Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:16][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:8]1[C:9]2[C:14]([NH2:15])=[N:13][CH:12]=[N:11][C:10]=2[O:16][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncnc2oc(-c3ccccc3)cc12
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1ncnc2oc(-c3ccccc3)c(Br)c12
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Heat 80 g (378.7 mmol) 6-phenylfuro[2,3-d]pyrimidine-4-amine in 770 ml carbon tetrachloride to 60° C. Add 84.3 g (473.4 mmol) N-bromosuccinimide, and stir the mixture overnight under reflux. After cooling, filter, mix the filter cake successively with dichloromethane and acetonitrile, and filter again. Then dry the filter cake under vacuum. 86 g of the target product (78.2% of theor.) is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:3].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].CO>C(O)CCC>[Br-:16].[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N+:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: ClCCCCBr
Reactant: CCCCCCCCCCCCN(C)C
Solvent: CO
Solvent: CCCCO
Product: CCCCCCCCCCCC[N+](C)(C)CCCCCl
Product: [Br-]
Temperature: 65 °C

Procedure:
Into a 1000 mL, round-bottomed flask equipped with air condensers and a magnetic stirring plate was charged N,N-dimethyldodecylamine (308.8 grams, 1.45 moles), 1-bromo-4-chlorobutane (249.98 grams, 1.45 moles) and 300 mL of methanol. The reaction was maintained at 65° C. for 48 hours. Solvent was removed by rotary evaporation under reduced pressure to yield brown oil. To the oil was added 100 ml of 1-butanol. The mixture was distilled under vacuum at 30° C. to 50° C. until distillate stopped collecting Yield 384.47 grams (0.99 moles, 69%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16].[NH4+].[Cl-]>C(OCC)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: Brc1ccccn1
Reactant: CCCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCCC(O)c1ccccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromopyridine (1.1 g, 6.96 mmol, purchased from Sigma-Aldrich) in diethyl ether (8 mL) at −78° C. under N2 was added butyllithium (3.1 mL×2.5 M) over 10 min. The reaction solution was stirred at −78° C. for 1.0 hr. To the mixture was added butyraldehyde (0.602 g, 8.35 mmol, purchased from Sigma-Aldrich) dropwise over 10 min. After stirring at −78° C. for 15 min, the mixture was allowed to warm to rt and stirred at rt for 1.5 hr. The reaction mixture was poured into saturated aqueous NH4Cl solution (10 mL), diluted with water (15 mL), and extracted with EtOAc (20 mL×3). The organic layers were combined, washed with water, sat. aq. NaCl solution, and dried over MgSO4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 20-80% EtOAc/Hexanes provided the title compound as a white solid. Mass Spectrum (ESI) m/z=152.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18]([OH:26])([CH2:19]3)[CH2:17]1)[CH2:23]2)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@H:27]12[CH2:32][C@H:31]1[CH2:30][C@@H:29]([C:33]([NH2:35])=[O:34])[NH:28]2.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:33]([C@@H:29]1[CH2:30][C@H:31]2[C@H:27]([CH2:32]2)[N:28]1[C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18]([OH:26])([CH2:19]3)[CH2:17]1)[CH2:23]2)(=[O:34])[NH2:35]
Reactant: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
(2S)-2-{[(Benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of Formula-XIV (20 gm), 1-ethyl-3-(3-dimethyl aminoporpyl)carbodiimide (13.8 gm), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide of formula-III (14.8 gm) and 1-hydroxy benzotriazole (10.2 gm) were dissolved in N,N-dimethyl formamide (80 ml). The reaction mixture was cooled to about 20° C. Addition of N,N-diisopropylethylamine (15.8 gm) was then carried out for 15 min. The reaction mixture was stirred for 4 hrs and the solvent was distilled off. To the residue 2N HCl solution was added. Aqueous phase was extracted with ethyl acetate. Organic phase was washed with NaHCO3 solution, dried and evaporated to yield 23.3 gms (90%) of title product. MP: 105-106° C., H1NMR (300 MHz, CDCl3): 0.81 (dd, 1H), 0.96 (m, 1H), 1.46-1.82 (m, 12H), 1.93 (s, 1H), 2.2 (m, 3H), 2.45 (dd, 1H), 3.6 (m, 1H), 4.5-4.61 (dd, 1H), 4.76-4.86 (dd, 1H), 5.0 (s, 2H), 5.34 (d, 1H), 5.69 (s, 1H), 5.82-5.85 (dd, 1H), 6.83-6.89 (s, 1H), 7.31-7.35 (m, 5H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:26][CH3:27])=[C:7]([CH:13]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>C1COCC1.CCOC(C)=O>[CH2:18]([O:17][C:16](=[O:25])[NH:15][CH:13]([C:7]1[CH:8]=[C:9]([Cl:12])[C:10]([Cl:11])=[C:5]([CH:3]2[CH2:4][N:1]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:2]2)[C:6]=1[O:26][CH3:27])[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(CC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of benzyl [1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]carbamate (170 mg, 0.43 mmol) in THF (5.8 mL) was treated with triethylamine (110 μL, 0.82 mmol), cooled to 0° C., treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (150 mg, 0.64 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, water, and brine, dried with sodium sulfate, filtered and concentrated to give the desired product (190 mg, 92%) that was used without further purification. LCMS for C22H24Cl2F3N2O3 (M+H)+: m/z=491.1, 493.1. Found: 491.1, 493.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][C:16]3=[O:19])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH:16]3[OH:19])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C1CCCc2ccc(OCc3ccncc3)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC1CCCc2ccc(OCc3ccncc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of Compound 1 (16.41 g, 64.9 mmol) in tetrahydrofuran (75 mL) at 0° C. was added dropwise a 1M solution of diisobutylaluminum hydride in toluene (97.3 mL). After 1 hr, the reaction was quenched with aqueous potassium sodium tartrate and diluted with ethyl acetate followed by warming to room temperature. After stirring for an additional hour, the layers were separated and the aqueous phase was re-extracted with ethyl acetate (2×). The extracts were combined, washed with brine, dried over anh. magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with ethyl acetate) provided 12.96 g of Compound 2 as an oil which crystallized upon standing.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-:43]>O>[Br:18][C:19]1[N:20]=[CH:21][C:22]([CH:2]=[C:1]([N:3]2[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]3[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]2=3)[F:43])=[CH:23][CH:24]=1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: [F-]
Reactant: Brc1ccc(Br)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C(F)=Cc2ccc(Br)nc2)CCN(C)C1
Temperature: 80 °C

Procedure:
A mixture of 5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (113 mg, 0.50 mmol), 2,5-dibromopyridine (100 mg, 0.42 mmol), dichlorobistriphenylphosphine palladium (II) (8 mg, 0.012 mmol) and TBAF.3H2O (396 mg, 1.26 mmol) were charged in a reaction vessel and heated at 80° C. for 5 min in microwave. After completion of reaction (as monitored by TLC & LCMS) the reaction mixture was poured into water (10 mL) and the desired compound extracted with EtOAc (20 mL×2). The organic layer was dried over sodium sulfate, concentrated under vacuum and purified by reverse phase chromatography to obtain 20 mg of 5-[2-(6-Bromo-pyridin-3-yl)-1-fluoro-vinyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.62 (s, 1H), 8.08 (d, 1H), 7.78 (d, 1H), 7.24 (s, 1H), 7.16 (d, 1H), 6.10 (d, 1H), 4.62 (d, 2H), 4.30 (d, 1H), 3.80 (m, 1H), 3.50 (m, 2H), 3.05 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH2:19])=[O:17])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:20][O:21][C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:23]>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([NH:18][NH:19][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:32][CH:31]=2)=[O:17])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCCOc1ccc(CCC(=O)NN)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(CCC(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a suspension of 3-(4-n-hexyloxyphenyl)propiono-hydrazide (0.92 g) in tetrahydrofuran (25 ml) and pyridine (0.84 ml) was added a solution of 4-methoxycarbonylbenzoyl chloride (0.73 g) in tetrahydrofuran (10 ml) dropwise at 5° C. The reaction mixture was stirred for 1 hour and poured into ice-water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 1-[3-(4-n-hexyloxyphenyl)propanoyl]-2-(4-methoxycarbonylbenzoyl)hydrazine (1.43 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29]C)=[O:22])[C:11](=[O:31])[CH:10]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]3[NH:46][N:45]=[N:44][N:43]=3)[CH:37]=2)=[O:34])[N:9]=1.B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[O:22])[C:11](=[O:31])[CH:10]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]3[NH:46][N:45]=[N:44][N:43]=3)[CH:37]=2)=[O:34])[N:9]=1
Reactant: COc1ccccc1C(=O)CN1C(=O)C(NC(=O)Nc2cccc(-c3nnn[nH]3)c2)N=C(c2ccccc2F)c2cccc(C)c21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cccc2c1N(CC(=O)c1ccccc1O)C(=O)C(NC(=O)Nc1cccc(-c3nnn[nH]3)c1)N=C2c1ccccc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
A mixture of N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-methoxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea (200 mg) and 1N boron tribromide in methylene chloride (3.87 ml) was stirred at 0° C. under nitrogen stream for 4 hours and allowed to stand in a refrigerator overnight. Ethyl acetate and water were added to the reaction mixture. The separated organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a pale brown powder, which was washed with diisopropyl ether and collected by filtration to give N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-hydroxyphenacyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea (202.0 mg) as a crystalline powder.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:27]([CH3:29])[CH3:28])[C:11]2[C:12]([CH3:26])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:14]3[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]=3[CH:21]=2)=[CH:6][CH:5]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH:27]([N:10]([C:11]1[C:12]([CH3:26])=[C:13]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:14]2[O:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]=2[CH:21]=1)[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc(N(c2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N(c2ccc(C(=O)O)cc2)C(C)C)cc2c(c1C(C)(C)C)OCC2(C)C
Temperature: 80 °C
Yield: 46.6 %

Procedure:
A solution of 4-[isopropyl-(7-t-butyl-3,3,6-trimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid methyl ester (Compound 69, 0.015 g, 0.038 mmol) in 3 mL of ethanol was treated with 1M sodium hydroxide (1.5 mL, 1.5 mmol) and the resulting clear solution was heated at 80° C. for 2 hours. The volatiles were removed by distillation in vacuo and the residue was neutralized with saturated ammonium chloride solution and extracted with diethylether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to afford, after flash column chromatography using 25% ethyl acetate in hexanes as the eluent, the title compound (0.007 g, 48%) as a solid. 1H NMR (300 MHz, CDCl3): δ 7.87 (d, 2H, J=9.1 Hz), 6.61 (s, 1H), 6.43 (d, 2H, J=8.9 Hz), 4.32 (heptet, 1H, J=6.5 Hz), 4.18 (s, 2H), 3.83 (s, 1H), 2.19 (s, 3H), 1.52 (s, 9H), 1.32-1.28 (m, 9H), 0.99 (d, 3H, J=6.6 Hz).
Reaction SMILES: Cl.[CH3:2][N:3]([C:12]([S:14][CH3:15])=[NH:13])[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24]([CH2:27][C:28](Cl)=[O:29])(=[O:26])=[O:25].O>ClCCl>[CH3:2][N:3]([C:12]([S:14][CH3:15])=[N:13][C:28](=[O:29])[CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)CC(=O)Cl
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(=NC(=O)CS(C)(=O)=O)N(C)N=Cc1ccccc1
Reaction time: 18 h
Yield: 35.2 %

Procedure:
To a stirred solution of methyl 1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate hydrochloride (5.71 g) and triethylamine (5.2 g) in dichloromethane (100 ml) was added methylsulphonylacetyl chloride (4.9 g) in dichloromethane (20 ml) dropwise during 0.5 h at 20°. The mixture was stirred at 20° during 18 h, water (100 ml) added and the phase separated. The dichloromethane layer was washed with water, dried, and evaporated. The residue was crystallised from ethanol to give the title compound (2.7 g) as off white needles. m.p. 149.5°-150.5°.
Reaction SMILES: C=C([C:4]1[CH:5]=[C:6]([NH2:20])[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:16]=1[C:17]([CH3:19])=[CH2:18])C.[CH2:21](O)[CH3:22].[C:24](O)(=O)C>[Pt].[Pd]>[CH:21]([C:5]1[CH:4]=[C:16]([CH:17]([CH3:18])[CH3:19])[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]=1[NH2:20])([CH3:22])[CH3:24]
Reactant: C=C(C)c1cc(N)c2c(oc3ccccc32)c1C(=C)C
Reactant: CC(=O)O
Reactant: CCO
Agent: [Pd]
Agent: [Pt]
Product: CC(C)c1cc(C(C)C)c2oc3ccccc3c2c1N
Reaction time: 8 h
Yield: 68 %

Procedure:
3,4-di(prop-1-en-2-yl)dibenzo[b,d]furan-1-amine (4.8 g, 18.2 mmol), and 5% Pt/C (0.48 g) and 10% Pd/C (0.48 g) were added to a mixture of ethanol (90 mL) and acetic acid (10 mL). Reaction mixture was hydrogenated overnight at 50 psi. Reaction mixture was filtered through a Celite pad and most of the organic solvent was evaporated under vacuum. Crude product was dissolved in ethylacetate and partitioned between 1N NaOH and ethylacetate to get rid of any acetic acid. Organic layer was dried over anhydrous Na2SO4, evaporated under vacuum and purified by flash chromatography over silica gel with 40% DCM/hexanes. Target compound (3.3 g, 68%) was isolated as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: COc1cccc(C=O)c1
Solvent: CCO
Solvent: O
Product: COc1cccc(C2CC(=O)c3cc(Br)ccc3O2)c1
Yield: 17.8 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (18 g, 84.1 mmol), 3-methoxy-benzaldehyde (11.4 g, 84.1 mol), and borax (51.5 g, 0.135 mol) in ethanol (112 mL) and H2O (187 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ether. The ether was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-methoxy-phenyl)-chroman-4-one (5 g, 18%). 1H-NMR (CDCl3): 2.89 (d, 1H), 3.04 (t, 1H), 3.81 (s, 3H), 5.43 (d, 2H), 6.96 (m, 3H), 7.32 (m, 1H), 7.58 (m, 1H), 8.01 (s, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:14]Br>C(O)(=O)C>[Br:14][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([OH:1])=[CH:3][C:4]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: COc1ccc(CC(=O)O)cc1O
Solvent: CC(=O)O
Product: COc1cc(Br)c(CC(=O)O)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3-hydroxy-4-methoxy-phenyl acetic acid (8 g) in 150 ml acetic acid was added drop wise 2.48 ml bromine. The mixture was stirred 18 hours at room temperature under nitrogen. The solvent was then removed in vacuo and the residue was triturated with toluene, filtered, washed with toluene then hexane to yield 11.1 g (2-bromo-5-hydroxy-4-methoxy-phenyl)-acetic acid a solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][C@H:6]1[CH2:11][NH:10][C@H:9]([CH3:12])[CH2:8][N:7]1[C@@H:13]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:5][C@H:6]1[CH2:11][N:10]([CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([F:34])[CH:36]=2)[C@H:9]([CH3:12])[CH2:8][N:7]1[C@@H:13]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: O=Cc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Yield: 70.7 %

Procedure:
Glacial acetic acid (0.635 mL, 11.1 mmol) was added to a solution of 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (1.98 g, 5 mmol) and 3-fluorobenzaldehyde (1.24 g, 10 mmol) in anhydrous tetrahydrofuran (35 mL). While stirring briskly, sodium triacetoxyborohydride (2.12 g, 10 mmol) was added in 50-100 mg portions, allowing effervescence to subside after each addition. The reaction was monitored for absence of starting material by HPLC. After stirring at room temperature for 16 hours, additional 3-fluorobenzaldehyde (0.62 g, 5 mmol), acetic acid (0.318 mL, 5 mmol), and sodium triacetoxyborohydride (1.06 g, 5 mmol) were added. After stirring an additional 4 hours, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and 3 M hydrochloric acid (25 mL). The layers were separated and the organic layer was extracted again with 3 M hydrochloric acid (25 mL). The aqueous solution was adjusted to pH 9-10 with 5 M sodium hydroxide solution, resulting in the formation of chunky white precipitate. Brief sonication followed by continuous stirring for 60 hours allowed hydrolysis of any residual ethyl acetate, as well as complete precipitation of product. The white solid was filtered, washed with cold water, and further dried under reduced pressure to yield 4-[(R)-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)(3-hydroxyphenyl)-methyl]-N,N-diethylbenzamide (1.78 g, 82.3% yield from 4-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenl)-methyl]-N,N-diethyl-benzamide). The product showed a single peak on HPLC (Zorbax C-8, isocratic 40% 0.01 M NH4OAc in MeOH, 3 min; linear gradient to 100% MeOH, 45 min; isocratic MeOH, 25 min; 1.0 mL/min; δobs=210 nm, Rt=43.51 min). Calc. for C31H38FN3O2.0.5H2O: % C, 72.63; H, 7.67; N, 8.20; F, 3.71. Found: % C, 72.77; H, 7.52; N, 8.18; F, 3.61.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].Cl[CH:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](O)=[O:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:21](=[O:22])[CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: O=C(O)C(Cl)c1ccccc1
Reactant: CC(C)CN
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(c2ccccc2)C(=O)N1CC(C)C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by α-chloro-α-phenylacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-phenyl-1,3-thiazolidin4-one.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1F
Solvent: ClCCl
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of 3-fluoro-2-methylaniline (6.00 g, 48 mmol) in dry DCM (100 mL) under nitrogen was added acetic anhydride (7.6 g, 75 mmol). The reaction mixture was stirred at r.t. for 18 h then washed with water (2×50 mL) and NaOH solution (1M, 2×50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (8.0 g, 100%) as a white solid. δH (CDCl3) 7.56 (1H, s), 7.16 (1H, q, J=7.6 Hz), 6.99 (1H, br s), 6.87 (1H, t, J=8.4 Hz), 2.27 (3H, s), 2.16 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1.C(=O)(O)[O-:23].[Na+].ClC1C=CC=C(C(OO)=O)C=1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@@H:10]1[CH2:9][O:8][C:4]1[CH:5]=[N+:6]([O-:23])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Cl)c[n+]([O-])c1
Product: Oc1cncc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of crude (R)-tert-butyl 2-((5-chloropyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (5.15 g, Ca. 11.28 mmol, EXAMPLE 29 Step 1) and sodium bicarbonate (2.77 g, 32.9 mmol) in dichloromethane was added m-chloroperbenzoic acid (mCPBA) (4.26 g, 24.7 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, and the mixture was warmed to room temperature during 30 min period. After being stirred at room temperature for 6 h, water was added to the mixture. The mixture was extracted with dichloromethane twice and washed with aq. sodium thiosulfate and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 7:3 to ethyl acetate) to afford 2.709 g (73% from 5-chloropyridin-3-ol) of the title compound as a colorless viscous oil.