:15][CH2:16]2)=[CH:12][CH:13]=1
Reactant: NC(=O)C1(c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
LAH powder (0.153 g, 4.02 mmol) was added portionwise to a solution of 1-(4-fluorophenyl)cyclopropane carboxamide (0.6 g, 3.35 mmol) in THF (10 mL) at rt and the resulting mixture was heated to reflux for 1 h. The suspension was cooled to rt, quenched with MeOH (2 mL), and then 1N HCl (2 mL). The mixture was filtered through Celite, and the Celite washed with 1N HCl (2 mL). The filtrate was made basic with 50% NaOH, and extracted with EtOAc (3×10 mL). The organic extracts were washed with brine, dried over potassium carbonate, and concentrated. The residue was purified by silica gel chromatography using 0-20% 2M ammonia in MeOH/EtOAc as the eluent to give (1-(4-fluorophenyl)cyclopropyl)methanamine (0.5 g, 2.72 mmol, 81% yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.35-7.22 (m, 2H), 7.04-6.92 (m, 2H), 2.75 (s, 2H), 1.15 (br. s., 2H), 0.84-0.68 (m, 4H). LCMS: m+1=166.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:22][CH:21]=1>CN1C(=O)CCC1>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: NC(=O)CCc1ccc(N)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: NC(=O)CCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.060 g, 0.20 mmol) and 3-(4-aminophenyl)propanamide (0.066 g, 0.40 mmol) in NMP (3 mL) was microwaved for 3 h at 120° C., then at 140° C. for 2.5 h. After this time, the mixture was purified by silica gel chromatography eluting first with ethyl acetate and hexanes followed by methylene chloride and methanol. The solids were further purified by preparative HPLC to afford the title compound (0.042 g, 54%) as a white solid. MW=391.89. 1H NMR (DMSO-d6, 500 MHz) δ 14.09 (br s, 1H), 9.82 (s, 1H), 7.90-7.89 (m, 1H), 7.71-7.58 (m, 3H), 7.33-7.27 (m, 5H), 6.98 (s, 1H), 6.77 (br s, 1H), 3.18-3.15 (m, 2H), 2.93-2.80 (m, 4H), 2.40-2.34 (m, 2H), 2.27-2.21 (m, 2H); ESI MS m/z 392 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[C@@H:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:27][CH3:28])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC[C@H](C(=O)O)c1ccccc1
Product: CC[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and substituting (R)-2-phenylbutanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, CDCl3) δ ppm 7.38-7.21 (m, 10H), 5.29 (d, J=6.9, 1H), 4.04-3.90 (m, 1H), 3.65 (d, J=12.9, 1H), 3.52 (d, J=12.9, 1H), 3.15 (t, J=7.6, 1H), 2.68 (t, J=8.6, 1H), 2.64-2.48 (m, J=8.5, 3H), 2.30-2.22 (m, J=3.7, 8.3, 1.5H), 2.14 (ddd, J=7.4, 13.9, 19.9, 1.5H), 1.93 (dt, J=6.2, 12.5, 1H), 1.84-1.62 (m, J=7.6, 14.5, 20.6, 2H), 1.45-1.27 (m, 2H), 0.95-0.80 (m, 4H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:20]Br>C(Cl)Cl>[Br:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH:12]=1
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3ccccc32)cc1

Procedure:
To a solution of compound 82 (13 g, 47.9 mmol) in methylene chloride (100 mL) at 0° C. was added bromine (2.7 mL, 52.7 mmol) dropwise. After reaction complete, the resulting solution was evaporated under reduced pressure. The residue was quenched with saturated Na2S2O4 solution, work-up with Et2O. After evaporation of volatile solvent, the title compound was obtained by trituration with hexane.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([NH:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:33][CH:34]([CH3:36])[CH3:35]>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:37]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CC(C)CCNCCC(C)C
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCOC(=O)c1c(CN(CCC(C)C)CCC(C)C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diisopentylamine to give ethyl 4-(3,4-dimethoxyphenyl)-2-(N,N-diisopentylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 114°-115° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.I[CH2:15][CH2:16][CH3:17].CN(C)C=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH2:16][CH3:17])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCI
Reactant: CC(=O)Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCN(C(C)=O)c1cccc(Br)c1

Procedure:
In a manner similar to that of Example (27b), by reaction of 820 mg (20.5 mmol, 1.1 eq) of 60% sodium hydride, 4.0 g (18.7 mmol, 1 eq) of N-(3-bromophenyl)acetamide (prepared in Example 27a) and 2.20 mL (22.4 mmol, 1.2 eq) of 1-iodopropane in 15 ml of tetrahydrofuran in the presence of 1.5 ml of dimethylformamide, N-(3-bromophenyl)-N-propylacetamide is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[N:23][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:24]=[N:23][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cc2c(cn1)[nH]c1ncc(Cl)cc12
Temperature: 60 °C
Yield: 64.9 %

Procedure:
A solution of 3-chloro-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (24.2 mg, 67.4 μmol) in THF (1.3 mL) was treated with TBAF (398 μL, 1.35 mmol) and heated to 60° C. for 2 h. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo. The resultant residue was dissolved in DCM/EtOAc, absorbed onto silica gel, and purified by flash chromatography (silica, 4 g column, Biotage, 1-20% methanol in DCM containing 0 1% 7N ammonia in MeOH). Collecting appropriate fractions afforded a solid which was further purified by preparative HPLC (5-85% MeCN in water (0.1% NH4OH) over 30 min, 35 mL/min) to afford the title compound as an off-white solid (10 mg, 66%). 1H NMR (400 MHz, DMSO-D6): 13.07 (s, 1H), 9.05 (d, J=0.9 Hz, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.92 (d, J=0.9 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H). LCMS (Method E): RT=3.98 min, M+H+=229.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:19][C:20]1[C:27]([F:28])=[C:26]([C:29]([F:32])([F:31])[F:30])[C:25]([F:33])=[C:24]([F:34])[C:21]=1[CH2:22]Br>CN(C=O)C>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:22][C:21]2[C:24]([F:34])=[C:25]([F:33])[C:26]([C:29]([F:30])([F:32])[F:31])=[C:27]([F:28])[C:20]=2[F:19])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a solution of 5-aminosalicylic acid (1.02 g, 6.66 mmole, purchased from Aldrich Chemical Company, USA, A7, 980-9) and triethylamine (1 ml) in dried DMF (80 ml) was added 2,3,5,6-tetrafluoro-4-trifloromethylbenzyl bromide (1.23 g, 7.18 mmole) (Aldrich, 40, 640-6) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hr at room temperature and then solvent was removed in vacuo. The reaction mixture was diluted with ethyl acetate and then extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous MgSO4. After evaporation of the solvent, the residue was recrystallized from ether/hexane (1:10) to give 1.60 g (64% yield) of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].C(N(C(C)C)C(C)C)C.Br.[C:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH:24](Br)[CH2:23]1)(=[O:21])[CH3:20]>C(#N)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:8][C:24]2[CH2:23][N:22]([C:19](=[O:21])[CH3:20])[CH2:27][CH2:26][C:25]=2[N:7]=1
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(=S)c1cccs1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCc2nc(-c3cccs3)sc2C1
Temperature: 50 °C

Procedure:
2.8 mmol of thiophene-2-thiocarboxamide was dissolved in 10 ml acetonitrile. 5.6 mmol of N-ethyl-diisopropylamine was added, followed by 3.4 mmol 1-acetyl-3-bromo-piperidin-4-one hydrobromide (prepared according to patent U.S. Pat No. 4,122,083). The reaction mixture was heated to 50° C. for 4 hours, cooled and concentrated. Chromatography of the residue (SiO2; ethyl acetate) yields the title compound as a yellowish gum. MS (m/e): 265.0 (M+H+).