Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([OH:50])[CH2:48]Br)=[CH:43][C:42]=1[NH:51][CH:52]=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:48][C@@H:47]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:42]([NH:51][CH:52]=[O:53])[CH:43]=2)[OH:50])=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: O=C(NCCCCc1ccc(OCCNCc2ccccc2)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CNc1cc([C@@H](O)CN(CCOc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)Cc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.6 %

Procedure:
Benzylamine 16 (619 mg, 1.43 mmol) was added to a suspension of bromoalcohol 5 (500 mg, 1.43 mmol) and K2CO3 (495 mg, 3.58 mmol) methanol (10 mL) and tetrahydrofuran (5 mL). The suspension was stirred at ambient temperature for 15 h, then heated to 55° C. for 75 h. The solid was vacuum filtered and the filtrate was concentrated under vacuum. The resulting oil was subjected to column chromatography eluting with 5-50% ethyl acetate in hexanes to afford the desired product 17 (508 mg, 5%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 1.45-1.62 (m, 4H), 2.54 (t, 2H), 2.65-2.71 (m, 1H), 3.14-3.23 (m, 3H), 3.58-3.74 (m, 1H), 3.88-4.09 (m, 3H), 4.71 (br, 2H), 5.04-5.21 (m, 4H), 6.79-7.25 (m, 6H), 7.34-7.52 (m, 16H), 7.65-7.87 (m, 1H), 8.32-8.49 (m, 1H); m/z, (ESI) 702 [C43H47N3O6+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([NH:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: CCOC(=O)C1=Cc2cccc(N)c2OCC1
Reactant: O=C(Cl)CCCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cccc(NC(=O)CCCCl)c2OCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (0.35 g), 4-chlorobutyryl chloride (0.202 ml) and pyridine (0.146 ml) in dichloromethane (3.5 ml) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (3:1) as an eluent to give colorless crystals of ethyl 9-(4-chlorobutyryl)amino-2,3-dihydro-1-benzoxepin-4-carboxylate (0.48 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:18]1([CH:17]2[N:11]([CH:9]([CH3:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH:13]([CH2:14][OH:15])[O:16]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC(CCc1ccccc1)NCC(O)CO
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(CCc1ccccc1)N1CC(CO)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 94 (24 g, 0.108 mol), toluene, benzaldehyde (40 ml) and benzoic acid (0.5 g) was heated at reflux with a Dean-Stark trap. After 1 hour, the theoretical amount of H2O was collected, the reaction cooled to room temperature and saturated Na2CO3 added. The aqueous layer was separated and washed with CHCl3 (3×). The combined extracts were dried, filtered and concentrated to dryness to yield 34 g (100%) of 95.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9]C.C=CCCCCCCC=C>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCCCCC=CC
Agent: C=CCCCCCCC=C
Product: C=CCCCCCC=C

Procedure:
1,8-decadiene; 1,9-decadiene;
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([NH2:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1>O=P(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]#[N:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(=O)c1ccc2ncsc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2ncsc2c1

Procedure:
A solution of 1,3-benzothiazole-6-carboxamide (1.96 g) in POCl3 (10 ml) was refluxed for 4 hours. The reaction solution was concentrated, and water was slowly added thereto at 0° C. It was extracted with EtOAc, and the organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20 to 60:40) to obtain 1,3-benzothiazole-6-carbonitrile as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10](O)=[O:11])[CH3:2].C(=O)(O)[O-].[Na+]>C1COCC1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])=[CH:19][CH:18]=1)#[N:21]
Reactant: CCOC(=O)CCCCC(Cc1ccc(C#N)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(CO)Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
34.42 ml of a 1 M borane-THF complex solution (34.42 mmol) are added dropwise to a solution of 6.64 g (22.94 mmol) of 2-(4-cyanobenzyl)heptanedioic acid 7-ethyl ester in 260 ml of THF at −10° C. After warming to 0° C., the mixture is stirred at this temperature for 2 hours. After the reaction is complete, saturated sodium bicarbonate solution is added to the reaction mixture, and the solvent is concentrated to dryness. The residue is taken up in dichloromethane, dried over sodium sulfate and again freed of solvent. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 1:8→1:2). 5.84 g (88% of theory, 20.19 mmol) of a colorless solid are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=3[CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:21]Br>C(Cl)(Cl)(Cl)Cl.ClCl>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=3[C:15]=2[Br:21])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C1(c2cc3cc(C)ccc3o2)CCCC1
Agent: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2oc3ccc(C)cc3c2Br)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of product of Step 4, above (58) (1.0 mmol) in 2 ml CCl4 was added bromine (1.0 mmol) at ambient temperature and the reaction mixture was stirred for 2 hours, refluxed for 1 hour to ensure completion of the reaction, cooled to ambient temperature, diluted with CH2 Cl2 and washed with saturated sodium bicarbonate and brine. The combined organics were dried over MgSO4, filtered and concentrated to dryness. The crude residue was chromatographed on silica gel using 5% EtOAc in hexanes as the eluant to obtain the title compound (59).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=1)=[CH:13][C:12]([O:18][CH3:19])=[CH:11][CH:10]=4.[H-].[Na+].[CH3:24]N(C=O)C>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]3[N:8]([CH3:24])[C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=1)=[CH:13][C:12]([O:18][CH3:19])=[CH:11][CH:10]=4
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)SCc1c-2[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)SCc1c-2n(C)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
CH3l (108 mg, 0.758 mmol, 1.5 eq.) was added to a mixture of 3,8-dimethoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (150 mg, 0.505 mmol) and NaH (61 mg, 60% in mineral oil, 1.515 mmol, 3.0 eq.) in DMF. The reaction mixture was then stirred at 25° C. for 2 hours. The reaction mixture was partitioned between EtOAc and saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a crude material. The crude material was purified by silica gel (Hexanes to EtOAc 4:1) to yield the title compound as a brown solid.
Reaction SMILES: O1CCCCC1[O:7][C:8]([CH3:29])([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:9]=[CH:10]/[CH:11]1[CH2:13][C:12]1([C:19]([O:21]CC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:30](C(OCC)=O)([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[C:42]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C@@H:11]([CH:10]=[CH:9][C:8]([OH:7])([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][C@H:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]1=[O:21])([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCCCCC(C)(/C=C/C1CC1(C(=O)OCC)C(=O)OCC)OC1CCCCO1
Reactant: CCOC(=O)CCCCCCC(C(=O)OCC)C(=O)OCC
Product: CCCCCC(C)(O)C=C[C@H]1C[C@H](C(=O)OCC)C(=O)C1(CCCCCCC(=O)OCC)C(=O)OCC

Procedure:
For example, the use of the compound of formula 4, diethyl trans-2-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}cyclopropane-1,1-dicarboxylate, described in Example 41and the compound of formula 5, triethyl heptane-1,1,7-tricarboxylate, described in Example 42, in the procedure of Example 45 gives diethyl trans-3-(6-carboethoxyhexanyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate, γmaxfilm 3500, 1725 cm-1, nmr (CDCl3) δ 0.88 (t, 3H), 4.17 (m, 6H), 5.64 (m, 2H), via the intermediate diethyl trans-3-(6-carboethoxyhexanyl)-4-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}-2-oxo-1,3-cyclopentanedicarboxylate, γmaxfilm 1730 cm-1.
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[C:15]2[C:5]([CH:6]([OH:24])[CH:7]([C:19](OCC)=[O:20])[C:8](=[O:18])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1.O.CCOC(C)=O>[F:1][C:2]1[C:16]([F:17])=[C:15]2[C:5]([C:6](=[O:24])[C:7]([C:19]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:20])=[C:8]([OH:18])[C:9]32[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1C(=O)C2(CCOCC2)c2c(ccc(F)c2F)C1O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(ccc(F)c2F)C1=O
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
A mixture of ethyl 7,8-difluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.23 g, 0.68 mmol), tert-butyl 2-aminoacetate hydrochloride (0.14 g, 0.82 mmol) in 3 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.26 g, 2.0 mmol). The mixture was warmed to 120° C. and stirred for 1.5 hours. The mixture was cooled to room temperature, diluted with 20 mL H2O, and 100 mL EtOAc. The organic layer was separated, washed with 20 mL 1N HCl, saturated NH4Cl, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (10-20% EtOAc/hexane) to give 0.13 g white solid. MS m/e: (M+H)+ 424.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.N1(C([O-])=O)CCCC1.[N:23]1([CH2:28][C:29]#[C:30][C@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2C(OC(C)(C)C)=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>CO>[NH:32]1[CH2:33][CH2:34][CH2:35][C@H:31]1[C:30]#[C:29][CH2:28][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#CCN1CCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])N1CCCC1
Solvent: CO
Product: C(#C[C@@H]1CCCN1)CN1CCCC1
Yield: 26 %

Procedure:
This compound was obtained as the dihydrochloride salt following Example 50, Part A by substituting (S)-t-butyl (1-pyrrolidinyl)-1-propynyl]-1-pyrrolidinecarboxylate for (R)-t-butyl 2-[3-(1-pyrrolidinyl)-1-propynyl]-1-pyrrolidinecarboxylate, a white hygroscopic powder, m.p. 208°-211° C. [a]D -23° (c 0.75, MeOH). Recrystallization of the mother liquor gave an additional 26% of product.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:5][CH:4]=1.[NH2:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][P:30]2(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH2:29][P:30]5(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:37][CH:38]=4)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: Nc1ccc(CP2(=O)CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CP4(=O)CCCCC4)cc2)CCO3)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 7—(4-dimethylaminophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.1 g), 1—(4-aminobenzyl)phosphorinane-1-oxide (0.08 g) and 1-hydroxybenzotriazole (0.05 g) in dimethylformamide (7 ml) was added l-ethyl-3—(3-dimethylaminopropyl)carbodiimide hydrochloride (0.1 g) under ice-cooling. Under nitrogen atmosphere, the mixture was warmed to room temperature. To the mixture were added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.15 ml), and the mixture was stirred over night. The solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7—(4-dimethylaminophenyl)-N-(4—((1-oxophosphorinan-1-yl)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 154) (0.12 g) as colorless crystals.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)C1C=CC=CC=1.[ClH:19]>CCO.[OH-].[OH-].[Pd+2]>[ClH:19].[NH:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:9]1
Reactant: c1ccc(CN2CC[C@@H](N3CCCCC3)C2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: C1CCN([C@@H]2CCNC2)CC1
Temperature: 50 °C
Reaction time: 10 h
Yield: 151.3 %

Procedure:
Compound 7 (1.4 g, 6.0 mmol) was added dropwise into a flask equipped with a H2 balloon and containing the mixture of Pd(OH)2 (400 mg, 20% on carbon) and HCl (1.15 mL, 35% in H2O, 19.5 mmol) in EtOH (50 mL). The mixture was stirred under H2 at 50° C. for 10 h. Solid was filtered out and washed with hot HOCH3 (2×10 mL). The combined liquid was evaporated to dryness to give HCl salt of (3R)-1-pyrrolidin-3-yl-piperidine 9 (1.4 g, 100%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.I[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1>[Cu]I.O1CCOCC1>[CH3:46][C:41]1[CH:40]=[C:39]([N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH:44]=[C:43]([CH3:45])[CH:42]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 13 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (200 mg, 1.05 mmol), phthalimide (185 mg, 1.26 mmol), K2CO3 (290 mg, 2.10 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (130 μL, 1.06 mmol), dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting brown suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 3:1; 15 mL fractions). Fractions 8-11 provided 34 mg (13% yield) of the product as a tan solid. The 1H NMR spectrum was in accord with that reported by Hashimoto et al. Shibata, Y.; Sasaki, K.; Hashimoto, Y.; Iwasaki, S. Chem. Pharm. Bull. 1996, 44, 156.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([CH:23](O)[C:24]([F:27])([F:26])[F:25])[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([CH2:23][C:24]([F:26])([F:27])[F:25])[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:15])=[O:16]
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)N2CCOCC2)c(C(O)C(F)(F)F)c(-c2ccccc2)n1CC(=O)O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCOCC2)c(CC(F)(F)F)c(-c2ccccc2)n1CC(=O)O
Temperature: 0 °C
Yield: 29.4 %

Procedure:
2-(2-methyl-3-(2-(morpholinosulfonyl)benzyl)-5-phenyl-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrrol-1-yl)acetic acid (0.063 g, 0.114 mmol) was dissolved in 2 mL DCM and cooled to 0° C. 2,2,2-trifluoroacetic acid (1 ml, 0.114 mmol) was then added followed by triethylsilane (0.2 ml, 1.252 mmol). LC/MS shows reduction was instantly complete. The reaction mixture was directly concentrated to yield ˜5 mg of crude material, which was purified by preparative HPLC chromatography to give 18 mg (29.4%) of the desired material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:10](=[O:15])[N:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.CN(C=O)C.S(Cl)([Cl:26])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:26][CH2:13][N:11]1[C:10](=[O:15])[N:9]([CH:16]2[CH2:18][CH2:17]2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: O=S(Cl)Cl
Reactant: O=c1n(CO)nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1n(CCl)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
875 mg (3.29 mmol) of the compound from Example 121A were suspended in 3 ml of dichloromethane, and a drop of DMF and 288 μl (3.95 mmol) of thionyl chloride were added. The mixture was stirred at RT for 3 h. For work-up, 5 ml of saturated aqueous sodium bicarbonate solution were added. The mixture was extracted once with 10 ml of tert-butyl methyl ether. The organic phase was washed once with 5 ml of water, dried over sodium sulfate, filtered and concentrated under reduced pressure. Drying of the residue under high vacuum gave 803 mg (86% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][CH3:7].C(N(C(C)C)CC)(C)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:6]([CH3:7])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CNCc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)CN(C)Cc2cccc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a solution of (3-bromo-benzyl)-methyl-amine (3.0 g, 15.0 mmol) in methylene chloride (60 mL) was added diisopropylethylamine (5.2 mL, 30.0 mmol). The reaction mixture was cooled to 0° C. and treated with 2-bromo-1-p-tolyl-ethanone (3.19 g, 15.0 mmol) portionwise over a period of 10 minutes. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water (3×), dried over sodium sulfate, filtered, and the solvent was evaporated to afford 2-((3-bromobenzyl)(methyl)amino)-1-p-tolylethanone (4.89 g, 98%) as a viscous, orange oil: 1H NMR (CDCl3, 500 MHz) δ 7.85 (d, J=8.2 Hz, 2H), 7.51 (br s, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.28-7.23 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 3.78 (s, 2H), 3.63 (s, 2H), 2.41 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:20])[C:15]4[CH2:21][CH:22]5[NH:26][CH:25]([C:14]=4[C:13]=3[C:12]=2C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[CH2:21][CH:22]4[NH:26][CH:25]([C:14]3=2)[CH2:24][CH2:23]4)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(Cl)c4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4cccc(Cl)c4)ccc31)C1CCC(C2)N1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of example 28, step B. The crude material was purified by flash column chromatography (SiO2, 90:9:1 chloroform/methanol/ammonium hydroxide) then converted to the HCl salt to give 2-(3-chlorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (49 mg, 56%, AUC HPLC 95.7%) as an off white solid: mp 208-212° C.; 1H NMR (CD3OD, 300 MHz) δ 8.30 (d, J=1.8 Hz, 1H), 7.86-7.95 (m, 2H), 7.72-7.78 (m, 1H), 7.57-7.63 (m, 2H), 7.49-7.56 (m, 1H), 5.32 (d, J=4.8 Hz, 1H), 4.51-4.58 (m, 1H), 3.72 (s, 3H), 3.43-3.55 (m, 1H), 3.03-3.12 (m, 1H), 2.24-2.52 (m, 3H), 1.90-2.04 (m, 1H); APCI MS m/z 387 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([NH:19][C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:29]([C:30](=[O:31])[NH:32][CH3:33])=[CH:34][CH:35]=[CH:36][C:37]=4[F:38])[C:24]([Cl:39])=[CH:23][N:22]=3)=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCOC(=O)N1CCCOc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCOC)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 2-methoxy-ethyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (80 mg, 52%). LCMS (m/e) 545 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.95-8.73 (m, 1H), 8.09 (s, 1H), 7.41-7.15 (m, 4H), 7.14-6.87 (m, 3H), 6.30-6.13 (m, 1H), 4.40-4.18 (m, 2H), 4.13-3.97 (m, 2H), 3.82-3.61 (m, 2H), 3.57-3.39 (m, 3H), 3.34-3.22 (m, 2H), 2.97-2.86 (m, 3H), 2.13-2.00 (m, 2H).