Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]([O:31]CC)=[O:30])=[N:20]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]([OH:31])=[O:30])=[N:20]2)=[CH:34][CH:35]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Yield: 57.9 %

Procedure:
Ethyl 2-[1-[4-(2-naphthamido)benzyl]-1H-indazol-3-yl]acetate (226 mg, 0.488 mmol) was dissolved in tetrahydrofuran (10 mL), and in an ice bath 10 mL aqueous solution of lithium hydroxide monohydrate (62 mg, 1.48 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated. It was filtered, and dried to obtain a white solid 123 mg, at a yield of 58%.
Reaction SMILES: [N+:1]([C:4]1[O:19][C:7]([CH:8]=[C:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]3=[N:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=3[NH:10][C:9]2=[CH:8][C:7]2[O:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Nc1cccc2c1=NC(=Cc1ccc([N+](=O)[O-])o1)N=2
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Nc1cccc2c1NC(=Cc1ccc([N+](=O)[O-])o1)N2C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 78.4 %

Procedure:
51.2 g (0.2 moles) 2-(5-nitro-furfurylidene)-amino-benzimidazole are stirred in a mixture of 120 ml of chloroform and 80 ml of dimethylformamide, whereupon 37.6 g (0.2 moles) of powdered 3.4-dichlorophenyl-isocyanate are added. The crystalline reaction mixture is stirred at room temperature for 7 hours while a mixture of 40 ml of dimethylformamide and 60 ml of chloroform are added. The precipitated crystals are filtered off, washed with 100 ml of chloroform and dried in vacuo at 40° C. to 60° C. Thus 70 g of 1-(3',4'-dichlorophenyl-carbamoyl)-2-(5-nitro-furfurylidene)-amino-benzimidazole are obtained. Mp.: 202°-204° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH3:21])[C:14]2[O:15]CC(C)(C)N=2)=[CH:9][CH:8]=1)=[O:6].Cl.[O:24]1CCOCC1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([CH3:22])([CH3:21])[C:14]([OH:15])=[O:24])=[CH:11][CH:12]=1)=[O:6]
Reactant: C1COCCO1
Reactant: CC1(C)COC(C(C)(C)c2ccc(C(=O)CCCCl)cc2)=N1
Agent: Cl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1

Procedure:
A mixture of 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene, prepared according to Example 3, (47.8 g, 0.15 mole), 150 mL concentrated hydrochloric acid, and 150 mL 1,4-dioxane is brought to reflux for 18 hours. The mixture is extracted three times with ethyl acetate. The organics are washed with saturated NaCl solution, dried over MgSO4, and concentrated. Crude product is purified by column chromatography using silica gel, and eluting with hexane/ethyl acetate/acetic acid. Cleaner fractions are combined and recrystallized from methylene chloride/hexanes to afford 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:5]([NH2:20])[N:4]=1.O.[CH2:22]([OH:25])[CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][O:25][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:5]([NH2:20])[N:4]=1
Reactant: Cc1ccc(Cn2cnc3c(N)nc(Cl)nc32)cn1
Reactant: OCCO
Agent: [Na]
Solvent: O
Product: Cc1ccc(Cn2cnc3c(N)nc(OCCO)nc32)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
After sodium (2.1 g, 91 mmol) was dissolved in ethylene glycol (30 ml), 2-chloro-9-{(6-methyl3-pyridyl)methyl}adenine (3.0 g, 11 mmol) was added thereto and the mixture was stirred at 100° C. for 3 hours. After the mixture was allowed to cool, water (80 ml) was added thereto and the resulting precipitate was filtered to give the captioned compound (3.1 g, 10 mmol, yield: 94%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][O:24][C:25]([CH2:27]P(OC)(OC)=O)=[O:26]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:27][C:25]([O:24][CH3:23])=[O:26])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cc1oc(COc2ccc(C=O)cc2)nc1-c1ccccc1
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)c(C)o2)cc1

Procedure:
According to the method described for Reference Example 22, 4-(5-methyl-4-phenyl-2-oxazolylmethoxy)benzaldehyde was allowed to react with trimethyl phosphonoacetate to give methyl 4-(5-methyl-4-phenyl-2-oxazolylmethoxy)cinnamate. Recrystallization from ethyl acetate--isopropyl ether gave colorless prisms, m.p.109°-110° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][NH:8][C:7]=2[CH:15]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>C(O)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([NH:21][CH2:18][CH:19]=[CH2:20])=[O:14])[CH2:9][NH:8][C:7]=2[CH:15]=1
Reactant: O=C(O)C1CNc2cc(C(F)(F)F)ccc2O1
Reactant: C=CCN
Solvent: CCO
Product: C=CCNC(=O)C1CNc2cc(C(F)(F)F)ccc2O1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 20.6 g of 6C, 25.7 g of 2-propenamine and 34 ml of ethanol was stirred at room temperature for 36 hours. The excess amine and solvent were evaporated under reduced pressure. The solid residue was mixed with 150 ml of ether and the remaining solid material was filtered. The filtrate was added to petroleum ether and cooled; the resulting viscous material was filtered. The filtrate was stripped and the residue was triturated with petroleum ether to give an off-white powder which was purified by dry-column chromatography (silica gel), using ether as eluent. The higher Rf band was collected and extracted with ether, the solvent was stripped and the solid residue was recrystallized from ether/hexane (4/5 v/v). Thin-layer chromatography indicated that two components were present. The product was purified by wet-column chromatography (silica gel) using petroleum ether/ethyl ether (1:4 v/v) as eluent. The solvent was stripped and the residue was recrystallized from ether/hexane (75:100 v/v) to give 6, as a solid, mp: 95°-97° C.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:9]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=[C:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc(-c3ccccc3)[nH]2)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(Cc2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of 2-benzyl-5-phenyl-1H-pyrrole (467 mg, 2.0 mmo) in DMF (5 ml) was added NaH (60% in mineral oil, 240 mg, 6.0 mmol) at room temperature in one portion. After stirring for 30 min at room temperature, the reaction mixture was heated to 60° C. and methyl bromoacetate (0.57 ml, 6.0 mmol) was added. After 1 h stirring at 60° C., the reaction was cooled and quenched with aqueous 1N HCl (30 ml). The aqueous was extracted with EtOAc (3×30 ml). The combined organic extracts were washed with aqueous 1N HCl (30 ml), H2O (30 ml), brine (30 ml), dried (MgSO4) and concentrated. The crude material was purified by chromatography (EtOAc/hexane: 3/97) to afford the titled compound (240 mg, 39%) as an oil: MS (+) ES, 306 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4]([N:5]([CH3:20])[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)=[N:3]1
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21
Reaction time: 8 h
Yield: 101.8 %

Procedure:
A mixture of 2.0 g (0.0087 mole) 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one, 1.1 ml (0.0174 mole) methyl iodide, anhydrous potassium carbonate (1 gram) and acetone (100 ml) was heated under reflux, with stirring, overnight. After refluxing had continued 21 hours an additional 1 ml of methyl iodide was added and solids removed from the mixture by suction filtration. The filtrate was evaporated under reduced pressure and the resulting residue dissolved in ethyl acetate, washed with water, then with brine and dried over MgSO4, filtered and solvent stripped off to give 1.8 g of crude product. Purification by high pressure liquid chromatography gave a solid, mp 79°-82° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:13][OH:14])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:13]([O:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC1CC=CCC1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC(COCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 208.3 %

Procedure:
A solution of potassium t-butoxide (1.0M in THF, 8.27 mL, 8.27 mmol) was added dropwise to a solution of (±)-3 cyclohexene-1-methanol (853 mg, 7.60 mmol) in THF (35 mL) at 2520 C. under N2. The resultant mixture was stirred at 25° C. for 30 minutes. Benzyl bromide (1.0 mL, 3.37 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 16 hours and then treated with saturated aqueous NH4 Cl (5 mL) and concentrated. The residue was dissolved in ether (50 inL), washed with water (20 mL) and brine (20 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure. The residue was subjected to radial chromatography on silica gel eluting with 5 percent EtOAc in hexane to give (±)-3-(benzyloxy)methyl-1-cyclohexene (1.42 g, 92 percent) as a colorless oil. NMR
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([NH:1][C@@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(N[C@H]1CCc2ccccc21)c1cccc(Br)c1
Yield: 52 %

Procedure:
3-bromo-N-[(1S)-2,3-dihydro-1H-indene-1-yl]benzenesulfonamide was synthesized according to the procedure described above from (S)-1-aminoindan and 3-bromobenzensulfonyl chloride. Yield 52%. 1H NMR (400 MHz, CDCl3): 7.20 (m, 1H), 7.90 (dd, 1H), 7.80 (dd, 1H), 7.50 (t, 1H), 7.20 (m, 2H), 7.15 (m, 1H), 7.02 br d, 1H), 4.80 (t, 1H), 2.90(m, 1H), 2.70 (m, 1H), 2.20 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C@@H](C2C=CC=CC=2)C)[C@@H:3]1[OH:17]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:4]1[C@H:3]([OH:17])[C:2]([F:18])([F:1])[CH2:7][CH2:6][CH2:5]1
Reactant: C[C@@H](N[C@@H]1CCCC(F)(F)[C@H]1O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H]1CCCC(F)(F)[C@H]1O
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A solution of (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexanol 31 (2 g, 7.83 mmol) in methanol (100 mL) was degassed with nitrogen, treated with Pd(OH)2/C (0.55 g) and then placed under an atmosphere of hydrogen and stirred vigorously for 16 hours. The reaction was filtered, washing with methanol, and evaporated in vacuo to give 1.0 g (84%) of (1S,6R)-6-amino-2,2-difluorocyclohexanol 32 as a white solid: 1H NMR (500 MHz, CD3OD) δ 3.34 (1H, m), 2.74 (1H, m), 2.07 (1H, m), 1.89 (1H, m), 1.73 (2H, m), 1.50 (1H, m), 1.27 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH3:15])[CH:5]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][Br:17])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(-c2ncsc2C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2ncsc2CBr)c1
Yield: 104.6 %

Procedure:
A mixture of 3-(5-methyl-thiazol-4-yl)-benzoic acid methyl ester (2.40 g), N-bromosuccinimid (2.01 g) and α,α′-bis(isobutyronitrile) (0.02 g) in CCl4 (40 mL) was heated at reflux for 30 min. The cooled mixture was filtered and the solvent was evaporated to give crude 3-(5-bromomethyl-thiazol-4-yl)-benzoic acid methyl ester (3.36 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C@@H:14]1[CH3:23].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C@@H:14]1[CH3:23])=[O:11]
Reactant: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO2006087543. 2.8 g, 14.53 mmol) and methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.5 g, 14.53 mmol) in dichloromethane (200 mL) was added HOBT (2.22 g, 14.53 mmol) and N-methyl morpholine (4.82 mL, 43.60 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (5.12 g, 26.16 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica, 35% ethylacetate in pet ether) afforded methyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate 3.4 g (67%) as brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:35]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.99 (s, 1H), 8.80 (d, 1H), 8.62 (s, 1H), 8.51 (d, 1H), 8.06 (m, 1H), 7.89 (d, 2H), 7.43 (m, 1H), 7.23 (m, 2H), 7.15 (m, 1H), 7.06 (d, 1H), 6.92 (d, 1H), 6.86 (s, 1H), 4.42 (s, 2H), 4.37 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.50 (t, 2H); MS 502 (M+1).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13]C=1C(O)=O>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
Oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-fluorobenzoic acid (3.44 g) in dichloromethane (50 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resultant solution was evaporated to give the crude 2-chloro-4-fluorobenzoyl chloride as a viscous oil (3.72 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[C:26]([CH:27]=[O:28])=[CH:25][C:20]3[C:21]([OH:24])=[N:22][O:23][C:19]=3[C:18]=2[F:29])[CH2:11]1>>[CH2:1]([O:24][C:21]1[C:20]2[CH:25]=[C:26]([CH:27]=[O:28])[C:17]([N:12]3[CH2:13][C@H:14]([CH3:16])[O:15][C@H:10]([CH3:9])[CH2:11]3)=[C:18]([F:29])[C:19]=2[O:23][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(O)noc3c2F)C[C@H](C)O1
Reactant: BrCc1ccccc1
Product: C[C@@H]1CN(c2c(C=O)cc3c(OCc4ccccc4)noc3c2F)C[C@H](C)O1

Procedure:
Benzyl bromide and 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-hydroxy-1,2-benzisoxazole-5-carbaldehyde (Intermediate 556) were reacted using a method similar to the one described for the synthesis of Intermediate 557, providing the title product, along with a by-product, 2-benzyl-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-oxo-2,3-dihydro-1,2-benzoxazole-5-carbaldehyde. The mixture was used in the next step with out further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8](O)=[O:9].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=C(O)CCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.5 %

Procedure:
To a solution of 3-(2-thienyl)propionic acid (5.0 g, 32.0 mmol) in tetrahydrofuran (20 ml) at 0° C. was added 1 M borane tetrahydrofuran complex (33.5 ml, 33.5 mmol) dropwise over 30 minutes. The reaction mixture was then stirred for 18 h whilst warming to room temperature. The temperature was then reduced to 0° C. and water (20 ml) was added to quench the reaction. The solution was then basified with potassium carbonate, the layers separated and the aqueous layer washed with diethyl ether. The combined organic layers were washed with brine, dried and concentrated to yield the title compound (4.71 g) as an oil. DCI MS m/z 142 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.[NH2:14][NH2:15].Cl.Cl.NN.O>C(O)CO>[Br:1][C:2]1[C:3]([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:14][NH:15][CH:11]=1
Reactant: NN
Reactant: Oc1nc2ccccc2cc1Br
Agent: Cl
Solvent: O
Solvent: OCCO
Product: Brc1c[nH]nc1Nc1ccccc1

Procedure:
The bromohydroxyquinoline (1.97 g, 8.79 mmol) was dissolved in 21 ml of ethylene glycol and hydrazine hydrate (4.2 ml) was added. To this mixture were added 1.3 g (12.2 mmol) of hydrazine dihydrochloride, and the resulting mixture was heated to reflux and stirred under nitrogen. The resulting material was poured onto 300 ml of H2O. The mixture was extracted with CH2Cl2, basified with NaHCO and extracted further with CH2Cl2. The combined organic portions were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oil, yielding bromoanilinopyrazole (i.e., 3-(2-amino-5-bromophenyl)pyrazole).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](O)=[O:24]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:24]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1cccs1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccs4)cc3c2C1
Yield: 46.5 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.0 mg (0.086 mMol) thiophene-2-carboxylic acid, 6.0 mg (47%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][NH:6][CH:5]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.Br[CH:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25]([NH:27][CH3:28])=[O:26].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[CH3:28][NH:27][C:25](=[O:26])[CH:24]([N:6]1[CH2:7][CH2:8][C:9]2[S:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:5]1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cc2c(s1)CCNC2CCc1ccc(C(F)(F)F)cc1
Reactant: CNC(=O)C(Br)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(c1ccccc1)N1CCc2sc(C)cc2C1CCc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 10.6 %

Procedure:
To a solution of 300 mg (0.92 mmol) 2-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in 13 mL acetonitrile was added 210.3 mg (0.92 mmol) 2-Bromo-N-methyl-2-phenyl-acetamide (commercially available), 473 uL (2.76 mmol) N-ethyldiisopropylamine and 138 mg (0.92 mmol) sodium iodide. The solution was stirred for 18 h at 60° C. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with water and Na2CO3 aq. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified on silica eluting with a gradient formed from heptane and ethyl acetate. The diastereoisomeric product eluting first (obtained after evaporation from the product containing fractions) was dissolved in methanol, treated with Norit, heated to reflux, filtered and evaporated to dryness to yield 46 mg (11%) of N-methyl-2-{2-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl}-2-phenyl-acetamide (diastereoisomer 1) (MS(m/e): 472.9 (MH+)) as light yellow oil.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:2]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21].C1C[O:25]CC1>O.C(Cl)Cl>[OH:25][CH:2]([CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21]
Reactant: N#CCCCCCCCC1OC1CCCCCCCC#N
Reactant: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: N#CCCCCCCCC(O)C(O)CCCCCCCC#N
Reaction time: 24 h

Procedure:
To a solution of 0.10 g like-8,8′-(oxirane-2,3-diyl)dioctanenitrile in 5.0 g THF was added 0.50 mL of a solution of 0.0988 g 70% HClO4 in 1.9104 g water. After standing for 24 h at room temperature, the mixture was diluted with 250 mL CH2Cl2, which resulted in the separation of aqueous droplets. The mixture was dried over Na2CO3 and evaporated to afford 0.10 g of product as a white powder.