Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:21][C:22]1[N:23]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=[CH:25][N:26]=1
Reactant: Cc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Triphenylmethyl chloride (16.0 g, 57.5 mmol) was added portionwise to a solution of 2-methylimidazole (4.10 g, 50.0 mmol) and Triethylamine (9.02 mL, 64.7 mmol) in 20 ml of N,N-dimethylformamide. The mixture was stirred for 18 hours, mixed with 300 ml of water and extracted with 1000 ml of ethyl acetate. The organic extract was washed with 1 L of water, brine, dried over MgSO4 and concentrate in vacuum to 50 ml volume. A precipitate was collected, washed with ethyl acetate and dried in high vacuum for 18 hours. Weight 15.0 g (92.5%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.29 (m, 9H), 7.16-7.11 (m, 6H), 6.90 (d, J=1.5, 1H), 6.71 (d, J=1.5, 1H), 1.65 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]#[N:15].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>CCO.N1CCCCC1>[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]#[N:15])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1c(Nc2cccnc2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(Nc2cccnc2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 53 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile (100 mg) was then suspended in EtOH (4 mL) and 4-hydroxybenzaldehyde (31 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carbonitrile as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (40 mg, 53% yield).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:10]1[C:11]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>O1CCCC1.CO.O>[C:32]([O:31][C@@H:9]([C:10]1[C:11]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH:21]([CH3:22])[CH3:23])[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:34])([CH3:35])[CH3:33]
Reactant: Cc1cc2nc(C(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2nc(C(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 45 °C
Yield: 96.5 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinolin-6-yl)ethyl pivalate (77 mg, 0.156 mmol) in tetrahydrofuran/methanol (2:1, 1 mL) was added 1 M sodium hydroxide (2 mL) and the reaction was heated to 45° C. overnight. The reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was then dried over sodium sulfate and concentrated, followed by co-evaporation with acetonitrile to give a clear oil (62 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H31ClNO2: 412.20. found: 412.96.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.[C:38]([O-:41])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH3:5][C:14]([O:41][CH2:38][CH2:6][N:7]([CH2:35][C:32]1[S:33][CH:34]=[C:30]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)[CH:31]=1)[CH3:8])([CH3:19])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCOC(C)(C)C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 5.4 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (400 mg, 1.08 mmol) in dioxane and water (4 mL/1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (462 mg, 1.94 mmol), Pd(PPh3)4 (100 mg) and K2CO3 (447 mg, 3.24 mmol). The reaction mixture was heated at 150° C. for 20 minutes by microwave irradiation. The organic phase was concentrated and redissolved in DMSO (10 mL). The resulting solution was split to eight. NaBH3CN (30 mg), ZnCl2 (30 mg) and -[(1,1-dimethylethyl)oxy]ethyl}methylamine (50 mg) were added. The mixture was heated at 100° C. for 30 minutes which was then filtered and purified by HPLC with TFA to afford the title compound (15 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([OH:13])=[O:12].[OH-].[Na+]>C(#N)C.CN(C=O)C.[Pd]>[NH:6]1[C:7]2[C:3](=[C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Brc1cccc2[nH]ccc12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a mixture of 4-bromoindole (11.81 g, 60.26 mmol), and 3-carboxyphenylboronic acid (10.0 g, 60.6 mmol) in acetonitrile (100 mL) and DMF (100 mL) were added Palladium catalyst Pd(PPh3)4 (2.09 g, 1.81 mmol) and the freshly prepared sodium hydroxide solution (9.64 g, 241 mmol in 80 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under argon at 110° C. oil bath for 4 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, filtered through celite, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, dried over MgSO4, and concentrated. The crude product was purified by a silica gel column eluting with DCM:Hexanes:acetic acid (100:1:1) to provide 10.2 g (71%) of 3-(1H-indol-4-yl)-benzoic acid as a gray yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:31])=[CH:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].O1CCCC1>C(N(CC)CC)C>[F:15][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][NH:2][C:28](=[O:29])[CH:27]=[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:25][CH:24]=1)[CH3:31]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(=CC(=O)O)c1ccc(C(C)(C)C)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18 %

Procedure:
To the 50 ml of round bottom flask were put N-(4-aminomethyl-2-fluoro-phenyl)-methanesulfonamide hydrochloride (0.14 g, 0.55 mmol), 3-(4-t-butylphenyl)-but-2-enoic acid (1.0 eq, 0.12 g) and DMTMM (1.2 eq, 0.183 g). To this mixture was poured 25 ml tetrahydrofuran, added triethylamine (excess, 0.5 ml) and stirred 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed 1N HCl solution. The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=1/1) to yield the title compound (41.5 mg)
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Br)C1C=CC=CC=1.[OH-].[K+]>O1CCOCC1>[CH2:1]([O:20][C@@H:21]1[C@@H:22]([CH2:23][OH:36])[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
In 50 ml of dioxane was dissolved 10 g of 2'-deoxy-5'-O-trityl-5-fluorouridine. To the solution were added 2.9 ml of benzyl bromide and 14.6 g of particles of potassium hydroxide. The mixture was stirred at room temperature for 1 hour. The solvent was distilled off and the residue was dissolved in 80 ml of a 80% solution of acetic acid to undergo reaction at 50° to 60° C. for 2 hours. The reaction mixture was cooled with ice for 1 hour, the trityl alcohol was separated by filtration and the mother liquor was concentrated. To the concentrate was added ethanol and the mixture was stirred. The crystals precipitated were separated by filtration and dried, affording 5.0 g of the title compound in a yield of 72
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(OCC)(=O)C.CCCCCC>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 71 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-chlorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 71%. Melting point: 201-203° C. (Ethyl acetate-hexane).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:3].[Cl:16][C:17]1[CH:18]=[C:19]([C@H:24]([CH2:36][CH:37]=O)[CH2:25][N:26]([CH3:35])[C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:20]=[CH:21][C:22]=1[Cl:23].ClCCl.CO>O>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]([C@H:24]([CH2:36][CH2:37][N:13]2[CH2:14][CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([S:2]([CH3:1])=[O:3])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:25][N:26]([CH3:35])[C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CS(=O)c1ccc(C2CCNCC2)cc1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CCC(c2ccc(S(C)=O)cc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(4-methylsulfinylphenyl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was prepared. Chromatography with dichloromethane:methanol followed by conversion to the hydrochloride salt gave a white solid; mp 94°-125° C.; MS: 557; NMR (CD3OD): 1.8-2.3 (m, 6), 2.8 (s, 6), 2.8-3.3 (br, 6), 3.4-3.9 (m, 4), 7.9-7.7 (m, 12). Analysis for C30H34Cl2NO2S·1.0 HCl·1.5 H2O: Calculated: C, 58.02; H, 6.17; N, 4.51; Found: C, 57.74; H, 6.00; N, 5.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH:14]=[O:15])[CH:9]=2)[CH:7]=1.[S:17]1[CH:21]=[C:20]([N:22]([S:30]([C:33]2[CH:38]=[C:37]([F:39])[C:36](F)=[CH:35][C:34]=2[F:41])(=[O:32])=[O:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:36]2[C:37]([F:39])=[CH:38][C:33]([S:30]([N:22]([C:20]3[N:19]=[CH:18][S:17][CH:21]=3)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:32])=[O:31])=[C:34]([F:41])[CH:35]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH:14]=[O:15])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Reactant: O=Cc1cc(-c2cc(Cl)ccc2O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(C=O)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(5-Chloro-2-hydroxyphenyl)pyridine-2-carbaldehyde, (Preparation 880, 0.3 g, 0.0013 mol) and tert-butyl 1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate, (Preparation 297, 0.456 g, 0.0012 mol) were dissolved in dimethyl sulfoxide (5 mL) and potassium carbonate (0.355 g, 0.0026 mol) was added and reaction allowed to stir at room temperature for 2 hours. Water (10 mL) was added to the reaction, the resultant white precipitate was filtered off and dried in vacuo to give the title compound as a white solid (0.658 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:14][C:13](=O)[NH:12][C:11](=O)[CH2:10]1>C1COCC1>[ClH:1].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: O=C1CC(c2c(Cl)cccc2Cl)CC(=O)N1
Solvent: C1CCOC1
Product: Cl
Product: Clc1cccc(Cl)c1C1CCNCC1
Temperature: 0 °C
Yield: 152.6 %

Procedure:
9.0 g (34.9 mmol) of 4-(2,6-dichloro-phenyl)-piperidine-2,6-dione were dissolved in 150 mL of dry THF under a nitrogen atmosphere. The resulting solution was cooled to 0° C. and 35 mL (ca 350 mmol) of borane-methylsulphide complex dissolved in 100 mL of dry THF were added dropwise. The reaction mixture was allowed to warm to room temperature, heated to reflux for 3 h, then cooled to −5° C. and quenched by careful addition of 150 mL of 10% HCl solution. The reaction mixture was subsequently heated to reflux for 3 h, then, after cooling, the volatiles were removed in vacuo. The residue was taken up in water, basified with 2 N NaOH solution and extracted with AcOEt The organic phase was dried and the solvent was removed in vacuo. The resulting oil was taken up in CH2Cl2, brought to acidic pH with Et2O/HCl and the solvent was removed in vacuo. The resulting solid was triturated with Et2O, filtered and dried, yielding 7.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:10])[C:3]=1[C:4]#[N:5].[OH:11][C:12]1[CH:19]=CC=C[C:13]=1C#N>>[NH2:5][C:4]1[C:3]2[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=2[S:10][C:13]=1[C:12](=[O:11])[CH3:19]
Reactant: N#Cc1ccccc1O
Reactant: N#Cc1c(S)cccc1Cl
Product: CC(=O)c1sc2cccc(Cl)c2c1N

Procedure:
The procedure was similar to step S1A, while the starting material was 2-chloro-6-mercapto-benzonitrile (2A) in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37](O)=[O:38])[C:30]=2[CH3:40])=[CH:25][CH:24]=1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37]([NH:2][C:3]3([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]3)=[O:38])[C:30]=2[CH3:40])=[CH:27][CH:28]=1
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)c(C)c1CC(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2c(C)ccc(-c3ccc(Cl)cc3)c2C)CCC(F)(F)CC1
Reaction time: 0.08 h

Procedure:
2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). At 20° C., 3.07 ml of triethylamine were added dropwise, the mixture was stirred for 5 min and 2.75 g (10 mmol) of (4′-chloro-2,4-dimethylbiphenyl-3-yl)acetic acid were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 2.59 g (53% of theory) of the title compound of melting point 179-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: COc1cc(C#N)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C(=O)Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Methoxy-4-cyanobenzoic acid (Tetrahedron Letters, 1986, 27(49), 5997-6000) (1 g, 5.6 mmol) was dissolved in CH2Cl2 (20 ml). Oxalyl chloride (1.5 ml, 8.2 mmol) was rapidly introduced into the solution and a drop of DMF was added. A vigorous reaction took place with the abundant evolution of gaseous products. The solution was stirred for 1 h then allowed to stand over night. Solvent was removed using a rotary evaporator to leave 1.1 g of an off white solid (5.6 mmol, yield 99%) that was used without further purification.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:26])=O>>[Cl:26][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Cl)c2cc1OC
Yield: 51 %

Procedure:
DMF (0.5 ml) was added to a mixture of 6-methoxy-7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (5.1 g, 20 mmol) in thionyl chloride (50 ml). The mixture was stirred and heated at reflux for 3 hours, allowed to cool and the excess thionyl chloride removed by evaporation. The residue was suspended in methylene chloride and washed with aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with methylene chloride and the combined extracts dried (MgSO4). The crude product was recrystallised from methylene chloride/hexane to give 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (2.8 g, 51%) as a fine white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][O:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:34]3[CH:33]=[N:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: COc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 54 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a white solid. UPLC-MS (condition 1) tR=2.10 min, m/z=475.2 [M+H]+, m/z=473.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.79 (m, 1H) 1.79-1.92 (m, 1H) 2.91 (d, J=11.25 Hz, 1H) 3.19-3.27 (m, 2H) 3.33-3.47 (m, 1H) 3.89 (s, 3H) 4.16-4.25 (m, 1H) 4.83 (d, J=3.42 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.41 (d, J=1.96 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.21 (d, J=1.47 Hz, 1H) 8.30 (d, J=2.69 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH2:3]1.S(OOS([O-])(=O)=O)(O)(=O)=[O:17].[K+].OOS([O-])=O.[K+].OS([O-])(=O)=O.[K+].[OH2:39]>CO>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([S:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:17])=[O:39])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(Sc2ccccc2)CC1
Reactant: O
Reactant: O=S(=O)([O-])OOS(=O)(=O)O
Agent: O=S(=O)([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CC1(C)CC=C(S(=O)(=O)c2ccccc2)CC1
Reaction time: 64 h

Procedure:
A stirred solution of (4,4-dimethylcyclohex-1enyl)phenyl sulphide (1.66 g.) in methanol (30.5 ml.) cooled at 0° C., was treated dropwise with a solution of potassium hydrogen persulphate ("Oxone" brand, containing 2KHSO5. KHSO4.K2SO4 ; "Oxone" is a registered trademark) (9.0 g.) in distilled water (30.5 ml.) at such a rate as to maintain the reaction temperature below 5° C. After the addition was complete, the reaction was stirred for 64 hours. The methanol was then evaporated and the residue was diluted with water (50 ml.) before extraction with ether (3×100 ml.). The combined extracts were washed successively with saturated sodium bicarbonate solution (3×50 ml.) and water (3×50 ml.), dried (MgSO4) and evaporated. The residue obtained was purified by flash chromatography on silica, eluting with ether hexane (40:60 v/v), to give (4,4-dimethyl-cyclohex-1-enyl)phenyl sulphone (1.52 g.), m.p. 51°-53° C.; NMR (CDCl3): 0.9 (6H,s), 1.45 (2H,t), 2.0-2.3 (4H,m), 7.0 (1H,br s), 7.4-7.7 (3H,m) and 7.8-8.0 (2H,m).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:13].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[CH:6]([C:5]1[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]([O:1][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[C:3]([CH3:13])[CH:4]=1)=[O:7]
Reactant: Cc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1c(C)cc(C=O)cc1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-3-methyl-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure of alkylation of substituted 2-nitrophenols gives a light tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.56 (m, 3H) 2.42 (s, 3H) 3.62 (s, 3H) 4.82 (q, J=6.82 Hz, 1H) 8.10 (d, J=1.52 Hz, 1H) 8.29 (d, J=1.52 Hz, 1H) 9.98 (s, 1H). ESI-MS: m/z 268.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:16][CH:21]=[C:19]([CH2:18][Cl:17])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CCl)CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1

Procedure:
To a solution of 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 20 mmol) in acetone (80 mL) was added 1,3-dichloroacetone (3.3 g, 26 mmol), MgSO4 (3.6 g, 30 mmol) and MgCO3 (1.68 g, 20 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (150 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3 and brine. After drying (Na2SO4), the solvent was removed to afford the desired product. 1H NMR (CDCl3): δ 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (1H, m), 2.87 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).