Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][Cl:35])=[O:32]>ClCCl>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]([C:31]([O:33][CH2:34][Cl:35])=[O:32])[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[C:4]2[CH:3]=1
Reactant: O=C(Cl)OCCl
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(s1)=Nc1ccccc1N(C(=O)OCCl)C=2N1CCN(C)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of olanzapine (18.0 g, 57.7 mmol) and triethylamine (16 mL, 0.12 mol) in dichloromethane (250 mL) was warmed to 35° C. and once a clear solution formed, the reaction was cooled to 5° C. To this was added chloromethyl chloroformate (7.6 mL, 86.5 mmol) over 20 minutes. The reaction was stirred at room temperature for 30 min and allowed to warm to room temperature. After 15 min at room temperature the reaction mixture was diluted with dichloromethane (100 mL), then washed with aq satd NaHCO3 (75 mL) and water (350 mL). The organic phase was dried over MgSO4 and filtered. The organic phase was then concentrated under vacuum at 45° C. to a volume of −150 mL. The mixture was diluted with ethyl acetate (30 mL) and ˜20-30 mL further was evaporated under vacuum. The mixture was cooled to room temperature and the resulting solid precipitate filtered and washed with ethyl acetate. After drying under vacuum at 35° C. for 90 min chloromethyl 2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate [A] (17.1 g, 73%) was obtained as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ 7.62-7.14 (4H, m), 6.27-6.22 (1H, m), 5.84-5.69 (1H, m), 5.47-5.23 (1H, m), 3.89-3.63 (4H, m), 2.66-2.22 (10H, m).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([N:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[O:9][C:10]([F:11])([F:12])[F:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)Oc1cc(Br)ccc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
To a mixture of 4-bromo-2-(trifluoromethoxy)aniline (5 g, 19.53 mmol) and potassium carbonate (8.09 g, 58.89 mmol) in acetonitrile (200 mL) was added (bromomethyl)benzene (6.96 mL, 58.59 mmol) and the mixture was refluxed for 20 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 5/1 petroleum ether/ethyl acetate to give the title compound. MS: 436 (M+H+)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:20]([S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 52.6 %

Procedure:
A mixture of 4,5-diphenyl-2-imidazolethiol (2.5 g), 8-bromooctane (3.8 g), anhydrous potassium carbonate (13.7 g) and dry butanone (60 ml) was stirred at reflux for 2 h. The cooled reaction mixture was filtered to remove solid and the filtrate was evaporated to dryness. The residue was mixed with hexane and the resulting precipitate was collected by filtration. Recrystallisation from ethanol and water gave 2-octylthio-4,5-diphenylimidazole (1.9 g, 53%) as a white solid, m.p. 133°-4°.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:22]=[CH:21][C:20]([C:23]([C:25]3[N:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]4=[C:27]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([O:42]C)=[O:41])[CH:35]=4)[N:26]=3)=[O:24])=[CH:19][C:14]=2[C:15](OC)=[O:16])=[O:11])=[CH:6][CH:5]=1.Cl>CO.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C:14]3[C:13](=[CH:22][CH:21]=[C:20]([C:23]([C:25]4[N:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]5=[C:27]([C:34]5[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=5)[C:40]([OH:42])=[O:41])[N:26]=4)=[O:24])[CH:19]=3)[NH:12][C:10]2=[O:11])=[CH:44][CH:45]=1
Reactant: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(NC(=O)NCc4ccc(F)cc4)c(C(=O)OC)c3)n3ccccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2nc(C(=O)c3ccc4[nH]c(=O)n(Cc5ccc(F)cc5)c(=O)c4c3)n3ccccc23)c1
Yield: 98.8 %

Procedure:
2.85 ml (0.0285 mol) of a 1N aqueous solution of sodium hydroxide are added to 3.3 g (5.7 mmol) of methyl 2-{[(4-fluorobenzyl)carbamoyl]amino}-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate dissolved in 250 ml of methanol. After refluxing for 2 hours, the reaction medium is acidified with 50 ml of a 1N aqueous solution of hydrochloric acid and then diluted with 700 ml of water. The precipitate obtained is filtered off, and dried under reduced pressure at 40° C. overnight. 3.01 g of a yellow solid are obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[OH:14])[CH3:2].[Br:15][CH2:16][CH2:17][CH2:18]O.C(P(CCCC)CCCC)CCC.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C1(C)C=CC=CC=1>[Br:15][CH2:16][CH2:17][CH2:18][O:14][C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([F:10])=[CH:9][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1cc(F)c([N+](=O)[O-])cc1O
Reactant: OCCCBr
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNc1cc(F)c([N+](=O)[O-])cc1OCCCBr
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Ethylamino-4-fluoro-5-nitro-phenol (910 mg, 4.5 mmol) was azeotroped with toluene to ensure dryness, then was dissolved in Tetrahydrofuran (100 mL) and was cooled at 0° C. 3-Bromo-1-propanol (0.65 mL, 7.2 mmol), Tributylphosphine (2.0 mL, 8.2 mmol), and 40% w/w DEAD in Toluene (3.8 g, 8.7 mmol) were added in succession, and the reaction was stirred under an atmosphere of Nitrogen overnight. The mixture was conc. in vacuo onto silica gel (10 g) and chromatographed (ISCO, 80 g silica gel, 0-35% EtOAc:Hex) to afford [2-(3-Bromo-propoxy)-5-fluoro-4-nitro-phenyl]-ethylamine as an orange solid. The bromide was dissolved in Tetrahydrofuran (100 mL) and Sodium hydride, 60% disp. in mineral oil (0.20 g) was added. After 2 h, no reaction was observed, so N,N-Dimethylformamide (5 mL) was added. After o.n. stirring, no reaction, so additional Sodium hydride, 60% disp. in mineral oil (0.35 g) was added and the mixture was heated at 65° C. After 4 h, the reaction was complete and was cooled to rt. The reaction was quenched with water, diluted with ether (300 mL) and washed with water (40 mL), satd. sodium bicarbonate (2×40 mL) and brine (80 mL), dried over sodium sulfate and conc. in vacuo onto 6 g silica gel. Chromatography (ISCO, 80 g silica gel, 0-30% EtOAc:Hex) afforded 9-Ethyl-2-fluoro-3-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange solid (517 mg, 47% two steps). 1H-NMR (CDCl3): 7.62 (d, 1H, J=7.9 Hz), 6.33 (d, 1H, J=14 Hz), 4.21 (t, 2H, J=6.5 Hz), 3.63 (t, 2H, J=5.8 Hz), 3.35 (q, 2H, J=7.0 Hz), 2.12 (m, 2H), 1.25 (t, 3H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([OH:52])[CH3:51]>[Na]>[CH2:50]([O:52][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[CH3:51]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCO
Agent: [Na]
Product: CCCn1c(=O)cc(OCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 69 %

Procedure:
6-Chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)-biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.8 g) was dissolved in a solution of sodium metal (69 mg) in ethanol (10 mL) and the mixture was heated under reflux for 14 hours with stirring. The reaction mixture was concentrated to dryness and the resulting residue was dissolved in methylene chloride-water. The solution was acidified with 1N hydrochloric acid (1.5 ml), extracted and the organic layer was separated. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give white amorphous powders (0.36 g, 69%). M.p. 108°-119° C.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH2:23]([N:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[C:28]([C:30]1[C:34]([Cl:35])=[C:33]([CH3:36])[NH:32][N:31]=1)=[O:29])[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[C:28]([C:30]1[C:34]([Cl:35])=[C:33]([CH3:36])[N:32]([C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][C:3]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:31]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1cc(C(=O)OCc2ccccc2)ccc1F
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1n[nH]c(C)c1Cl
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)OCC)c(C)c1Cl
Yield: 78328.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 1-benzyl 3-ethyl 4-fluoroisophthalate (Intermediate 91B, 270 mg, 0.89 mmol) and N-butyl-4-chloro-N-(3,4-dichlorobenzyl)-5-methyl-1H-pyrazole-3-carboxamide (Intermediate 179B, 502 mg, 1.34 mmol) were converted to the title compound (458 g, 78%). 1H NMR (CDCl3, mixture of amide rotamers) δ 8.68 (dd, J=19.3, 1.9 Hz, 1H), 8.33 (dt, J=7.9, 2.0 Hz, 1H), 7.54-7.34 (m, 8H), 7.24-7.07 (m, 1H), 5.43 (d, J=3.1 Hz, 2H), 4.79-4.63 (m, 2H), 4.19 (q, J=7.3 Hz, 1H), 3.94 (q, J=7.2 Hz, 1H), 3.48-3.33 (m, 2H), 2.16 (d, J=6.6 Hz, 3H), 1.68-1.46 (m, 2H), 1.41-1.31 (m, 1H), 1.25-1.14 (m, 2.5H), 1.09 (t, J=7.2 Hz, 1.5H), 0.96-0.88 (m, 1.5H), 0.79 (t, J=7.4 Hz, 1.5H); MS(ESI+) m/z 656.0 (M+H)+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[OH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH:18]=1
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccnc2)c(C(F)(F)F)c1

Procedure:
2 mmol of methyl 4-fluoro-3-trifluoromethylbenzoate, 2 mmol of 3-hydroxypyridine and 4 mmol of K2CO3 were stirred at 110° C. for 1.5 h in 15 ml of DMF (anhydrous). The mixture was then poured onto 100 ml of water and extracted 3 times using 50 ml of EA each time. It was dried over Na2SO4, the solvent was removed in vacuo and the product was reacted further without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][N:15]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH3:23])[NH:17][C:16]3=[C:12]2[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([N:8]1[C:13]2=[N:14][N:15]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH3:23])[N:17]([CH3:29])[C:16]3=[C:12]2[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1cn2nc3c(c(=O)n(CCC)c(=O)n3Cc3ccccc3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCc1cn2nc3c(c(=O)n(CCC)c(=O)n3Cc3ccccc3)c2n1C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
In DMF (20 ml) was dissolved 1-benzyl-6-butyl-3-propyl-1,2,3,4-tetrahydro-5H-imidazo [2',1':5,1]pyrazolo[3,4-d]pyrimidine-2,4-dione (0.5 g). To the solution were added, at room temperature, K2CO3 (0.5 g) and methyl iodide (0.5 g). The mixture was stirred for 8 hours and concentrated to dryness. To the residue was added water, then precipitating crystals were recrystallized from aqueous methanol to give colorless crystals (0.51 g, 98%), m.p. 139°-140° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[N:5]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C(=O)([O-])[O-].[K+].[K+]>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>[Cl:31][C:32]1[CH:33]=[C:34]([C:2]2[C:7]([CH3:8])=[C:6]([N:9]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10]3)[N:5]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:3]=2)[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: Cc1c(Cl)nc(N2CCOCC2)nc1N1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(F)c(Cl)c2)nc(N2CCOCC2)nc1N1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-(4-chloro-5-methyl-6-{4-[3-(trifluoromethyl)(2-pyridyl)]piperazinyl}pyrimidin-2-yl)morpholine (66 mg, 0.15 mmol), 3-chloro-4-fluorophenylboronic acid (35 mg, 0.2 mmol), Pd(PPh3)4 (10 mg) and 2M potassium carbonate (0.2 mL) in toluene (3 mL) is heated, under a nitrogen atmosphere, at 80° C. for 4 hours. The reaction mixture is cooled and the layers separated. The aqueous layer is extracted with EtOAc (3×10 mL) and the combined organics washed with 4M NaOH (10 mL), water (10 mL), brine (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (70% hexane/30% ether) to give the title compound. MS 537 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[NH:9][C:8]=2[C:22]([F:25])([F:24])[F:23])[CH:3]=1.[Br:26]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[NH:9][C:8]([C:22]([F:23])([F:24])[F:25])=[C:7]([C:4]3[C:3]([Br:26])=[C:2]([Br:1])[S:6][CH:5]=3)[C:11]=2[N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1csc(Br)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1csc(Br)c1Br

Procedure:
A solution of 3-(5-bromo-3-thienyl)-5-(p-chlorophenyl)-4-nitro-2-(trifluoromethyl)pyrrole (0.50 g, 1.1 mmol), bromine (0.20 g, 1.3 mmol) and sodium acetate (0.11 g, 1.3 mmol) in acetic acid (10 mL) is heated overnight at 50° C. and poured into water. The solids are collected and recrystallized from 1,2-dichloroethane to give the title product as a yellow solid, mp 241°-242° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCCN1CCCCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of N-3-aminopropylpiperidine (1.4 g, 10 mmol) in dichloromethane (20 mL) was added DIEA (1.9 mL, 11 mmol) followed by slow addition of 4-methoxy benzoyl chloride (1.9 g, 11 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was washed with 1 N KOH (aq.) (1×20 mL) and brine (1×20 mL). The organic phase was dried (K2CO3) and concentrated in vacuo to afford 4-methoxy-N-(3-piperidin-1-ylpropyl)benzamide (1.9 g, 6.9 mmol, 69%) as an oil.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[C:41]1([CH:47]([CH3:51])[CH2:48][CH:49]=O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOC(C)=O>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH:15]=[CH:49][CH2:48][CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:51])=[CH:7][CH:8]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(CC=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C=CCC(C)c1ccccc1
Reaction time: 0.25 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-triphenyl-phosphonium bromide (0.2678 g, 0.451 mmol) was dissolved in THF (2.7 mL) at 0° C. Potassium tert-butoxide (1 M in THF, 0.5 mL, 0.50 mmol) was added and after stirring 15 minutes 3-phenyl-butyraldehyde (0.074 mL, 0.50 mmol) was added and the ice bath was removed. After 15 minutes, analytical LCMS indicated complete reaction. Standard aqueous workup followed by silica gel chromatography (0-20% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][CH2:16][CH:17]([N:20]1[CH2:24][CH2:23][C@@H:22]([NH2:25])[CH2:21]1)[CH2:18][F:19].C(N(C(C)C)C(C)C)C>O1CCCC1>[F:19][CH2:18][CH:17]([N:20]1[CH2:24][CH2:23][C@@H:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:21]1)[CH2:16][F:15]
Reactant: N[C@@H]1CCN(C(CF)CF)C1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@@H]2CCN(C(CF)CF)C2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To 4-fluoro-3-nitrobenzenesulfonamide (0.272 g) and (R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine (0.195 g) in tetrahydrofuran (3.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.512 mL) and the reaction was stirred at room temperature. After stirring for 6 hours, the reaction was concentrated, loaded onto silica gel (Reveleris 40 g) and the product was purified by flash chromatography using a gradient of 25% to 100% ethyl acetate/hexanes over 30 minutes to provide the title compound.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12]C)=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[H-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.B(Br)(Br)Br>CCOC(C)=O.C(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:7]2[C:6]3[CH:10]=[C:11]([OH:12])[C:3]([OH:2])=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:19][CH:18]=1
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: Clc1ccc(CBr)cc1
Agent: BrB(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1cc2ncn(Cc3ccc(Cl)cc3)c2cc1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,6-dimethoxybenzimidazole (0.100 g, 0.8 mmol) was added 60% NaH (0.021 g, 0.88 mmol). After stirring for 30 min, the 4-chlorobenzylbromide (0.171 g, 0.8 mmol) was added and the solution was heated to 60° C. for 2 h. The reaction solution was diluted with EtOAc (10 mL) and washed with aqueous saturated NaHCO3 (2×10 mL). The organic layer was dried with Na2SO4 and concentrated in vacuo. To a solution of the crude alkylated intermediate (0.8 mmol) in CH2Cl2 (10 mL) was added 1 M BBr3 in CH2Cl2 (1 mL, 1 mmol). After stirring for 16 h, the solvent was removed in vacuo and the crude product was purified by reverse-phase preparative HPLC to provide 1-(4-chloro-benzyl)-1H-benzoimidazole-5,6-diol.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]=12.[H-].[Na+].Cl.Cl[CH2:20][CH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[CH3:27]>CN(C)C=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[N:12]([CH:21]([C:22]3[N:23]=[CH:24][NH:25][C:26]=3[CH3:27])[CH3:20])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)NCC2
Reactant: Cc1[nH]cnc1CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]cnc1C(C)N1CCc2c(C)c3ccccc3n2C1=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dihydro-5-methylpyrimido[1,6-a]-indol-1(2H)-one (1.88 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in mineral oil 1.12 g) at 5° C. After being stirred at 5° C. for 30 minutes, 4-(2-chloroethyl)-5-methyl-1H-imidazole hydrochloride (2.17 g) in N,N-dimethylformamide (30 ml) was added dropwise over 20 minutes. The mixture was stirred at 5° C. for 30 minutes and at ambient temperature for 16 hours. The reaction mixture was diluted with chilled water and extracted with a mixture of ethyl acetate and tetrahydrofuran (2:1, 30 ml×2). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (3%-methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1H-imidazol-4-yl)ethyl]pyrimido[1,6-a]indol-1(2H)-one as a powder.
Reaction SMILES: [CH:1]1([C@@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26]C(=O)[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.[OH-].[Li+]>O>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:10][CH2:11][C@@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]3)[C:14]=2[C:30]([F:32])([F:33])[F:31])[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@@H](C5CCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](C4CCCC4)CC3)ccc2c1
Temperature: 80 °C
Yield: 72.6 %

Procedure:
(R)-4-[6-(cis-4-Cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol) was dissolved in ethanol (2.2 g, 0.049 mol) and treated with 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol). The mixture was then heated to 80° C. overnight. The reaction was then cooled to room temperature and diluted with water. Solid formed. Solid was removed via filtration and dried on the filter for 4 hours to give 158 mg the desired product as a white solid (58%). ESI-MS: 419 (M-16)+. 1H NMR (400 MHz, MeOD) δ=8.64-8.50 (m, 1 H), 8.17-7.98 (m, 2 H), 7.98-7.87 (m, 1 H), 7.73-7.62 (m, 1 H), 7.50-7.40 (m, 1 H), 4.21-4.09 (m, 2 H), 3.80-3.58 (m, 2 H), 2.12-1.96 (m, 2 H), 1.85-1.42 (m, 18 H), 1.21-1.05 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15](O)=[O:16])[N:14]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=1>>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[N:30]=[CH:31][C:32]([NH:35][C:15]([C:13]2[N:14]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:22])([F:1])[F:23])[O:11][C:12]=2[C:18]([F:20])([F:21])[F:19])=[O:16])=[CH:33][N:34]=1
Reactant: O=C(O)c1nc(-c2ccccc2OC(F)(F)F)oc1C(F)(F)F
Reactant: COCCN(C)c1ncc(N)cn1
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3OC(F)(F)F)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C20H17F6N5O4 (m/e) 505. obsd 506 (M+H).