Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([C:10]2[CH:11]=[CH:12][C:13]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([F:7])[CH:9]=2)=[CH:22][CH:21]=1)[CH3:24]
Reactant: Brc1ccc[se]1
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1

Procedure:
A mixture of 34.2 g (0.16 mol) of 2-bromoselenophene, 40.0 g (0.16 mol) of 3-fluoro-4′-ethylbiphenyl-4-ylboronic acid, 10.0 g (8.65 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 200 ml of 2 N sodium carbonate soln. in 500 ml of toluene/ethanol (2:3) is heated at 90° C. for 2 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-selenophene is obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10]OC1C=CC(N)=CC=1>>[CH3:10][NH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[O:2][CH3:1]
Reactant: COc1cccc(N)c1
Reactant: COc1ccc(N)cc1
Product: CNc1cccc(OC)c1
Yield: 77 %

Procedure:
m-Anisidine (Aldrich Chemical Corp.) was substituted for p-anisidine in the procedure described in Journal Chemical Society, London, 1969:2223, Perkin Transactions I., which gave N-methyl-m-anisidine, as an oil, 24.5 g, 77% yield. NMR was consistent with structure. MS: APCI: M+1: 138.2 (M: 137.2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(OC)(OC)OC.[CH2:20](O)[CH2:21][OH:22]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:21]1[O:22][C:7]2([CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH2:8]2)[O:12][CH2:20]1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: COC(OC)OC
Product: Brc1ccc2c(c1)CCC1(C2)OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
A mixture of 6-bromo-2-tetralone (8.80 g, 39 mmol), trimethyl orthoformate (17.2 ml, 157 mmol), ethylene glycol (16.2 ml, 290 mmol) and p-toluenesulfonic acid (0.07 g, 0.37 mmol) in dry dichloromethane (200 ml) was stirred at room temperature for 18 h, then partitioned between saturated aqueous NaHCO3 (100 ml) and dichloromethane (2×50 ml). The combined organic extracts were dried (Na2SO4) then evaporated in vacuo to give an oil. Column chromatography on silica with 0-10% diethyl ether-hexane gradient elution gave 6-bromo-2-tetralone ethylene ketal as a yellow oil (8.84 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)(=[O:23])=[O:22])[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:32])([F:33])[F:34])[CH:25]=2)(=[O:23])=[O:22])[CH:3]=1
Reactant: COC(=O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-(((4-chloro-2-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)phenyl)thio)methyl)benzoate (635 mg, 1.155 mmol), NaOH (5M, 2 ml) in MeOH (10 ml) was stirred at room temperature overnight. The solvent was removed and the residue was diluted with water, acidified with 10% HCl. The mixture was extracted with EtOAc (2×20 ml). The combined organic layer was washed with brine and concentrated under vacuum. The desire product was purified by MPLC (50% to 100% EtOAc/Hexane).
Reaction SMILES: [CH2:1]([P:3]([OH:10])([CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])[CH3:2].[OH-].[Na+:12]>O>[Na+:12].[CH2:1]([P:3]([OH:10])([CH2:5][CH2:6][C:7]([O-:9])=[O:8])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCP(=O)(O)CCC(=O)[O-]
Yield: 110.6 %

Procedure:
498 g (3 mol) of 3-(ethylhydroxyphosphinyl)propionic acid (produced as in Example 15) are dissolved in 860 g of water and initially charged into a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel and neutralized with about 480 g (6 mol) of 50% sodium hydroxide solution. The water is subsequently distilled off in vacuo to leave 624 g (99% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid sodium salt as a solid material.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:32][N:33](C)C=O>O>[C:32]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1)#[N:33]
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(-c2cc(-c3ccc([N+](=O)[O-])cc3)cc(-c3ccccn3)n2)n1
Temperature: 160 °C
Reaction time: 4.5 h

Procedure:
A mixture of 6-bromo-4′-(4-nitrophenyl)-2,2′:6′,2″-terpyridine (5.63 g), cuprous cyanide (4.66 g), sodium cyanide (2.55 g), and dimethylformamide (35 ml) was heated under argon with stirring to 160° C. for 4.5 hours, cooled to room temperature, and treated with 175 of water. After 15 min, the resulting slurry was filtered, the dark brown paste so obtained was placed in water (85 ml) containing sodium cyanide (3.2 g), and the reaction mixture was stirred for 15 minutes. The solid product was isolated by filtration, washed with water and dried under vacuum. Yield: 4.38 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:25])[F:24])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[CH3:21])=[O:8].[C:27]([Si:31]([CH3:40])([CH3:39])[O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:31]([O:32][CH:33]1[CH2:34][CH2:35][N:36]([C:2]2[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:25])[F:24])=[C:6]([CH:22]=2)[C:7]([NH:9][C:10]2[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[CH3:21])=[O:8])[CH2:37][CH2:38]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:40])[CH3:39]
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2C(F)(F)F)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc2C(F)(F)F)c(C)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of methyl 4-[[5-bromo-2-(trifluoromethyl)benzoyl]amino]-3,5-dimethyl-benzoate (0.10 g, 232.44 μmol), tert-butyl-dimethyl-(4-piperidyloxy)silane (55.08 mg, 255.68 mmol, see preparation 3) and Cs2CO3 (227.2 mg, 697.32 μmol) in 1,4-dioxane (2.5 ml) is added Pd2(dba)3 (21.28 mg, 23.24 μmol) followed by 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (9.54 mg, 23.24 μmol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 120° C. After 8 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrates are dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by flash chromatography (neutral alumina) using of 15%-85% ethyl acetate in hexanes as eluent to afford the title compound as a pale yellow oil (0.10 g, 80%). Mass spectrum (m/z): 565.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8](C)(C)[C:9](OCC)=[O:10])=O)=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH2:8][C:9](=[O:10])[NH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccc(Cl)cc2)=NN1
Yield: 82.2 %

Procedure:
A mixture of 26 g (0.10 mol) of ethyl α-(4-chlorobenzoyl)isobutyrate, 10 g (0.20 mol) of hydrazine monohydrate and 200 ml of ethanol was heated under reflux for 18 hours. The reaction solution was concentrated under reduced pressure. The obtained crude product was washed successively with water, methanol-water and diethyl ether-n-hexane and then air dried, to give 16 g of the object compound as white crystals (yield 84%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:6][CH:7]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:17]2[O:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: Oc1ccccc1-c1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Clc1ccc(-c2ccccc2OCC2CO2)nn1

Procedure:
A mixture of 3-chloro-6-(2-hydroxyphenyl)pyridazine (2.69 g.), epibromohydrin (4.5 ml.), anhydrous potassium carbonate (3.6 g.) and dry butane-2-one (100 ml.) was stirred and heated under reflux for 16 hours. The mixture was filtered and the filtrate was evaporated to dryness and the residue was twice recrystallized from ethanol to give 3-chloro-6-(2-epoxypropoxyphenyl)pyridazine, m.p. 118°-119°.
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:19][C:18]1[C:13]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: C1CNCCN1
Reactant: Clc1cccnc1Cl
Agent: C[Si](C)(C)c1cccc(N)c1
Product: Clc1cccnc1N1CCNCC1
Yield: 86.8 %

Procedure:
Compound A-01 can be synthesized according to method 1. Just R1, R2, and R3 of Scheme 1 are respectively —Cl, —H and p-SiMe3. More specifically, compound 1 is 2,3-dichloro-pyridine (2 g); compound 2 is piperazine; compound 3 is 1-(3-chloro-2-pyridyl)piperazine (2.3 g, yield 86.8%); compound 7 is compound 7a-p-(trimethylsilyl)phenyl isocynate.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1([CH3:23])[O:22][CH2:21][CH2:20][NH:19][CH2:18]1>CC(O)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][O:22][C:17]([CH3:23])([CH3:16])[CH2:18]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNCCO1
Solvent: CC(C)O
Product: Cc1c(N2CCOC(C)(C)C2)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C

Procedure:
2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) and 2,2-dimethylmorpholine (0.46 mL, 4.03 mmol) were slurried in 2-propanol (10 mL) and heated in a microwave reactor at 120° C. for 5 h. The reaction was then concentrated to dryness and purified by column chromatography (hexanes:EtOAc, 1:0 to 1:1) to give 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2,2-dimethylmorpholine. 1H NMR (400 MHz, chloroform-d) δ ppm 7.31 (1H, ddd, J=9.7, 2.7, 1.5 Hz), 6.89 (1H, ddd, J=12.3, 8.9, 2.5 Hz), 3.93-3.98 (2H, m), 3.23-3.28 (2H, m), 3.10 (2H, s), 2.47 (3H, s), 1.37 (6H, s). Mass Spectrum (ESI) m/e=327.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:24]=[CH:23][C:17]3[O:18][C:19]([F:22])([F:21])[O:20][C:16]=3[CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:25]>ClCCl>[ClH:25].[F:22][C:19]1([F:21])[O:18][C:17]2[CH:23]=[CH:24][C:14]([CH2:13][CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:15][C:16]=2[O:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Agent: Cl
Solvent: ClCCl
Product: FC1(F)Oc2ccc(CC3CCNC3)cc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution consisting of 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.36 g, 3.98 mmol) and dichloromethane (20 mL) was added HCl (4 M solution in dioxane, 6 mL). The reaction mixture was stirred at rt for 18 h. The resultant mixture was concentrated to give the title compound in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:32]3[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=3)(=[O:44])=[O:43])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(S(N)(=O)=O)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(S(N)(=O)=O)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and benzene-1,4-disulfonamide: 1H-NMR (DMSO-d6) δ 8.10-8.01 (4H, m), 7.63 (2H, s), 7.48-7.27 (9H, m), 6.62-6.59 (1H, m), 3.28-3.21 (2H, m), 2.73 (21H, t, J=7.2 Hz), 2.27 (3H, s), 2.23 (3H, s).
Reaction SMILES: ON(C)[C:3](=[O:26])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N.[CH3:29][NH:30][OH:31].CN(C)O>>[CH3:29][NH:30][O:31][C:3](=[O:26])[CH:4]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:17]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CN(O)C(=O)C(CC1CCCCC1)c1ccc(OCc2ccccn2)cc1
Reactant: CNO
Agent: CN(C)O
Agent: N
Product: CNOC(=O)C(CC1CCCCC1)c1ccc(OCc2ccccn2)cc1

Procedure:
The above material was obtained as a side product of Example 11. 1H NMR (DMSO-d6, 300 MHz) δ 0.9 (m, 2H), 1.1 (m, 4H), 1.63 (m, 6H), 1.81 (m, 1H), 2.6 (d, J=6Hz, 3H), 3.65 (t, J=7Hz, 1H), 5.17 (s, 2H), 7.0 (d, J=7Hz, 2H), 7.23 (d, J=7Hz, 2H), 7.35 (m, 1H), 7.5 (d, J=8Hz, 1H), 7.83 (dt, J=8Hz, 2Hz, 1H), 7.9 (q, J=6Hz, 1H), 8.6 (m, 1H). IR (CDCl3): 3245, 1735, 1610 cm-1. MS (DCI/NH3) m/e 369 (M+H)+. The above material was also obtained according to the procedures described in Example 17 substituting N-methylhydroxyl-amine for N,N-dimethylhydroxylamine.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[NH:13][CH:14]=[C:15]([C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)=[O:11]>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10]([C:12]1[NH:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)c2ccccc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cc2ccccc2)c[nH]1
Reaction time: 8 h
Yield: 57.5 %

Procedure:
Triethylsilane (0.215 mL, 1.35 mmol) was added to a stirring, room temperature solution of methyl-4-benzoyl-1H-pyrrole-2-carboxylate (0.1118 g, 0.488 mmol) in trifluoroacetic acid (TFA) (1.04 mL, 0.47 M) under N2. After stirring overnight, the reaction was complete by HPLC. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc) to obtain pure 25 (0.0604 g, 57.5%): 1H (CDCl3, 400 MHz): δ 9.44 (1H, broad s), 7.34-7.21 (5H, m), 6.78 (1H, s), 6.75 (1H, s), 3.853 (2H, s), 3.846 (3H, s) ppm. 13C (CDCl3, 100 MHz): δ 162.09, 141.68, 128.85, 128.70, 126.25, 125.55, 122.67, 121.86, 115.74, 51.70, 33.41 ppm. HPLC: 9.693 min. (Starting material: 8.611 min.)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([O:24][CH2:25][C:26]3[C:27]([Cl:48])=[C:28]([S:33]([N:36]4[CH2:40][CH2:39][CH2:38][C@H:37]4[C:41]([NH:43][CH2:44][CH2:45][CH2:46][NH2:47])=[O:42])(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=3[Cl:32])[CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([O:24][CH2:25][C:26]3[C:27]([Cl:48])=[C:28]([S:33]([N:36]4[CH2:40][CH2:39][CH2:38][C@H:37]4[C:41]([NH:43][CH2:44][CH2:45][CH2:46][NH:47][C:7]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)=[O:9])=[O:42])(=[O:34])=[O:35])[CH:29]=[CH:30][C:31]=3[Cl:32])[CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCCCN)c3Cl)c2n1
Agent: Cl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCCCNC(=O)c4ccc(C#N)cc4)c3Cl)c2n1
Yield: 75 %

Procedure:
By following a procedure analogous to Example 5, starting from 4-cyanobenzoic acid and 1-[[3-[(2-methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-aminopropyl]-2(S)-pyrrolidinecarboxamide hydrochloride, the expected product (yield=75%) is obtained after purification by chromatography on silica gel using a dichloromethane/methanol mixture (98/2; v/v) as the eluent. M.p.=78-80° C. [α]D24 =-39° (c=0.3; CH3OH)
Reaction SMILES: [S:1]1[C:5]2[CH2:6][N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[Br:23][C:2]1[S:1][C:5]2[CH2:6][N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCCc2ccsc2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)N1CCCc2cc(Br)sc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of Compound 1044 (1.78 g, 7.90 mmol) in acetonitrile (80 mL) at 0° C. was slowly added NBS (1.69 g, 9.48 mmol). The reaction was stirred at room temperature for 30 minutes, at which point HPLC analysis indicated disappearance of starting material. The reaction was quenched by addition of saturated sodium bicarbonate (50 mL) and stirred for one hour. The reaction was then extracted with diethyl ether (3×100 mL), the organics concentrated, and the residue purified by silica chromatography (5-30% ethyl acetate in hexanes) to give ethyl 2-bromo-5,6-dihydro-4H-thieno[2,3-c]azepine-7(8H)-carboxylate as a pale yellow oil (Compound 1045, 2.07 g, 86% yield); 1H NMR (300 MHz, CDCl3): δ 6.67 (s, 1H), 4.38 (s, 2H), 4.15-3.99 (m, 4H), 3.64 (d, J=3.8 Hz, 2H), 2.73-2.67 (m, 2H) and 1.22-1.09 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:39][C@H:40]1[CH2:45][C@@H:44]([OH:46])[CH2:43][CH2:42][NH:41]1>CN(C)C(=O)C>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]1[N:7]=[C:2]([N:41]2[CH2:42][CH2:43][CH:44]([OH:46])[CH2:45][CH:40]2[CH3:39])[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=1
Reactant: C[C@H]1C[C@@H](O)CCN1
Reactant: Cc1cccc(C)c1-c1nc(Cl)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1nc2c(c(N3CCC(O)CC3C)n1)CN(c1cc(C(C)C)nn1C)CC2
Temperature: 125 °C

Procedure:
To a solution of 4-chloro-2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (40 mg, 0.101 mmol) in N,N-dimethylacetamide (1.5 mL), was added diisopropylethylamine (0.141 mL, 0.808 mmol) and cis racemic-2-methylpiperidin-4-ol hydrochloride, (CAS#344329-35-7, 30.6 mg, 0.202 mmol). The reaction was heated to 125° C. for 42 h. After cooling, the mixture was directly purified via HPLC ((0.1% ammonium hydroxide in acetonitrile/water 35%-100%) to give 26 mg of product. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.14-7.24 (m, 1 H), 7.04-7.12 (m, 2 H), 5.70 (s, 1 H), 4.15 (d, J=15.2 Hz, 1 H), 3.94 (d, J=15.4 Hz, 1 H), 3.78-3.91 (m, 1 H), 3.69 (s, 3H), 3.57-3.67 (m, 1 H), 3.27-3.39 (m, 2 H), 3.19-3.27 (m, 1 H), 3.02-3.12 (m, 2 H), 2.96 (ddd, J=12.8, 9.3, 3.2 Hz, 1 H), 2.86 (ddd, J=13.8, 7.1, 6.9 Hz, 1 H), 2.09 (s, 6 H), 1.87-2.02 (m, 2 H), 1.82 (d, J=3.0 Hz, 1 H), 1.56-1.71 (m, 1 H), 1.49 (dt, J=12.9, 8.3 Hz, 1 H), 1.22 (d, J=7.1 Hz, 6 H), 1.14 (d, J=6.3 Hz, 3 H); MS (ESI+) m/z 475.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-bromo-phenol (5.5 g, 31.8 mmoles), imidazole (4.3 g, 63.6 mmoles) in CH2Cl2 (70 ml) was added dropwise to a solution of tert-butyl-chloro-dimethylsilane (5.3 g, 35 mmoles) in CH2Cl2 (5 ml) at 0° C. The reaction mixture was stirred for 3 hours at room temperature then evaporated to dryness under vacuum. The residue was partitioned between water and ethyl acetate and from the organic solution after essiccation over MgSO4, filtration and evaporation the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[CH2:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[Cl:19].[OH2:20]>CN(C=O)C.Cl[Pd]Cl>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[C:5]([CH2:10][CH:11]=[O:20])[CH:4]=1
Reactant: C=Cc1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Reactant: O
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1CC=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
To a mixture of 2,2′,5′-trichloro-4-methoxy-5-vinylbiphenyl (1.0 g, 3.2 mmol) in anhydrous DMF (10 mL), PdCl2 (1.14 g, 6.4 mmol) was added and the resulting mixture was stirred at room temperature under nitrogen for 16 h. To this mixture, water (0.5 mL) was added and the resulting mixture was stirred at room temperature for another 6 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-3% ethyl acetate/petroleum ether) to afford the desired product (300 mg, 29% yield) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cc1ccc(C2CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
Methyl 2-(4-cyclopropylphenyl)acetate (3.10 g, 16.30 mmol) was dissolved in a mixture of THF/MeOH/water (2:2:1, 80 mL), and the solution was treated with lithium hydroxide hydrate (0.8548 g, 20.37 mmol). The mixture was then stirred at ambient temperature for 4 hours. The reaction mixture was neutralized to a pH of 4 with 3N HCl and concentrated in vacuo. The solids were re-dissolved in ethyl acetate and water. The pH was re-adjusted to a pH of about 3 to about 4 with 3N HCl. The layers were then separated. The aqueous layer was washed with ethyl acetate (2×). The combined organic layers were then washed with saturated NaCl, dried over Na2SO4 and concentrated to yield 2-(4-cyclopropylphenyl)acetic acid (2.82 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 7.16 (d, J=8.2, 2H), 7.03 (d, 2H), 3.60 (s, 2H), 1.92-1.83 (m, 1H), 098-0.91 (m, 2H), 0.70-0.64 (m, 2H).