Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([F:36])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:24]4[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:26]([NH:28][C@H:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]4[OH:35])=[O:27])[CH:16]=3)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:37][Zn]C>C1COCC1.C(OCC)(=O)C.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>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[N:18]=[C:17]([C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[OH:35])=[O:27])[CH:16]=[C:15]2[CH2:14][N:11]1[CH2:12][CH2:13][C:8]([F:36])([C:4]2[CH:3]=[C:2]([CH3:37])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(CN2CCC(F)(c3cc(Cl)ccn3)CC2)c2cccc(F)c2n1
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccnc(C2(F)CCN(Cc3cc(C(=O)N[C@H]4CCCC[C@@H]4O)nc4c(F)cccc34)CC2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 4-{[4-(4-chloropyridin-2-yl)-4-fluoropiperidin-1-yl]methyl}-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (Example C) (0.022 g, 0.043 mmol) in THF (3 mL) under an atmosphere of nitrogen was added dimethyl zinc (2.0 M in THF, 0.043 mL, 0.085 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0011 mg, 0.00090 mmol). The reaction was heated to 90° C., cooled to RT, and retreated with additional dimethyl zinc (2.0 M in THF, 0.043 mL, 0.085 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0011 mg, 0.00090 mmol). The reaction was heated to 100° C. for 5 h, then at 50° C. for an additional 16 h. The mixture was cooled to RT, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-5% MeOH in dichloromethane to provide the title compound (Example D) as a white solid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 495.1 for M+H+. 1H NMR (400 MHz, CDCl3) δ 8.39-8.36 (m, 2H), 8.30-8.20 (m, 2H), 7.69-7.38 (m, 3H), 7.00 (br s, 1H), 4.03 (s, 2H), 3.89 (br s, 1H), 3.59-3.49 (m, 1H), 3.48-3.14 (m, 1H), 2.85-2.81 (m, 2H), 2.61-2.57 (m, 2H), 2.44-2.37 (m, 2H), 2.37 (s, 3H), 2.18-2.13 (m, 2H), 1.87-1.79 (m, 4H), 1.50-1.14 (m, 4H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:15]=[C:14]([C:16]([OH:18])=O)[O:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O>[C:5]1([C:11]2[CH:15]=[C:14]([C:16]([Cl:3])=[O:18])[O:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(-c2ccccc2)no1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2ccccc2)no1

Procedure:
Added to 500 g (4.2 mol) of thionyl chloride were 110 g (0.58 mol) of 3-phenylisoxazole-5-carboxylic acid prepared above in the procedure (2), followed by the further addition of 2 ml of dimethylformamide. The resulting mixture was heated under reflux for 3 hours. After completion of the reaction, thionyl chloride was distilled off under reduced pressure, followed by the addition of 500 ml of benzene. When the mixture thus obtained was distilled under reduced pressure, the title compound, i.e., 3-phenylisoxazole-5-carboxylic acid chloride was obtained as a solid. It was provided for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1.I[CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:30][CH3:31])=[CH:24][N:23]=1
Reactant: CCI
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(O)cn2)c1
Product: CCOc1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1

Procedure:
N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.05 mmol) was used in Procedure L with excess iodoethane. Purified by silica gel chromatography (0-100% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-ethoxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.64 (50% ethyl acetate/hexanes); MS (Q1) 436 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:35])[C@H:13]([O:14][Si](C)(C)C)[C@@H:12]([O:19][Si](C)(C)C)[C@H:11]([O:24][Si](C)(C)C)[C@@H:10]([CH2:29][O:30][Si](C)(C)C)[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([F:46])[C:38]=1[F:47].[CH3:48]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:35][CH3:48])[C@H:13]([OH:14])[C@@H:12]([OH:19])[C@H:11]([OH:24])[C@@H:10]([CH2:29][OH:30])[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([F:46])[C:38]=1[F:47]
Reactant: CCOc1ccc(Cc2cc([C@]3(O)O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]3O[Si](C)(C)C)ccc2Cl)c(F)c1F
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.9 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyetetrahydropyran-2-ol 23f (0.97 g, 1.3 mmol) in tetrahydrofuran (10 mL) was added a solution of methylsulfonic acid (0.05 mL, 0.65 mmol) in methanol (2 mL) at −70° C. The mixture was warmed up to room temperature and stirred for 16 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 6-7 and extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by re-crystallization from a toluene/petroleum ether mixture ((v/v)=1/1, 30 mL) at −5° C. to give the title compound 23g as a pale yellow sticky solid (0.33 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:28])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].B(Br)(Br)Br>ClCCl>[Cl:28][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([Cl:1])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:25]([CH3:26])[CH3:27])[CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: COc1ccc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a solution of the title compound from Step C (26 mg, 0.060 mmol) in dichloromethane (1 ml) at room temperature was added boron tribromide (1M in dichloromethane, 0.12 ml, 0.12 mmol). After the addition, a brown solution was obtained which was stirred at room temperature for about three hours. An additional 4 equivalents of boron tribromide was added and the mixture was stirred for 15 minutes at room temperature. A brown precipitation formed. The reaction was quenched with water (5 ml) and extracted with dichloromethane (3×10 ml). The combined extracts were dried, filtered, and concentrated, and the residue was purified by preparative TLC (7% methanol in dichloromethane) to give the title compound (13 mg) as an off-white solid. MS (APCI−) Calc: 423.0, Found: 422.0 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[N:6]=1)=[O:4]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cccc(Br)n1
Product: COC(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
The title compound, MS: m/e=282.0 (M+) was obtained as a light yellow solid (7% yield) by the reaction of 6-bromo-pyridine-2-carboxylic acid methyl ester with 3,4-dichlorophenyl boronic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[N:19][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:29][CH:30]([OH:43])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O.O>[CH2:7]([C:15]1[CH:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:29][C@@H:30]([OH:43])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:23][CH:22]=2)=[N:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCOCCOCCOCC(O)CCl
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1cnc(-c2ccc(OC[C@@H](O)COCCOCCOCCCC)cc2)nc1
Temperature: 25 °C

Procedure:
Potassium carbonate (2.1 g, 15.7 mmol) was added to a solution of 5-octyl-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 10.5 mmol) and 1-chloro-3-(2-(2-butoxyethoxy)ethoxy)-2-propanol (2.7 g, 10.5 mmol) in N,N-dimethylformamide (100 ml). The resulting mixture was stirred at reflux temperature for 18 hours and then cooled to ambient temperature. The mixture was diluted with water (100 ml) and was extracted with three 100 ml aliquots of diethyl ether. The extracts were dried (over MgSO4), filtered, and concentrated to give crude product as an oil. 5-octyl-2-[4-((S)-2-hydroxy-3-(2-(2-(butoxy)ethoxy)ethoxy)propoxy)phenyl]pyrimidine was then isolated by chromatography. The chiral (S)-hydroxy compound (3.5 g, 7.5 mmol) was treated with diethylaminosulfur trifluoride (5.3 g, 15 mmol) to produce Comparative Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[K+].C(O[C:17]([S-])=[S:18])C.Cl>N1C=CC=CC=1>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:12][C:17](=[S:18])[NH:1][C:2]=2[CH:7]=1)=[O:9]
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
In a round bottom flask equipped with a mechanical stirrer, reflux condenser and drying tube were placed 2-amino-4-methoxycarbonylphenol (8,3 g, 0.05 mole), O-ethylxanthic acid potassium salt (8.8 g, 0.055 mole) and pyridine (125 mL). The mixture was stirred and heated at reflux for 2 hours and cooled to room temperature. The mixture was poured into ice and concentrated HCl (50 mL). The product was collected as a solid and washed thoroughly with water. The material was air dried to give 9.9 g (95%) of the 5-methoxycarbonylbenzoxazol-2-thione as a white powder, m.p. 218°-221° C.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:13])[CH:7]=1>O1CCCC1>[OH:13][CH:12]([C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: O=Cc1cccnc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1cccnc1
Yield: 22 %

Procedure:
According to Reference Example 8-1, by use of isopropylmagnesium bromide (a 0.76 mol/L solution in tetrahydrofuran, 4.18 mL, 3.18 mmol), 3-pyridinecarboxaldehyde (200 μL, 2.12 mmol) and tetrahydrofuran (2.0 mL), the mixture was stirred and reacted at 0° C. for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 3-(1-hydroxy-2-methylpropyl)pyridine (Compound CE) (69.0 mg, yield: 22%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][C@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>>[OH:20][CH2:21][C@H:22]([NH:30][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@@H](CO)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)Cc2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-1-hydroxymethyl-2-phenyl-ethylamine and DIEA to give 2-((R)-1-hydroxymethyl-2-phenyl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([C:16]([O:18]C)=[O:17])=[C:14]([C:20]([O:22]C)=O)[C:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:12]2[C:4]=1[CH:5]=[CH:6][C:7]1[O:11][CH2:10][O:9][C:8]=12.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:15]2[C:16](=[O:17])[O:18][C:20](=[O:22])[C:14]=2[C:13]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:12]2[C:4]=1[CH:5]=[CH:6][C:7]1[O:11][CH2:10][O:9][C:8]=12
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)cc2)c2c3c(ccc2c1OC)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c3c(c(OC)c4ccc5c(c24)OCO5)C(=O)OC3=O)cc1
Temperature: 150 °C

Procedure:
To an ethanol (10Oml) solution of dimethyl 6-methoxy-9-(4-methoxyphenyl)-naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate (2.33 g, 5.04 mmol) was added 4N sodium hydroxide solution (10 ml) and heated under reflux for 2 hours. Ethanol was distilled off under reduced pressure. Concentrated hydrochloric acid was added to the residue to adjust the pH of the mixture to about 1 and extracted with THF-ethyl acetate(1:1) twice. The organic layer was washed with saturated sodium chloride solution and dried with magnesium sulfate, then the solvent was distilled off under reduced pressure. The obtained residue was heated for 10 minutes at 150° C. to give crude crystals of 6-methoxy-10-(4-methoxyphenyl)-furo[3',4':6,7]naphtho[1,2-d]-1,3-dioxol-7,9-dione.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:33]B1OB(C)OB(C)O1>C1COCC1.CCOC(C)=O>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([CH3:33])[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: CB1OB(C)OB(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 140 °C

Procedure:
A microwave vial was charged with a suspension of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.200 mg, 0.515 mmol) in 2.0 ml THF/0.400 mL water. To this suspension was added potassium phosphate (330 mg, 0.0015 mol) and trimethylboroxine (0.14 ml, 1.00 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and Bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (18 mg, 0.02 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 140° C. for 40 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 481. MS: (ESI+)=324.1
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.C(O)C.[Cl-].[NH4+]>[Zn].C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N)c2)cc1
Yield: 102.5 %

Procedure:
To a flask containing 4,5-difluoro-2-methoxy-4′-(3-nitro-benzyloxy)-biphenyl (1.49 g, 4.0 mmol) was added ethanol (40 ml), zinc (2.5 g, 40 mmol) and ammonium chloride (3.2 g, 60.2 mmol). Additional solvent was added over time, ethanol (30 mL at 15 min) and ethyl acetate (10 mL at 45 min). After 1 hr the reaction was filtered through Celite, concentrated, diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL), dried over magnesium sulfate, concentrated and dried from hexanes/methylene chloride mixtures to yield 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamine as a yellow oil (1.4 g, 100%). LC-MS (ES) calculated for C20H17F2NO2, 341.12; found m/z 342 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:24]([O:26][C:27]([N:29]=[C:30]=[S:31])=[O:28])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:13][C:30]([NH:29][C:27]([O:26][CH2:24][CH3:25])=[O:28])=[S:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: CCOC(=O)N=C=S
Reactant: COC(=O)C(N)Cc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NC(=S)NC(Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Methyl ester 1-1 (394 mg, 1.58 mmol) was dissolved in methylene chloride (4.0 mL) and diisopropylethylamine (0.82 mL, 4.73 mmol). The solution was cooled to 0° C. and ethoxycarbonyl isothiocyanate (0.21 mL, 1.73 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was stirred 30 min. Methylene chloride (20 mL) was added, and the organic layer was washed with water (20 mL), 10% aqueous HCl (20 mL), and saturated brine (20 mL). The organic layer was dried with MgSO4, filtered and the solvent was removed in vacuo to yield the product as a yellow oil in 92% yield (502 mg, 1.45 mmol). 1H NMR (300 MHz, CDCl3): δ=10.10 (d, 1H, J=6.6 Hz), 8.11 (s, 1H), 7.27 (d, 2H, J=8.1 Hz), 7.10 (d, 2H, J=8.1 Hz), 5.25 (t, 1H, J=6.3 Hz), 4.23 (q, 2H, J=7.2 Hz), 3.73 (s, 3H), 3.32 (dd, 1H; J=14.1, 6.0 Hz), 3.20 (dd, 1H, J=13.8, 6.0 Hz), 1.30 (t, 3H, J=7.2 Hz); 13C NMR (75 mHz, CDCl3): δ=179.4, 170.8, 152.6, 134.2, 133.4, 130.8, 129.0, 63.2, 59.2, 53.6, 52.8, 36.8, 14.4; ESI-MS calcd for C14H17ClN2O4S [M+Na]+: 267.0495. found 267.0495.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:4]=1[C:5]([NH2:7])=O>C(OCC)C.ClCCCl>[NH2:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:4]=1[C:5]#[N:7]
Reactant: Cc1ccc(Cl)c(N)c1C(N)=O
Agent: Cl
Solvent: ClCCCl
Solvent: CCOCC
Product: Cc1ccc(Cl)c(N)c1C#N
Temperature: 120 °C
Reaction time: 3 h

Procedure:
1.18 g (0.033 mol) of hydrogen chloride, dissolved in 35 ml of diethyl ether, were added at 22 to 30° C. with stirring to a suspension of 5 g (0.027 mol) of the compound from example 3 in 50 ml of 1,2-dichloroethane and the mixture was then concentrated in vacuo. The residue was treated with 150 ml of phosphorus oxychloride and the mixture was stirred at 120° C. for 3 h. The reaction mixture was then concentrated in vacuo, the residue was dissolved in methylene chloride, and the solution was treated with water and neutralized using 2 N sodium hydroxide solution. After the phase separation, the organic phase was again washed with water, then with saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, 2.4 g (48% of theory) of the title compound were obtained as a yellowish powder of m.p. 77-80° C.
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]2[CH:24]([C:28]([OH:30])=[O:29])[CH2:25][S:26](=[O:27])[CH:20]2[CH2:19][CH2:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C>CO.O.[OH-].[Na+]>[C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]2[CH:24]([C:28]([OH:30])=[O:29])[CH2:25][S:26](=[O:27])[CH:20]2[CH2:19][CH2:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCCC2N(C1=O)C(C(=O)O)CS2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CCc1ccccc1)NC1CCCC2N(C1=O)C(C(=O)O)CS2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3R-[3α,6α(S*R*),9aα]]-6[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-1-oxo-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid (0.5 mmole) in 4 ml of a methanol-water mixture (1:1), 1.5 ml of 1N NaOH can be added. The reaction mixture can be stirred overnight at room temperature and then absorbed onto a strong acid ion-exchange resin such as Dowex 50 X-2, 50-100 mesh. The column can then be first eluted with water and then with 4% pyridine-water. The appropriate fraction can be freeze-dried to give the product as a diastereomeric mixture which can be separated by reverse-phase chromatography.
Reaction SMILES: [CH:1]([C:3]([Cl:11])(Cl)[CH2:4][C:5]([CH3:9])(Cl)[C:6]#[N:7])=O.[ClH:12]>>[Cl:12][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([Cl:11])=[CH:1][N:7]=1
Reactant: CC(Cl)(C#N)CC(Cl)(Cl)C=O
Reactant: Cl
Product: Cc1cc(Cl)cnc1Cl
Temperature: 145 °C

Procedure:
21.4 g of the 4-formyl-2-methyl-2,4,4-trichlorobutyronitrile obtained in (a) are heated for 4 to 5 hours to 145° C. while introducing a weak stream of dry HCl gas. After it has cooled, the dark melt is subjected to steam distillation, affording 9.9 g of 2,5-dichloro-3-methylpyridine in the form of colourless crystals (recrystallised from CH3OH/H2O in the volume ratio of 4:1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
A solution of 2-(trifluoromethyl) aniline (693 mg, 4.30 mmol) and pyridine (438 μL, 5.87 mmol) in DCM (40 mL) was treated with 4-bromobenzene sulfonyl chloride (1.0 g, 3.91 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1N HCl, sat. NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-20% EtOAc in cyclohexane) and triturating with pentane gave 4-bromo-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (719 mg, 48% yield) as a colourless crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.2 Hz, 1H), 7.65-7.47 (m, 6H), 7.29-7.20 (m, 1H), 6.85 (br s, 1H), LCMS (m/z, Method A) ES+ 380.0 [M+1]+.
Reaction SMILES: ClC1C=NC=C(Cl)C=1C(NCC1C=CC([CH2:14][N:15]([CH2:26][CH2:27][C:28]2[N:32](C)[C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[N:29]=2)[CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=CC=1)=O.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1>>[NH:29]1[C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[N:32]=[C:28]1[CH2:27][CH2:26][N:15]([CH2:14][C:18]1[CH:19]=[C:20]([CH:25]=[CH:16][CH:17]=1)[CH2:21][NH:51][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1)[CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1
Reactant: NC(=O)c1ccncc1
Reactant: Cn1c(CCN(Cc2ccc(CNC(=O)c3c(Cl)cncc3Cl)cc2)C2CCCc3cccnc32)nc2ccccc21
Product: O=C(NCc1cccc(CN(CCc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1)c1ccncc1

Procedure:
3,5-Dichloro-N-(4-{[[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-isonicotinamide 8-yl)-amino]-methyl}-benzyl)-isonicotinamide