Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([S:18]C#N)=[CH:10][C:9]=1[CH3:21])([CH3:4])([CH3:3])[CH3:2].O.[SH-].[Na+].[BH4-].[Na+].[H][H]>C(O)(=O)C.C1(C)C=CC=CC=1.O.CO.O1CCCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([SH:18])=[CH:10][C:9]=1[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(S)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 10 h

Procedure:
N-(5-tert-Butyl-2-methyl-4-thiocyanatophenyl)carbamic acid tert-butyl ester (31) (114 g, 356 mmol) was treated with sodium hydrosulfide hydrate (57.5 g), sodium borohydride (76.8 g), and tetrahydrofuran (1.24 L) under a nitrogen atmosphere. The mixture was stirred and cooled to 0-5° C. and a solution of water (180 mL) and methyl alcohol (300 g) added dropwise over 75 minutes at 5-10° C. The mixture was stirred at 5-15° C. for 5 hours and then at 15-25° C. for 10 hours. Water (1.25 L) and toluene (1.25 L) were added and the mixture stirred and cooled to 5° C. Glacial acetic acid (250 mL) was added slowly at 5-10° C. over 1.5 hours (caution! foaming with hydrogen gas evolution). The organic phase was separated and the aqueous phase discarded. The organic layer was washed with water (2×1.2 L) and then concentrated under vacuum to give N-(5-tert-butyl-4-mercapto-2-methylphenyl)carbamic acid tert-butyl ester (32) which was used without further purification in the next step. The N-(5-tert-butyl-4-mercapto-2-methylphenyl)carbamic acid tert-butyl ester (32) was dissolved in toluene (500 mL) and pyridine (32.0 g) added. The resulting solution was added dropwise over 3 hours and 45 minutes to a cold (8-13° C.) solution of p-toluenesulfonyl bromide (95.3 g) in ethyl acetate (750 mL). The resulting mixture was agitated at 10-15° C. for 3 hours. Water (800 mL) was added to the mixture and the organic phase separated and washed with 1N hydrochloric acid (2×500 mL) and then with water (500 mL). The organic layer was concentrated under vacuum to give 188 g crude toluene-4-thiosulfonic acid S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methylphenyl). This was treated with heptane (440 mL) and toluene (25 mL) and the resulting solution treated with S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methyl-phenyl) ester seed crystals. The mixture was stirred and cooled overnight to −5° C. The mixture was filtered and the product washed with cold heptane (2×125 mL) and vacuum dried at 40° C. to give 136 g (302 mmol, 85% yield) toluene-4-thiosulfonic acid S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methyl-phenyl) ester (33a): mp: 106-108° C.; Assay (HPLC): 99.2 area %.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[NH3:21]>CO.C(#N)C>[F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:21])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: N
Reactant: N#CCCCCn1cnc(NC(=S)NCC(F)(F)F)n1
Solvent: CO
Solvent: CC#N
Product: N#CCCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
This nitrile (3.6 g.) in MeOH (80 ml.) and acetonitrile (5 ml.) was treated with mercuric oxide (3.06 g.) and methanolic ammonia (15 ml.). After stirring for 1.5 hours the black suspension was filtered through diatomaceous earth and the filtrates evaporated to give a white solid. The solid was washed with ether and filtered to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile (2.87 g.) as a white solid, m.p. 200°-201° after recrystallisation from EtOH.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[O:5][CH:6]=1.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[CH3:7][C:4]1[O:5][CH:6]=[C:2]([C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:8])[CH:3]=1
Reactant: Cc1cc(Br)co1
Reactant: Nc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(-c2cccc(N)c2)co1
Temperature: 100 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
500 mg (3.1 mmol) of 4-bromo-2-methylfuran was dissolved in 12 mL of toluene, and then 3 mL of methanol, 638 mg (4.7 mmol) of m-aminophenyl boronic acid, and 3 mL of 2M aqueous sodium carbonate solution were added thereto. Subsequently, 180 mg (0.16 mmol) of triphenylphosphine palladium was added, and the mixture was stirred at 100° C. for 17 hours. After cooling, anhydrous magnesium sulfate was added to the mixture, and the mixture was stirred. Filtration was then conducted, and the filtrate was condensed. The resulting product was separated and purified using silica gel column chromatography to give 3-(5-methylfuran-3-yl)aniline (yield: 52%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][CH2:12]Cl.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH2:23][CH2:24][OH:25])[CH:16]=1.[OH-].[NH4+]>ClCCl.O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH2:23][CH2:24][O:25][CH2:10][O:11][CH3:12])[CH:16]=1
Reactant: COc1ccc(Br)cc1CCO
Reactant: COCCl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOCCc1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 3.33 h

Procedure:
1.48 g of N-ethyl-diisopropylamine and 0.49 g of chlorodimethyl ether are added at room temperature to a solution of 948 mg of 4-bromo-2-(2-hydroxyethyl)-anisole in 30 ml of dichloromethane. The reaction mixture is stirred for 200 minutes at room temperature, and then 1 ml of water and 1 ml of 25% ammonium hydroxide solution are added thereto. The two-phase mixture is stirred vigorously for a further 15 minutes and then the organic phase is separated off, dried over sodium sulfate and concentrated by evaporation. Purification of the residue by means of FC (hexane/dichloromethane=1:1) yields the title compound: Rf (dichloromethane)=0.6; HPLC Rt =17.33 minutes.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11]([Mg]Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>O1CCCC1>[CH2:11]([CH:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: c1ccc2ncccc2c1
Solvent: O
Solvent: C1CCOC1
Product: C1=CC(Cc2ccccc2)Nc2ccccc21
Reaction time: 0.5 h

Procedure:
Quinoline (6.0 g, 0.0047 mol) in 15 ml of tetrahydrofuran was added to benzyl magnesium bromide (47 ml of 2M in tetrahydrofuran, 0.0094 mol) via a syringe. After stirring for 0.5 hour, the reaction mixture was cooled to 0°, and an equal volume of H2O was added slowly. An exothermic reaction was noted. The aqueous solution was extracted 3×125 ml of ether. The organic layers were combined, dried (K2CO3) and stripped in vacuo to yield intermediate 2-benzyl-1,2-dihydroquinoline as an oil, 11.3 g (0.0051 mol). The latter was taken up in 50 ml of nitrobenzene, refluxed for 2 hours, cooled to room temperature, poured into 150 ml of 1M HCl, and extracted 2×200 ml ether. The aqueous layer was adjusted to pH 8 with saturated NaHCO3 and extracted 3×200 ml ether. The latter ether extracts were combined, dried (MgSO4) and stripped in vacuo to an oil, 4.56 g. The latter was twice chromatographed on a thick layer of silica gel, using 12:1 hexane:ethyl acetate as eluant. In each case, the second band to elute was separated. In this manner 1.3 g of intermediate 2-benzylquinoline was isolated. The latter intermediate (0.5 g, 0.0023 mol) was dissolved in 10 ml of dry ethanol and brought to reflux. Sodium metal (0.8 g) was added over the course of 2 hours. After an additional 1.5 hours of reflux, the contents of the flask began to solidify. The reaction mixture was then cooled to room temperature, stripped of ethanol in vacuo, and the residual solid dissolved in 50 ml of H2O and extracted 3×50 ml benzene. The combined benzene extracts were dried (K2CO3) and stripped to an oil, 0.39 g. The latter was chromatographed on a thick layer plate of silica gel using CHCl3 as eluant to yield purified title product, 0.35 g.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([F:21])[CH:14]=2.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([OH:20])=[C:10]([NH:9][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1cnc2cc(F)ccc2c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2cc(F)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.4 mL, 46.2 mmol) was added to a suspension of 3-amino-7-fluoro-4-quinolinol hydrochloride (3 g, 14.0 mmol) in tetrahydrofuran (50 mL). Butyryl chloride (1.6 mL, 15.4 mmol) was added dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 hours. Aqueous sodium bicarbonate was added and the reaction mixture was allowed to stir at ambient temperature for about 1 hour. The resulting biphasic mixture was filtered to remove solids. The solids were rinsed with diethyl ether to provide a slightly pink powder. The tetrahydrofuran layer was concentrated under vacuum to provide a dark pink solid. This solid was triturated with ether and then oven dried. The solids were combined to provide 3.0 g of N-(7-fluoro-4-hydroxyquinolin-3-yl)butanamide. A 300 mg portion was recrystallized from ethyl acetate/ethanol to provide a light gray fluffy solid, m.p. 306-308° C. Analysis: Calculated for C13H13FN2O2: %C, 62.90; %H, 5.28; %N, 11.28; Found: %C, 62.95; %H, 5.34; %N, 11.14.
Reaction SMILES: [I-:1].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:9]([CH2:32]Cl)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[CH:15][C:14]([O:28][CH3:29])=[C:13]([O:30][CH3:31])[CH:12]=2)=[O:7])[CH3:4]>CC(=O)CC>[CH2:3]([O:5][C:6]([C:8]1[C:9]([CH2:32][I:1])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[CH:15][C:14]([O:28][CH3:29])=[C:13]([O:30][CH3:31])[CH:12]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A mixture of sodium iodide (1.68 g) and 2-butanone (15 ml) was stirred at 80° C. for 1 hour, after which 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (2.68 g) was added, followed by stirring at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured over water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (1:1, v/v) to yield -6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-iodomethylquinoline-3-carboxylic acid ethyl ester (1.4 g, 58%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 170 to 171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH2:14])[CH:3]=1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[Cl-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CCCCCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH:14][C:21](=[O:23])[CH3:22])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)ccc1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Cl)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A stirred solution of 4-chloro-1,1′-biphenyl-2-ylamine (3.46 g, 17.0 mmol) in dichloromethane (8.5 mL) was treated with pyridine (3.2 mL, 39 mmol), acetic anhydride (1.77 mL, 18.7 mmol), and 4-(dimethylamino)pyridine (0.62 g, 0.51 mmol) and stirred at room temperature for 12 hours. A saturated, aqueous solution of ammonium chloride (150 mL) was added, and the layers were separated. The aqueous phase was extracted with dichloromethane (3×75 mL). The combined organic phase was washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL) and a saturated, aqueous sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered and the solvent evaporated in vacuo to yield a brown oil. Toluene was added and removed in vacuo (×3) to afford a brown solid which, upon trituration with ethyl acetate/hexane, afforded the title compound as a homogeneous, colorless, crystalline solid (2.28 g, 93%), m.p. 125-127° C.;
Reaction SMILES: F[C:2]1[C:7](F)=[C:6](I)C=C[C:3]=1[C:10]1C=[CH:14][C:13](C2C=CC(CCC)=CC=2)=[CH:12][C:11]=1F.OCC(C)(CO)C.O.CC(C)=O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:6][CH2:7][CH2:2][CH2:3][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCc1ccc(-c2ccc(-c3ccc(I)c(F)c3F)c(F)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCC
Yield: 60 %

Procedure:
A solution of (0.1 mmol) of 10 (0.12 mmol) of 4, 14 mg (0.13 mmol) of neopentyl glycol, 95 mg (0.3 mmol) of Ba(OH)2.8 H2O, 80 μl (6.08 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 2 ml of 95% i—PrOH is stirred at 80° C. for 12 hours. The solvent is subsequently removed under reduced pressure. 2 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×2 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is purified by recrystallisation twice from nonane (yield: 60%).
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25]=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH2:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19][CH2:20]1)[CH:25]=[CH2:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of methyltriphenylphosphonium bromide (5.3 g, 14.8 mmol) in THF (50 mL) was cooled to 0° C. under nitrogen. Potassium hexamethyl disilazide (27.7 mL, 0.5M toluene solution, 13.9 mmol) was added and the mixture was stirred for 30 min. A solution of (1-t-butoxycarbonylpiperidin-4-yl)acetaldehyde from Step A (2.25 g, 9.9 mmol) in THF (10 mL) was added and the mixture was warmed to rt. After 30 min, the reaction was complete by tlc analysis. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine (100 mL each). The organic phase was dried over sodium sulfate and concentrated to give an oil which was purified by FC (75 g silica, 10/1 hexane/ethyl acetate) to afford the title compound (1.61 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[S:12][C:13]=1[CH3:14].[BH4-].[Na+].[OH-].[Na+]>CCOCC>[CH2:15]([C:11]1[S:12][C:13]([CH3:14])=[C:9]([CH3:8])[CH:10]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(C(O)c2ccccc2)sc1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cc2ccccc2)sc1C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (50 mL) was added dropwise over a 60 minute period to a stirred, 0° C. suspension of 4,5-dimethylthiophene-2-yl-(phenyl)-methanol (7.7 g, 35.3 mmol), sodium borohydride (6.67 g, 177 mmol) and ether (600 mL). After an additional 1.5 hours the reaction mixture was added to 10% aqueous sodium hydroxide (600 mL) and stirred for 30 minutes. The layers were separated and the ether phase was washed with 10% aqueous sodium hydroxide, brine and dried (magnesium sulfate). The ether phase was concentrated to provide the title compound as a an oil (6.73 g, 94%): NMR (CDCl3); δ7.33-7.19 (m, 5H), 6.47 (s, 1H), 4.03 (s, 2H), 2.27 (2, 3H), 2.06 (s, 2H); MS (EI) (M+) 202 (45%, MI).
Reaction SMILES: [C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]([OH:25])=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Reaction time: 6 h
Yield: 99.2 %

Procedure:
To a solution of 3.00 g of 4-fluorenyloxycarbonyl-morpholine-2-carboxylic acid in 150 mL of acetone was added 1.77 g of potassium carbonate and 1.33 g of dimethyl sulfate. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled, filtered, and concentrated. The residue was dissolved in 125 mL of Et2O and washed with 50 mL each of saturated NaHCO3, water, and brine. The organic phase was dried over MgSO4 and concentrated to yield 3.10 g of the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[CH3:13][O-:14].[Na+].C=O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:13][OH:14]
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: C[O-]
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a stirred solution of (4-Chloro-phenyl)-acetic acid methyl ester (2 g, 10.8 mmol) in DMSO (22 mL) was added sodium methoxide (29.2 mg, 0.54 mmol) at 0° C. Paraformaldehyde (342 mg, 11.4 mmol) was then added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3×20 mL), brine (20 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 84:16) to afford the title compound as a colourless gum in 52% yield, 1.2 g.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:14]([CH:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C[O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:15]1([N:14]2[C:8]3[N:9]=[C:10]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([C:25]([OH:33])=[O:24])=[CH:27][N:28]=4)[N:11]=[CH:12][C:7]=3[CH:6]=[C:5]2[C:3](=[O:4])[N:2]([CH3:22])[CH3:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Temperature: 130 °C
Yield: 44.2 %

Procedure:
To a mixture of 2-Chloro-7-cycloheptyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (517 mg, 1.2 mmol, 1.0 eq), 6-Amino-nicotinic acid methyl ester (221 mg, 1.5 mmol, 1.2 eq), Cs2CO3 (591 mg, 1.8 mmol, 1.5 eq) and BINAP (38 mg, 0.06 mmol, 0.05 eq) was bubbled in N2 via a pipette for 3 min. Pd(OAc)2 (14 mg, 0.06 mmol, 0.05 eq) was added and the flask was sealed and stirred in an oil bath heated to 130° C. for 3 hr. The mixture was filtered through a pad of celite and washed with etOAc. The organic layer was washed with water, then brine and the organic layers combined, dried over Na2SO4. The solvent was evaporated and the brown solid was triturated with acetonitrile, filtered, washed with ACN and dried under high vacuum to yield the title compound as a light pink solid (236 mg, 0.53 mmol, 44% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.84-8.90 (m, 1H) 8.69 (s, 1H) 8.61 (d, J=9.09 Hz, 1H) 8.51 (br s, 1H) 8.20-8.26 (m, 1H) 6.40 (s, 1H) 4.40-4.53 (m, 1H) 3.87 (s, 3H) 3.10 (s, 6H) 2.48-2.64 (m, 2H) 1.90-2.00 (m, 2H) 1.76-1.86 (m, 2H) 1.63-1.72 (m, 4H) 1.45-1.56 (m, 2H). MS (m/z, MH+): 437.5
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:18]([OH:20])=O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C@@H:38]([NH2:45])[C:39]3[O:43][N:42]=[C:41]([CH3:44])[N:40]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C@@H:38]([NH:45][C:18]([C:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=4)[CH:7]=[C:2]([F:1])[C:3]=3[O:21][CH3:22])=[O:20])[C:39]3[O:43][N:42]=[C:41]([CH3:44])[N:40]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COc1c(F)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Product: COc1c(F)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1

Procedure:
5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide was prepared from 5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.06 g, 0.19 mmol) and 2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (0.063 g, 0.19 mmol) following general procedure A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.O1CCCC1.[CH3:25][NH2:26]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:26][CH3:25])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
A solution of 63.2 g. (0.2 mol) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one in 1.7 l. of tetrahydrofuran and 400 ml. of benzene was saturated with methylamine. A solution of 45.5 g. of titanium tetrachloride in 400 ml. of benzene was added slowly with ice cooling. After addition was complete, the reaction mixture was stirred and refluxed for 2 hours. It was then partitioned between water and methylene chloride. The organic layer was dried over sodium sulfate and evaporated. Crystallization from methylene chloride/hexane yielded 7-bromo-2-methylamino-5-(2-pyridyl)-3H-1,4-benzodiazepine, having a melting point of 208°-214°.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N:8]1[C:13]2[C:14]([C:17]([OH:19])=[O:18])=[CH:15][S:16][C:12]=2[CH:11]=[N:10][CH:9]=1>ClCCl.CO>[CH3:1][O:18][C:17]([C:14]1[C:13]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[S:16][CH:15]=1)=[O:19]
Reactant: O=C(O)c1csc2cncnc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1csc2cncnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylsilyldiazomethane (2 M in hexane, 1 mL) was added to a suspension of thieno[3,2-d]pyrimidine-7-carboxylic acid (50 mg) in a mixture of dichloromethane and methanol (95/5, 1 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated under reduced pressure and the crude residue was purified by flash chromatography (DCM/MeOH, 97/3) to give 40 mg of thieno[3,2-d]pyrimidine-7-carboxylic acid methyl ester.