Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=[C:14]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:18]([C:17]3[S:13][C:14]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:16]=3)=[O:19])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(-c2cccs2)s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2cccs2)s1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2,2′-bithiophene-5-carboxylic acid (Acros) according to methods A and C; yield 105 mg, 0.27 mmol (76%): 1H NMR (300 MHz, methanol-d4) δ 1.97 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.32 (d, J=14 Hz, 2H), 2.47 (s, 2H), 3.56 (s, 2H), 3.66 (s, 4H), 4.37 (s, 1H), 7.08 (dd, J=5, 4 Hz, 1H), 7.24 (d, J=4 Hz, 1H), 7.35 (dd, J=4, 1 Hz, 1H), 7.43 (dd, J=5, 1 Hz, 1 H), 7.78 (d, J=4 Hz, 1H); MS (DCI/NH3) m/z 345 (M+H)+; Anal. C18H20N2OS2.HCl: C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Br:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[C:26]([N:27]=[C:28]=[S:29])=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C=O)C.ClCCl>[ClH:20].[Br:19][C:5]1[CH:6]=[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[C:2]([NH:1][C:28]2[S:29][C:21]3[C:26]([N:27]=2)=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:3][CH:4]=1
Reactant: S=C=Nc1cccnc1Cl
Reactant: COC(=O)c1ccc(Sc2cc(Br)cnc2N)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Sc2cc(Br)cnc2Nc2nc3cccnc3s2)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
Added methyl 4-(2-amino-5-bromopyridin-3-ylthio)benzoate (1.00 g, 2.95 mmol) to a mixture of 2-chloro-3-isothiocyanatopyridine (0.503 g, 2.95 mmol) in DMF (4 mL). Stirred at 80° C. for an hour, then at 110° C. for 2 hours. Cooled, diluted with dichloromethane (8 mL), filtered, washed with dichloromethane, and dried to afford the title compound (0.625 g, 41.6% yield). 1H NMR (d6-DMSO) δ 3.84 (s, 3H), 7.40 (dd, 1H), 7.45 (d, 2H), 7.72 (d, 1H), 7.79 (bs, 1H), 7.96 (d, 2H), 8.34 (d, 1H), 8.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:19]Br.C1(C)C=CC=CC=1>C(O)(=O)C>[Br:19][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: BrBr
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen purge, a suspension or 2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.6 g; 0.005 mol) in acetic acid (25 mL) is heated, all the material dissolving to a clear solution at about 60° C. A solution of bromine (0.8 mL; 0.015 mol) in acetic acid (10 mL) is added dropwise over 15 minutes to the refluxing solution. The solution is refluxed 6 hours then allowed to stir 18 hours at room temperature. The HPLC of the reaction mixture shows about 80% conversion to product. The mixture is heated back to reflux and more bromine (0.5 mL; 0.01 mol) in acetic acid (5 mL) is added dropwise. After refluxing another 3 hours, the aliquot shows >95% conversion to product. The reaction is cooled, and solvent removed under reduced pressure on a rotary evaporator to obtain a dark grey solid. Toluene is added to the mixture and removed under reduced pressure, but the odor of acetic acid still remains. The entire material is dissolved in hot toluene (75 mL) to a turbid solution which is treated with DARCO filter and filtered. The light pink solution deposits a white solid upon cooling to ambient. After cooling in the freezer, the solid is collected by filtration, washed with hexanes, and dried on the filter. Further drying in a vacuum oven at 45° C. provides the product (1.2 g; app. 60% theoretical); m.p. 247°-250° C.(dec.)
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:17](=[O:18])[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1)[CH3:3].[I:19][CH3:20]>>[I-:19].[CH3:3][N+:2]([CH3:20])([CH3:1])[CH2:4][CH:5]1[C:17](=[O:18])[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1
Reactant: CI
Reactant: CN(C)CC1CCc2[nH]c3ccccc3c2C1=O
Product: C[N+](C)(C)CC1CCc2[nH]c3ccccc3c2C1=O
Product: [I-]

Procedure:
A solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.53 g) in iodomethane (15 ml) was heated under reflux for 5 h and evaporated to dryness, giving the title compound as a white solid (0.84 g) m.p. 202°-205°.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>>[O:17]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH:12][C:30](=[O:31])[O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 45 °C

Procedure:
To a 400 L glass-lined reactor containing the 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluoroaniline/tetrahydrofuran solutions (Step 3, 12.6 kg, 48 moles, 1.0 eq) was added 47% potassium carbonate solution (14.1 kg, 48 moles, 1.0 eq). The mixture was heated to approximately 45° C., and isobutyl chloroformate (7.2 kg, 53 moles, 1.1 eq) was added while maintaining a reaction temperature between 45° C. and 55° C. The reaction was stirred at 45°-55° C. Once deemed complete, the reaction was quenched by slowly adding water (45 L) over 15 minutes. The reaction mixture was cooled to 25° C. and the phases are separated. The tetrahydrofuran solution was swapped to an isopropanol (150 L)/water (50 L) suspension, and the slurry was slowly cooled to 5° C. The yellow slurry was then filtered and the cake washed with cold isopropanol (2×30 L). The yellow solids are dried with 60° C. nitrogen to give the title compound, 1H NMR (CDCl3) (δ): 7.02 (m, 2H), 6.81 (s, 1H), 3.95 (d, 2H), 3.60 (m, 4H), 3.17 (m, 4H), 1.97 (m, 1H), 0.94 (d, 6H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[C:10]=1[C:16]([O:18][CH3:19])=[O:17].CCOCC>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[C:10]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1=C(OC)CCC1CO
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(OC)CCC1C=O
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
25.5 g of chromic oxide were added in small fractions at 15° to 20° C to a solution of 41 ml of pyridine in 400ml of anhydrous methylene chloride and the mixture was stirred for 15 minutes. The mixture was cooled to -15° C and a solution of 4.3 g of the product of Step A in 10 ml of methylene chloride was added thereto. After 11/2 hours, 50 g of celite and 100 ml of ether were added thereto and the mixture was filtered. The filtrate was washed with ether and the filtrate was evaporated to dryness at 30° C to obtain methyl (5RS) 2-methoxy-5-formyl-1-cyclopentenecarboxylate.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[N:16][C:15]([Br:30])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C(Cl)Cl.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:30][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:19]3[CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=[CH:23][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCCCCCCC(=O)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 85 °C
Yield: 1040 %

Procedure:
1,2-Dichloroethane (14 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(4-morpholinophenyl)isonicotinate (4.66 g, 11 1 mmol), rhodium octanoate dimer (0.521 g, 0.669 mmol) and crushed 4A° molecular sieves (4.66 g) and this was heated at 85° C. for 26 hr. It was diluted with DCM, filtered, and the solid was washed with multiple portions of DCM. The solvent was removed from the combined filtrate and the residue was suspended in MeOH. The solid was collected by filtration, washed with MeOH, and dried to leave methyl 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxylate (4.05 g, 10.4 mmol, 93% yield) as a yellow solid. MS (ESI) m/z 390.11 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.43 (1H, br. s.), 8.20 (1H, d, J=8.85 Hz), 7.86 (1H, s), 7.00 (1H, dd, J=8.70, 1.68 Hz), 6.89 (1H, s), 4.06 (3H, s), 3.91-3.96 (4H, m), 3.32-3.37 (4H, m).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(O[CH:10]1[C@H:15]([N:16]=[C:17]=[S:18])[C@@H:14]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:23][C:24](=[O:26])[CH3:25])[C@@H:12]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:11]1)(=O)C.C(N(CC)CC)C>ClCCl>[C:24]([O:23][C@@H:13]1[C@@H:12]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:11][C@H:10]2[C@H:15]([N:16]=[C:17]([N:2]3[CH2:5][CH2:4][CH2:3]3)[S:18]2)[C@H:14]1[O:19][C:20](=[O:22])[CH3:21])(=[O:26])[CH3:25]
Reactant: C1CNC1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of azetidine hydrochloride (12 g, 129 mmol) and (3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (48 g, 123 mmol) in dichloromethane (500 mL) was treated with triethylamine (18.7 g, 185 mmol) for 1 h at room temperature, and followed by addition oftrifluoroacetic acid (56.2 g, 493 mmol). The reaction mixture was stirred overnight at room temperature, and then quenched by aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous MgSO4, and condensed under vacuum to give a residue, which was purified by a silica gel column, eluted with 1% methanol in dichloromethane to provide compound 2 as a light yellow syrup (29 g, 61%). (ES, m/z) [M+H]+ 386.9; 1H NMR (300 MHz, CDCl3) 6.28-6.30 (d, J=6.6 Hz, 1H), 5.44-5.46 (m, 1H), 4.95-4.99 (m, 1H), 4.34-4.37 (t, J=5.4 Hz, 1H), 4.04-4.17 (m, 6H), 3.86-3.92 (m, 1H), 2.34-2.44 (m, 2H), 2.06-2.14 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22](O)=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:52][O:53][C:54](=[O:59])[C@H:55]([CH2:57][OH:58])[NH2:56].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:21]=[C:20]([C:22]([NH:56][C@@H:55]([CH2:57][OH:58])[C:54]([O:53][CH3:52])=[O:59])=[O:23])[O:19][N:18]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)Nc1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.7 %

Procedure:
3-(4-(3-(2-fluorophenyl)ureido)phenyl)isoxazole-5-carboxylic acid (example 105, step 2, 1 g, 293 mmol) was dissolved in DMF (20 ml) and, to it N,N′-Dicyclohexyl carbodiimide (724 mg, 3.51 mmol) and 1-Hydroxy benzotriazole (593 mg, 4.39 mmol) were added. Reaction mixture was stirred RT for 10 minutes followed by the addition of L-serine methyl ester hydrochloride (683 mg, 4.39 mmol) dissolved in DMF (5 ml) neutralized with triethylamine (0.6 ml, 4.39 mmol). The above reaction mixture was stirred at RT for 8 hours. DMF was distilled off under reduced pressure to give pale brown solid, which was taken in THF. DCU precipitated out and was filtered off. Water was added and the aqueous layer was extracted with EtOAc. Organic layer was dried over Na2SO4 and concentrated under vacuum. Crude compound was purified through precipitation using DCM and petroleum ether to yield 500 mg (39%) of the required compound as white solid. MS: ES (−): m/z 441(M−1); ES (+): m/z 443 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 9.342 (s, 1H), 9.109 (d; 1H), 8.633 (s, 1H), 8.161 (t, 1H), 7.369 (d, 2H), 7.676 (s, 1H), 7.619 (d, 2H), 7.242 (m, 1H), 7.066 (t, 1H), 7.024 (m, 1H), 5.149 (t, 1H), 4.575 (m, 1H), 3.821 (t, 2H), 3.657 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([CH3:14])[C@H:12]([OH:15])[C:11]([F:17])([F:16])[C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1I.O.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([CH3:14])[C@H:12]([OH:15])[C:11]([F:17])([F:16])[C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[C:20]#[N:21]
Reactant: CN(C)C=O
Reactant: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1ccc(I)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of (4S,5S)-1-(3-chloro-4-iodophenyl)-3,3-difluoro-4-hydroxy-5-methylpyrrolidin-2-one (113 mg) in DMF (3.5 mL) were added zinc cyanide (12 mg) and tetrakis(triphenylphosphine)palladium(0) (34 mg), and the mixture was stirred at 100° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=30/1→1/2) to give the title compound as a colorless solid (yield: 75 mg, 90%).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([CH3:11])=[O:10]>>[CH3:11][C:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:8].[CH3:8][C:9]([OH:10])([CH3:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: Oc1ccccc1
Product: C=C(C)c1ccccc1
Product: CC(C)(O)c1ccccc1

Procedure:
Substantial quantities of α-methyl styrene (AMS) are produced as a byproduct in the cumene-phenol peroxidation process. Purified cumene is oxidized to form cumene hydroperoxide (CHP) which is then cleaved to phenol and acetone. A small amount of AMS is produced as a byproduct from the decomposition of dimethylbenzyl alcohol which is also formed with CHP in the oxidation step. The AMS can either be recovered as a byproduct or hydrogenated to cumene and recycled to the phenol process. Since the market for AMS is limited, hydrogenation to cumene is the usual option. The typical composition of the cumene/AMS stream is 5 to 80% AMS with trace amounts of methyl benzofuran, mesityl oxide and acetophenone.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([N:12]=[C:13]=[O:14])[CH2:4][CH2:3]1.[OH-].[NH4+:16]>O1CCCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:16])=[O:14])[CH2:4][CH2:3]1
Reactant: [NH4+]
Reactant: O=C=NC1CCC(=O)c2ccccc21
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
A solution of 1,2,3,4-Tetrahydro-4-oxo-1-naphthylisocyanate (5.0 g) in tetrahydrofuran is added to a rapidly stirred aqueous concentrated ammonium hydroxide solution (excess) to afford 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea.
Reaction SMILES: C([O:5][C:6]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:28]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)O)[CH:12]=2)[N:7]=1)(C)(C)C.O.O.[Sn](Cl)Cl.Cl>CC(O)=O>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:28]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:5])[CH:15]=[C:14]3[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:19][CH:18]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(C)Oc1cc(Cc2ccc(OC(F)(F)F)cc2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(Cc2ccc(OC(F)(F)F)cc2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Temperature: 110 °C

Procedure:
(2-(tert-Butoxy)-4-(4-(trifluoromethoxy)benzyl)quinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol (55 mg, 0.0918 mmol) and tin(II) chloride dihydrate (83 mg, 0.367 mmol) were combined in AcOH (2 mL). HCl (conc. 36%, 0.115 mL) was then added. The solution was heated to 110° C. After 45 min the reaction was cooled to room temperature and concentrated. The residue was taken up in CH2Cl2 and washed with NaHCO3 (satd), dried (Na2SO4) and concentrated. The resulting residue was purified by silica column (70-80% EtOAc/hexanes) chromatography to yield 6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-(4-(trifluoromethoxy)benzyl)quinolin-2(1H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([NH:14][NH2:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)#[N:17].C[O-].[Na+].CO>C(OCCO)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)NN)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(c2n[nH]c(-c3ccccn3)n2)C1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
3-hydrazinocarbonyl-azetidine-1-carboxylic acid tert-butyl ester (2.74 g, 12.73 mmol) and 2-cyano-pyridine (1.45 g, 13.95 mmol) were dissolved in 2-ethoxyethanol (30 mL) and a 30 wt % solution of NaOMe in MeOH (1.19 mL, 6.38 mmol) was added. The resulting mixture was heated to 130° C. and stirred overnight. On cooling the mixture was neutralised by the addition of acetic acid and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase was dried (Na2SO4) and concentrated in vacuo to give a yellow solid. Further purification was achieved by trituration with diethyl ether followed by recrystallisation from MeOH.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)cccc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2c(Cl)cccc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, m.p.: 115-119° C., ISP-MS: m/e=381.3 (M+H+) and aD20=−8.0, was prepared in accordance with the general method of example 12b) from 4-chloro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)[nH]c1ccccc12

Procedure:
2-Nitrocarbazole [Meridenhall, G. D.; Smith, P. A. S. Org. Syn. Coll. Vol. 5 1973, 829, the disclosure of which is herein incorporated by reference](structure 14 of Scheme IV, where R1 -6 =H, X=NH) (1.0 g, 4.7 mmol) in 50 mL of ethyl acetate was hydrogenated over 10% Pd/C (50 mg) under an atmosphere of hydrogen for 1.5 h at rt giving, after filtration through Celite™, 840 mg (100%) of 2-aminocarbazole. Data for 2-aminocarbazole: 1 H NMR (400 MHz, CDCl3) 7.94 (d, J=9.0, 1H), 7.83 (d, J=8.0, 1H), 7.80 (br s, 1H), 7.35 (m, 2H), 7.15 (dd, J=8.2, 1H), 6.67 (d, J=1.8, 1H), 6.58 (dd, J=9.0, 1.8, 1H), 3.73 (br s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1)([CH3:18])[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH:21]1[CH2:22][CH2:23][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(O)cc2[nH]1
Reactant: CC(C)N1CCC(O)C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(OC3CCN(C(C)C)C3)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
A mixture of 1 g (4.8 mmol) ethyl-6-hydroxyindole-2-carboxylate (Journal of the American Chemical Society (1967), 89(13), 3349-50), 0.81 g (6.3 mmol) 1-isopropyl-3-pyrrolidinol, 2.83 ml (11 mmol) tri-n-butyl-phosphine and 2.56 g (9.75 mmol) 1,1′azodicarbonyl-dipiperidine in 50 ml THF was stirred at room temperature for 16 h. The suspension was filtered and the filtrated evaporated to dryness. The residue was purified with column chromatography on silica eluting with a gradient from DCM/2N NH3 in MeOH 99/1 to 19/1. The product containing fractions were combined and evaporated to dryness to yield a brown oil which was crystallized from diethyl ether and heptane to afford 0.5 g of brownish crystals (MS (m/e): 317.1 (MH+, 100%)). and after evaporation of the filtrate 0.6 g of slightly impure product which was used without further purification in the consecutive step.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: O=C(O)c1ccccc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1ccccc1
Yield: 48.1 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and benzoic acid (40 mg, 0.33 mmol) as starting materials. The title compound (60 mg, 43.5%) was isolated as off white solid; MS (ESI): 379 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:10][C:11]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[OH:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C:11]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH2:10]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: C=C(c1cc(F)ccc1O)n1ccnc1
Yield: 18.2 %

Procedure:
Thionyl chloride (17.8 g, 0.15 mole) was added dropwise over 30 minutes to 1H-imidazole (41.1 g, 0.60 mole) in dried methylene chloride (200 ml) with stirring and ice-cooling. After stirring for additional 30 minutes, 2-hydroxy-5-fluoroacetophenone (15.4 g, 0.10 mole) in dried methylene chloride (50 ml) was added dropwise over 30 minutes. After stirring for 1 hour, methylene chloride (200 ml), water (400 ml) and an aqueous saturated solution of sodium bicarbonate (200 ml) were added to the reaction mixture and the mixture was stirred for 5 minutes. Then, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate to obtain the title compound (3.71 g, 18.2%), m.p. 164°-166° C.