Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1)[CH3:4].[H-].[Na+].F[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([N+:32]([O-:34])=[O:33])=[CH:24][CH:23]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.CO>[N+:32]([C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=2)[CH3:4])=[CH:23][CH:24]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: CC(CO)c1ccnc(NC(=O)OC(C)(C)C)c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=C([O-])O
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(COc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the alcohol (53) (0.62 g, 2.46 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.246 g, 6.14 mmol) in a single portion and the mixture sonicated under a flow of nitrogen and then stirred at RT for 30 min. The resulting yellow suspension was cooled to 0° C. and a solution of 1-fluoro-4-nitronaphthalene (14) (0.470 g, 2.457 mmol) in DMF (2 mL) was added over 10 min. The reaction mixture was warmed to RT and glacial acetic (1.0 mL) was added. The mixture was poured onto saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with saturated aqueous Na2CO3, solution, three times with water and twice with brine then dried (MgSO4) and evaporated in vacuo to give a yellow solid. The solid was suspended in MeOH (20 mL) and sonicated and the insoluble residue was collected by filtration and was washed with MeOH (10 mL) and then ether to afford the title compound (54) as an off white solid (0.73 g, 67%): m/z 424 (M+H)+ (ES+).
Reaction SMILES: C[Al](C)C.[NH3:5].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[N:14]1[C:19]2[N:20]=[C:21]([NH:32][CH2:33][C:34](OC)=[O:35])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[C:18]=2[CH:17]=[CH:16][C:15]1=[O:38]>ClCCl.CCOC(C)=O>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[C:8]=1[N:14]1[C:19]2[N:20]=[C:21]([NH:32][CH2:33][C:34]([NH2:5])=[O:35])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[C:18]=2[CH:17]=[CH:16][C:15]1=[O:38]
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: N
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1nc(NCC(N)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 16 h
Yield: 54 %

Procedure:
To a soln of trimethylaluminum (3.3 mL, 6.6 mmol) in dichloromethane was bubbled NH3 gas for 30 min, the product of Example 190 (500 mg, 1.1 mmol) was then added. The resulting mixture was stirred for 16 h. The mixture was diluted with EtOAc and washed with H2O to give the crude material. Purification by flash chromatography, eluting with EtOAc/triethylamine (100/2, v/v), gave the desired product (263 mg, 54%). LC-MS: 440.0 (MH+, m/z), 1.75 (Rt, min).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](Br)=[CH:8][S:7][CH:6]=1)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.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>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:9]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][S:7][CH:8]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1cscc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cscc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 53.8 %

Procedure:
A solution of 4-bromothiophene-3-carboxylic acid methyl ester (500 mg, 2.3 mmol, 1.0 eq.) in THF (40 mL) was combined with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.7 g, 2.3 mmol, 1 eq.) under nitrogen. A solution of Na2CO3 (960 mg) in water (4.5 mL) was added, followed by the addition of PdCl2(PPh3)2 (80 mg, 0.1 mmol, 0.4 eq.). The resulting solution was stirred for 18 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (50 mL), then washed with saturated aqueous NaCl (2×100 mL). The organic layer was concentrated and the residue was applied onto a silica gel column and eluted with EtOAc/PE (1:30) to yield 4-(4-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.4 g) as a light yellow oil.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12](Br)=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[CH2:15]([O:17]/[CH:18]=[CH:19]\[Sn](CCCC)(CCCC)CCCC)[CH3:16]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([NH:6][C:7]3[C:12](/[CH:16]=[CH:15]\[O:17][CH2:18][CH3:19])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: Clc1ncc(Br)c(NC23CC(C2)C3)n1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCO/C=C\c1cnc(Cl)nc1NC12CC(C1)C2
Temperature: 110 °C
Yield: 77 %

Procedure:
To a stirred solution of Bicyclo[1.1.1]pent-1-yl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine (Preparation 280, 2 g, 7.29 mmol) in dry toluene (70 mL) was added (Z)-1-ethoxy-2-(tributylstannyl)ethene (2.7 mL, 8.03 mmol). The reaction mixture was purged with N2 for min and then Pd(PPh3)4 (421 mg, 0.36 mmol) was added, followed by degassing for another 20 min and heating to 110° C. under N2 overnight. The reaction was cooled to room temperature, quenched with a 2M solution of KF and filtered through a pad of Celite. The filtrate was partitioned between water (50 mL) and EtOAc (200 mL). The organic phase was washed with brine (2×25 mL), dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (EtOAc: Hexane 18: 82) to afford the title compound as a pale green solid in 77% yield, 1.5 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:44])[C:34]2[C:14]([CH:15]=[C:16]3[CH:33]=[C:32]4[C:19]([C:20]5[C:25]([C:26]6[C:31]4=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:18][C:17]3=2)=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+].CCO>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:13]=[C:14]3[C:34]([C:10]([CH3:44])([CH3:9])[CH:11]=2)=[C:17]2[C:16]([CH:33]=[C:32]4[C:19](=[CH:18]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]4=2)=[CH:15]3)=[CH:3][CH:4]=1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2ccc(Br)cc2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 52.9 %

Procedure:
A mixture of 6.6 g (28 mmol) of 1,4-dibromobenzene, 15.1 g (32 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetra methyl-1,3,2-dioxaborolane, 0.32 g (0.28 mmol) of tetrakis(triphenylphosphine) palladium, 22 ml of 2M Na2CO3, 60 ml of EtOH and 130 ml toluene was degassed and placed under nitrogen and then heated at 90° C. for 12 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 7.4 g (53%) as a white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]1.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C1COCC1>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:9]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]2)=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccc(Br)cc2)CCC1
Temperature: -40 °C

Procedure:
To a solution of LDA (1.2 eq) in THF at −78° C. was added ethyl cyclobutanecarboxylate (1 eq) and reaction mixture was warmed up to −40° C. for 10 min. The reaction was cooled back to −78° C. for 1 h, then 4-bromobenzyl bromide (1.1 eq) was added as a solid to the mixture. The reaction mixture was warmed to 0° C. in an ice bath. The reaction was quenched with a saturated solution of NH4Cl and extract 3× with ethyl acetate, dried with MgSO4 and evaporated to dryness. Flash chromatography with 95:5 hexanes:ethyl acetate afforded ethyl 1-(4-bromobenzyl)cyclobutanecarboxylate.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[N:8]([C:9](=[C:26]([CH3:28])[CH3:27])[C:10]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:29])[C@@H:6]1[NH:30][C:31](=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]#[CH:3].[OH2:40]>CO.S(=O)(=O)(O)O.C(OCC)(=O)C>[CH2:1]([O:4][C@H:5]1[N:8]([C:9](=[C:26]([CH3:28])[CH3:27])[C:10]([O:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:11])[C:7](=[O:29])[C@@H:6]1[NH:30][C:31](=[O:39])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:2]([CH3:3])=[O:40]
Reactant: C#CCO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=C(C)C
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=C(C)C

Procedure:
To a solution of diphenylmethyl α-[4(R)-propargyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]-α-isopropylideneacetate (2.236 g; 4.28 mmole) in methanol (20 ml) is added water (2 ml). To this solution is added a saturated solution of mercuric sulfate in 10% sulfuric acid (0.8 ml), and the mixture is refluxed for 30 minutes. The reaction mixture is cooled, diluted with ethyl acetate, and washed with water. The ethyl acetate layer is dried over sodium sulfate, and concentrated under reduced pressure. Purification of the residue by chromatography over silica gel containing 10% water (100 g) using a mixture of benzene and ethyl acetate (2:1) as eluting solvent gives the product.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33](N3CCCC3)=[CH:32][CH:31]=2)[CH2:24]1)(=O)=O.[Cl-].[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[N:25]1([C:34]2[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=2)[CH2:29][CH2:28][N:25]2[CH2:24][CH2:23][C@@H:27]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:26]2)[CH2:26][CH2:27][CH2:23][CH2:24]1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (132 mg, 3.3 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (10 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (600 mg, 3.0 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 30 minutes. A solution of (S)-3-methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine (340 mg, 1.0 mmol) in dimethyl sulfoxide (5 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 42 hours. The reaction mixture was distributed into saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(3-pyrrolidinophenethyl)pyrrolidin-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (225 mg, 51%).
Reaction SMILES: C1(C)C=CC=CC=1.CS(O[CH2:13][C:14]1[S:22][C:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:16]=2[CH:15]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[N:36]1([CH2:13][C:14]2[S:22][C:21]3[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:16]=3[CH:15]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCCC3)cc2C1
Temperature: 25 °C
Yield: 35 %

Procedure:
To a toluene solution (30 ml) of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) was added potassium carbonate (26.5 mmol) and pyrrolidine (6.36 mmol) and the resulting reaction mixture was refluxed for 16 h. It was cooled to 25° C., diluted with ethyl acetate and the organic layer was successively washed with water and brine. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure to give the crude product which was purified by column chromatography (5% methanol in dichloromethane). Yield: 35%.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH:12]2[O:13][CH2:14][CH:15]([NH2:16])[CH:11]2[O:10][CH2:9]1.[ClH:17]>C(Cl)Cl.CCOC(C)=O>[ClH:17].[NH2:16][CH:15]1[CH:11]2[O:10][CH2:9][CH:8]([OH:7])[CH:12]2[O:13][CH2:14]1
Reactant: NC1COC2C(OC3CCCCO3)COC12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC1COC2C(O)COC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-amine (2.8 g, 12.2 mmol) in DCM (50 mL) was added a solution of HCl in EtOAc (15 mL, 3.8M), and the mixture was stirred at rt overnight and concentrated in vacuo. The residue was washed with DCM (50 mL), and then dried in vacuo at 60° C. overnight to give the crude product as a brown solid (3.3 g, not pure).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[C:8]([C:17]([NH2:19])=[O:18])[CH:9]=[CH:10][C:11]=3[Br:16])[NH:6][C:5]=2[CH2:4]1.[Br:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1.C(Cl)Cl>[Br:16][C:11]1[CH:10]=[CH:9][C:8]([C:17]([NH2:19])=[O:18])=[C:7]2[C:12]=1[C:13]1[CH2:14][CH2:15][CH:3]([CH2:2][NH:1][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Br:20])[CH2:4][C:5]=1[NH:6]2
Reactant: O=C(Cl)CCCBr
Reactant: NCC1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CNC(=O)CCCBr)CC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.1 %

Procedure:
Step 4 A suspension of 2-(aminomethyl)-5-bromo-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (130 mg, 0.403 mmol) and TEA (0.067 mL, 0.484 mmol) in THF (2 mL) was treated with 4-bromobutanoyl chloride (74.8 mg, 0.403 mmol). The mixture was stirred at rt for 20 min, diluted with DCM, washed with NaHCO3 (aq), dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc) to provide 5-bromo-2-((4-bromobutanamido)methyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a white solid (80 mg, 42%). Mass spectrum m/z 470, 472, 474 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:29])=[O:28])[CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[O:25][CH3:26].Cl[CH2:46][C:47](Cl)=[O:48].O>CN(C=O)C>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[N:14]1[C:47](=[O:48])[CH2:46][O:7][C:8]2[CH:9]=[C:10]([S:27]([N:30]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:29])=[O:28])[CH:11]=[CH:12][C:13]1=2
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Nc3ccc(C(F)(F)F)cc3OC)c(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(=O)N3c2ccc(C(F)(F)F)cc2OC)cc1

Procedure:
In a 10-mL round bottom flask under N2 was dissolved cesium carbonate (807 mg, 2.48 mmol) and 3-hydroxy-4-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (350 mg, 0.619 mmol) in 4 mL of DMF followed by a slow addition of chloroacetyl chloride (0.099 mL, 1.24 mmol) at rt. After 1 h the reaction mixture was neutralized with H2O and ice and the product 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was collected as a solid and dried under reduced pressure and used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([C:31]([NH:1][C:2]2[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[C:17]([F:19])[CH:18]=3)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=2)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(F)c2)nc(N)n1
Reactant: O=C(Cl)C1CCC1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(F)c2)nc(NC(=O)C2CCC2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-6-methylpyrimidine-4-carboxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and cyclobutanecarbonyl chloride (13 mg, 0.1 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(OC)ccc2C1=O
Yield: 31 %

Procedure:
A solution of 50.0 g of 5-methoxy-1-indanone, 80 ml of 3-buten-2-ol, 132 ml of 2,2-dimethoxypropane and 600 mg of p-toluenesulfonic acid in 500 ml of toluene was brought to boiling. The resulting methanol/acetone mixture was distilled off and the reaction solution was subsequently boiled under reflux for an additional 48 hours. After cooling, the solution was evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 5:1) yielded 19.2 g (31%) of (RS)-2-(2-buten-1-yl)-5-methoxy-1-indanone as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C@@H:6]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.[OH-].[Li+]>C1COCC1>[CH2:25]([C@H:6]1[CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:9][CH2:10][N:5]1[CH2:4][C:3]([OH:32])=[O:2])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid methyl ester (Example 57) (342 mg, 0.78 mmol) in THF (5 mL) at room temperature was treated with an aqueous solution (1 mL) containing lithium hydroxide monohydrate (36 mg, 0.858 mmol). The reaction mixture was allowed to stir for 2 h and then evaporated to a small volume. The reaction mixture was then dissolved in water (5 mL) and the pH adjusted to ˜7 with 1 N HCl to precipitate product. The precipitate was then triturated with water (2×5 mL) and dried under a stream of nitrogen to afford product as a colorless solid (318 mg, 96%). 1H NMR (CDCl3) 1.43-1.57 (m, 2 H), 1.77-1.79 (m, 6 H), 3.02-3.15 (m, 2 H), 3.27 (br s, 2 H), 3.51 (br s, 1 H), 3.74 (s, 3 H), 3.77-3.89 (m, 2 H), 4.57-4.59 (m, 1 H), 6.24-6.31 (m, 2 H), 6.55 (br s, OH), 6.67 (d, J=8.6, 1 H)7.18-7.27 (m, 5 H). LC/MS 5.34 min, [M+1]+ 425.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:4](=[O:5])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[F:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cc(F)ccc2F)sc1C(=O)NCc1ccccc1
Yield: 86 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2,5-difluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 86% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.63 (t, J=5.8 Hz, 1H), 7.60-7.17 (m, 8H), 4.36 (d, J=5.8 Hz, 2H), 2.51 (s, 3H); MS (ES+) m/z 388.2 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:11]/[C:12]1[C:19]([Cl:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[Cl:21])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:21][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:20])[C:12]=1[N:11]1[CH:10]=[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]2=[N:1]1)[C:16]#[N:17]
Reactant: N#Cc1cc(Cl)c(/N=C/c2cnccc2N=[N+]=[N-])c(Cl)c1
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)c(-n2cc3cnccc3n2)c(Cl)c1
Temperature: 105 °C
Yield: 66.3 %

Procedure:
A mixture of 4-{[1-(4-azidopyridin-3-yl)meth-(E)-ylidene]amino}-3,5-dichlorobenzonitrile (21.4 mmol) in toluene (80 mL) was heated to 105° C. for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (4.10 g, 66% yield). 1H NMR (300 MHz, CDCl3): δ 9.36 (d, J=1.4 Hz, 1H), 8.39 (d, J=6.5 Hz, 1H), 8.35 (d, J=1.0 Hz, 1H), 7.85 (s, 2H), 7.68-7.66 (m, 1H). LCMS (Method D): RT=1.66 min, m/z: 289 [M+H+].