Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=O.[CH:15]([C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:19]=1[NH2:20])([CH3:17])[CH3:16]>C(O)(=O)C>[CH:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:18]([CH:15]([CH3:17])[CH3:16])[C:19]=1/[N:20]=[C:2]1/[C:1](=[N:20]/[C:19]2[C:21]([CH:25]([CH3:26])[CH3:27])=[CH:22][CH:23]=[CH:24][C:18]=2[CH:15]([CH3:17])[CH3:16])/[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[C:3]/1=[CH:4][CH:5]=[CH:6]3)([CH3:27])[CH3:26]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1C(=O)c2cccc3cccc1c23
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1/N=C1C(=N/c2c(C(C)C)cccc2C(C)C)/c2cccc3cccc/1c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
A mixture of 1.82 g (10 mmol) of acenaphtoquinone, 3.54 g (20 mmol) of 2,6-diisopropylaniline, and 40 ml of glacial acetic acid was refluxed for 2 h and then stirred for 12 h at room temperature. The resulting precipitate was separated, washed with 20 ml of cold water, and dried under vacuum. 3.89 g of dark-yellow solid were obtained with a yield of 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[N:6][CH:7]=1.Cl.O1CCOC[CH2:36]1>CO>[CH3:36][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:8]([C:5]1[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:21])=[O:22])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: C1COCCO1
Reactant: O=C(O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]benzoic acid (20 mg), 4N HCl/dioxane (1 mL) and 1.5 mL of methanol was refluxed overnight. After cooled to room temperature, the mixture was concentrated and the residue was diluted with ethyl acetate, washed with sodium bicarbonate and brine and dried. Removal of the solvents afforded the title compound as an off white solid: 1H NMR: (CDCl3, ppm) δ 11.20 (s, 1H), 8.22 (m, 2H), 8.04 (m, 2H), 7.94 (m, 1H), 7.62 (m, 2H), 7.54 (m, 1H), 7.31 (m, 1H), 3.54 (s, 3H); MS: (M+H)/z=533.0.
Reaction SMILES: [NH2:1][NH2:2].[OH:3][C:4]1[C:5]([C:10]([O:12]C)=O)=[N:6][CH:7]=[CH:8][CH:9]=1>C(O)C>[OH:3][C:4]1[C:5]([C:10]([NH:1][NH2:2])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: NN
Reactant: COC(=O)c1ncccc1O
Solvent: CCO
Product: NNC(=O)c1ncccc1O

Procedure:
Hydrazine (0.248 mL, 7.91 mmol) was added under argon to a solution of methyl 3-hydroxy-2-pyridinecarboxylate (808 mg, 5.28 mmol) in ethanol (25 mL). The reaction mixture was stirred at reflux overnight (yellow solution). After cooling, a solid which has crashed out was filtrered to afford the desired product in 826 mg as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH:11]=[N:12][NH:13][C:14]([NH2:16])=[S:15])[CH:9]=2)[NH:4][N:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:16][C:14](=[N:13]/[N:12]=[CH:11]/[C:8]1[CH:9]=[C:10]2[C:2]([CH3:1])=[N:3][NH:4][C:5]2=[N:6][CH:7]=1)[SH:15])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1n[nH]c2ncc(C=NNC(N)=S)cc12
Product: CC(=O)NC(S)=N/N=C/c1cnc2[nH]nc(C)c2c1
Temperature: 80 °C

Procedure:
The staring material 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methylene)thiosemicarbazide (500 mg, 2.0 mmol) and acetic anhydride (20 ml) was mixed and heated to 80° C. for 1 hour. The reaction mixture was then cooled down to room temperature. The yellow solid was precipitated out and was filtered off. The yellow solid was washed with ether (50 ml). The product was obtained in quantitative yield and used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[O:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1.[Br:18][C:19]1[C:28]([O:29][CH:30]([C:38]([O:40][CH3:41])=[O:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH2:42][NH3+:43])=[CH:24]2.[Cl-].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH:30]([O:29][C:28]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:42][NH:43][C:11]([C:9]3[O:10][C:6]([O:5][C:4]4[CH:3]=[C:2]([Cl:1])[CH:16]=[C:15]([Cl:17])[CH:14]=4)=[CH:7][CH:8]=3)=[O:12])[CH:24]=2)[C:19]=1[Br:18])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(C[NH3+])ccc2c1Br
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
5-(3,5-Dichloro-phenoxy)-furan-2-carbonyl chloride (0.194 g, 0.6655 mmol) was added under nitrogen to a suspension of 5-bromo-6-(1-methoxycarbonyl-2phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.30 g, 0.6655 mmol), prepared in the previous step, in 20 mL of methylene chloride at room temperature. Triethylamine (0.186 mL, 1.33 mmol) was then added to the mixture. The reaction was stirred at room temperature for 18 h (overnight). The reaction was diluted with methylene chloride, extracted one time with 1N HCl and two times with 5% NaHCO3. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (0.4079 g, 92%) as a tan oil, MS m/z: 668 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[F:28])=[C:10]([C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:11]=[CH:12][CH:13]=[O:14].[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=[O:32]>O1CCCC1>[F:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[C:10]([C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:11]=[CH:12][CH:13]([OH:14])[CH2:33][C:31](=[O:32])[CH2:30][C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=C(C=CC=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Solvent: C1CCOC1
Product: Cc1ccc(C(=C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of 5,5-bis(2-fluoro-4-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (1.3 g, 3.4 mmoles) in tetrahydrofuran (15 mL) at -50° C. was added the dianion of t-butyl acetoacetate (3.4 mL of a 1M solution, 3.4 mmoles). After stirring for 2 hours, another 0.7 mL of dianion solution was added and the solution stirred for an additional hour. The reaction was quenched with 1N hydrochloric acid and the mixture extracted with methylene chloride. The extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 1.3 g of the title compound; m.p.=55°-63° C.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[OH:20][CH2:19][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c(Cl)n(-c2cccc(CO)c2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(-c2cccc(CO)c2)c2ccccc12
Yield: 32 %

Procedure:
2-Chloro-1-(3-hydroxymethylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-hydroxymethylphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (32% yield) as a red solid. ESI/MS 336 (M+H); RT 2.37 min.
Reaction SMILES: [CH3:1][C@@:2]12[C:22]([CH3:24])([CH3:23])[C@@H:5]([C:6]3[C:7](=[O:21])[N:8]([C:11]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]=[CH:13][CH:12]=4)[NH:9][C:10]=31)[CH2:4][CH2:3]2.I[CH2:26][CH3:27]>CN(C)C=O>[CH2:26]([N:9]1[C:10]2[C@@:2]3([CH3:1])[C:22]([CH3:24])([CH3:23])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:21])[N:8]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:27]
Reactant: CCI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cccc4ccccc34)c(=O)c12
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1cccc3ccccc13)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 44.2 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 46; 150 mg, 0.47 mmol) and iodoethane (151 μL, 1.88 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 12 g column, eluting with 90-100% ethyl acetate/hexanes to give (4S,7R)-1-ethyl-7,8,8-trimethyl-2-naphthalen-1-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (72 mg, 44%) as a light yellow foam. ES(+)-MS (M+H) 347.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[NH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1>>[OH:13][CH:10]1[CH2:11][CH2:12][N:7]([C:1](=[O:6])[CH:2]([CH3:4])[CH3:3])[CH2:8][CH2:9]1
Reactant: OC1CCNCC1
Reactant: CC(C)C(=O)O
Product: CC(C)C(=O)N1CCC(O)CC1

Procedure:
Prepared as in Example 24a from isobutyric acid and piperidin-4-ol as a colorless oil (43%). MS 172 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11]([CH:17](N3CCCC3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10][C:9]=2[CH:8]=1.[ClH:30].C(OCC)(=O)C>CO>[ClH:30].[CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10][C:9]=2[CH:8]=1
Reactant: Cc1[nH]ncc1-c1cc2nc(C(Cc3ccccc3)N3CCCC3)[nH]c(=O)c2s1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]ncc1-c1cc2nc(/C=C/c3ccccc3)[nH]c(=O)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a crude product (5.0 mg) of tert-butyl 3-methyl-4-{4-oxo-2-[(E)-2-phenylethenyl]-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-1H-pyrazole-1-carboxylate produced in Example 94, step B, in methanol (1.0 mL) was added 4M hydrochloric acid/ethyl acetate solution (0.50 mL). The reaction system was stirred at room temperature for 30 min, and the mixture was concentrated under reduced pressure. The residue was crystallized from methanol/ethyl acetate to give the title compound (1.7 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:29]12([O:44][CH2:43][CH2:42][O:41]1)[C:38]1[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:32][C@@H:31]([CH:39]=O)[CH2:30]2>O1CCCC1>[CH3:1][O:2][CH:3]=[CH:39][C@@H:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]2([O:44][CH2:43][CH2:42][O:41]2)[CH2:30]1
Reactant: O=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reactant: COC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a stirred solution of (methoxymethylene)triphenylphosphorane (6.74 g, 21.99 mmol) in tetrahydrofuran (30 mL) was added drop-wise a solution of potassium tert-butoxide (3.08 g, 27.5 mmol) in THF at −30° C. under argon, and the mixture was stirred for 30 min. Then a solution of (R)-3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-3′-carbaldehyde (4.0 g, 18.33 mmol) in THF was added drop-wise and reaction was stirred for 1 h at −30° C. Reaction was monitored by TLC. Reaction mixture quenched with water at −30° C. and allowed to RT, diluted with water (25 mL) and extracted with ethyl acetate (2×50 mL), dried over Na2SO4, filtered and concentrated to give crude product (8 g). The crude compound was purified with silica gel flash column chromatography (Biotage) to give (R)-3′-(2-methoxyvinyl)-3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene] (3.5 g, 14.21 mmol, 78% yield) as colourless liquid; m/z 246.6.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=O)=[O:15])[CH:5]=[CH:4][C:3]1=2.P(Cl)(Cl)Cl.[CH2:30]([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:30]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:15])[CH2:31][CH2:32][CH3:33]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Reactant: CCCCNCCCC
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1ccccc1C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 26.8 %

Procedure:
To a solution of 1.68 g (5 mmoles) of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid in 20 cm3 of anhydrous dichloromethane, there is added 0.22cm3 (2.5 mmoles) of phosphorus trichloride. The mixture is heated for 3 hours at reflux. After cooling to +5° C., 2.6 cm3 (15 mmoles) of dibutylamine are added. Stirring is maintained for 30 minutes at +5° C., and then for 1 additional hour so as to permit the reaction mixture to return to ambient temperature. The reaction mixture is then diluted to about 80 cm3 by the addition of dichloromethane. It is then transferred to a decanting ampoule and washed first with diluted HCl and then with water. The dichloromethane phase is dried on sodium sulfate and then concentrated under reduced pressure. The resulting crude product is purified by chromatography on silica 60 gel in a 5/3/2 toluene/dichloromethane/ethyl acetate eluant mixture. After evaporation and drying under a vacuum a 80° C., 0.6 g of N,N-di-n-butyl 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]benzamide in the form of a colorless thick oil is obtained. The NMR1H 80 MHz and IR spectra correspond to the expected structure.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[C:5][CH2:6][O:7][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[P:25](OCC)([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][P:25]([CH2:2][CH2:3][C:4]#[C:5][CH2:6][O:7][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:26])[O:30][CH2:31][CH3:32])[CH3:29]
Reactant: CC(C)(C)[Si](OCC#CCCBr)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(CCC#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Yield: 98 %

Procedure:
A mixture of compound 6 (3.24 g, 80.7 mmol) and triethyl phosphate (40 mL) was refluxed under nitrogen atmosphere for overnight. After evaporation, the residue was purified with 50% EtOAc in hexanes by silica gel column chromatography to give 3.26 g of product 7 (7.90 mmol, 98% yield); 1H NMR (CDCl3) δ 7.77˜7.64 (m, 4H), 7.46˜7.32 (m, 6H), 4.29 (t, J=1.9 Hz, 2H), 4.16˜4.02 (m, 4H), 2.50˜2.34 (m, 2H), 1.96˜1.82 (m, 2H), 1.31 (t, J=7.1 Hz, 6H), 1.04 (s, 9H); 31P NMR (CDCl3) δ 30.43.
Reaction SMILES: Cl[S:2]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:10]([CH3:12])=[N:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].ClS(C1C=CC2N=C(C)[N:33](CC3C=CC(Cl)=CC=3Cl)C=2C=1)(=O)=O>N>[NH2:33][S:2]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:10]([CH3:12])=[N:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2n1Cc1ccc(Cl)cc1Cl
Reactant: Cc1nc2cc(S(=O)(=O)Cl)ccc2n1Cc1ccc(Cl)cc1Cl
Agent: N
Product: Cc1nc2cc(S(N)(=O)=O)ccc2n1Cc1ccc(Cl)cc1Cl

Procedure:
The mixture of 5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, which is obtained in Example 285, is immediately processed with a 25% aqueous ammonia (100 ml) for one hour at room temperature. Separation of solids through filtration produced a 1/1 mixture (2.68 g) of 5-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 6-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole. 1H-NMR (CD3OD, δ): 2.52 (3/2H, s), 2.54 (3/2H, s), 5.54 (2H, s), 6.55 (1H, d, J=6.9 Hz), 7.17 (1H, d, J=8.0 Hz), 7.52 (1H, s), 7.65-7.78 (2H, m), 7.82 (1/2H, s), 8.11 (1/2H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33][CH3:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33][CH3:34])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1SC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Allyl(rac)-4-[4-cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (750 mg, 1.54 mmol; Example 39) was dissolved in THF (10 ml), and morpholine (201 mg, 2.308 mmol) was added. The reaction solution was saturated with argon (argon was bubbled through the solution for 30 min). Tetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) was then added, and the mixture was stirred at RT overnight. Since, by HPLC control, only little conversion could be observed, more tetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) was added, and the mixture was stirred at RT for a further 3 h. The contents of the flask was then filtered through kieselguhr, and the residue was washed with THF. The filtrate was concentrated under reduced pressure and the residue was recrystallized from diethyl ether (15 ml). The crystals were filtered off with suction and dried under high vacuum. This gave 663 mg (96% of theory) of the target compound.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:26][OH:27])[O:7][N:6]=[C:5]([C:8]2[C:9]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:10]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]3=[N:12][CH:13]=2)[CH2:4]1.O.[OH-].[K+]>C(O)C>[CH:20]1([NH:19][C:9]2[C:10]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]=3[N:12]=[CH:13][C:8]=2[C:5]2[CH2:4][C:3]3([CH2:26][O:27][CH2:2]3)[O:7][N:6]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CO)(CBr)C3)cnc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(COC4)C3)cnc21
Yield: 28 %

Procedure:
{5-(Bromomethyl)-3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-4,5-dihydroisoxazol-5-yl}methanol (110 mg, 0.00025 mole) (example 20) was dissolved in ethanol (10 ml). Water (2 ml) was added followed by potassium hydroxide (20 mg, 0.00050 mole). The reaction mixture was stirred at refluxing temperature overnight. The solvent was removed under reduced pressure. Water was added and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product obtained was purified by column chromatography.
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:11](I)=[CH:10]2.[O:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1>C1COCC1.[Cl-].[NH4+]>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:11]([C:31]1([OH:34])[CH2:32][CH2:33][O:28][CH2:29][CH2:30]1)=[CH:10]2
Reactant: O=C1CCOCC1
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2C2(O)CCOCC2)cc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
Isopropylmagnesium chloride, 2M THF (1.322 mL, 2.64 mmol) was added to a solution of 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine (1.24 g, 2.64 mmol) in THF (25 mL) cooled to −20° C. After stirring for 5 min, an additional amount of iso-propylmagnesium chloride, 2M THF (1.322 mL, 2.64 mmol) was added and the solution was stirred 10 min at this temperature. Next, dihydro-2H-pyran-4(3H)-one (0.293 mL, 3.17 mmol) was added and the reaction was allowed to come to 0° C. After 20 min, the reaction mixture was diluted with saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material which was purified by silica gel chromatography by eluting with 1:3 to 1:1 EtOAc in hexane, to provide 4-(6-bromo-2-(4-methoxybenzylamino)quinolin-3-yl)tetrahydro-2H-pyran-4-ol as light-yellow oil.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=1)(C)(=O)=O.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[Na]>CN(C=O)C>[N:21]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2ccnc2)c1
Temperature: 70 °C
Yield: 68 %

Procedure:
The title compound from Step A above (14.54 g, 44.8 mmoles) was dissolved in anhydrous DMF (100 mL) and sodium imidazole (6.52 g, 72.4 mmoles) was added. The mixture was heated under argon at 70° C. for 2 h. The solution was evaporated to dryness and chromatographed on silica gel using 2% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (8.92 g, 68%):
Reaction SMILES: O[CH2:2][C@:3]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1.C1(C)C=CC=CC=1.C(N(S(F)(F)[F:38])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:38][CH2:2][C@:3]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]([CH3:8])[C:6](=[O:9])[N:5]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:4]1
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO)C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CF)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Tert-butyl(3S)-3-hydroxymethyl-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (1.70 g, 5.10 mmol) was dissolved in dichloromethane (20 mL). To this solution, toluene (20 mL) was added, and diethylaminosulfur trifluoride (1.68 mL, 12.8 mmol) was added dropwise in an ice bath. After stirring at 60° C. for 8 hours, saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added to the reaction mixture, and the mixture was extracted by ethyl acetate (100 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was then purified by silica gel column chromatography (solution by hexane:ethyl acetate, 9:1→2:3) to obtain 0.910 mg (53%) of the title compound as a pale yellow oily substance.