Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C)C=O.O>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OC[C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of methyl 4-(4-hydroxyphenyl)benzoate (0.94 g), (S)-(−)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-1-propanol (1.00 g) and triphenylphosphine (1.62 g) in N,N-dimethylformamide (20 ml) was added dropwise diisopropyl azodicarboxylate (1.21 ml) for 10 minutes under ice-cooling in a stream of nitrogen. The solution was stirred for 16 hours at ambient temperature, and then water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixed solvent of n-hexane-ethyl acetate (from 0% to 20% gradient elution) to give methyl (S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoate (290 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[C:12]1[N:13]=[CH:14][C:15]2[CH:20]=[CH:19][NH:18][C:16]=2[N:17]=1.[OH-:21].[Na+]>CO>[CH3:12][O:21][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:2][O:21][C:12]1[N:13]=[CH:14][C:15]2[CH:20]=[CH:19][NH:18][C:16]=2[N:17]=1
Reactant: [OH-]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Clc1ncc2cc[nH]c2n1
Agent: [Na+]
Solvent: CO
Product: COc1ncc2cc[nH]c2n1
Product: COc1ncnc2[nH]ccc12

Procedure:
4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3) or 2-methoxy-7H-pyrrolo[2,3-d]pyrimidine (4) is prepared by reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1) or 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (2), respectively, with sodium hydroxide in methanol as described by Girgis, N. et. al., J. Heterocyclic. Chem. 1989, 26:317-325.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:15]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1
Reactant: COC(=O)C[C@H]1CCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C[C@H]1CCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.5 %

Procedure:
To a solution of 2.0 g (0.012 mole) of D-beta-homoproline hydrochloride in 20 mL of methanol was added slowly 1.8 mL (0.024 mole) of thionyl chloride at 0 degrees. The mixture was stirred overnight, then concentrated under reduced pressure. The solid was slurried in ether, and collected by filtration to give 2.2 g of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride as a white solid. A solution of 2.2 g (0.012 mole) of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride in 3 mL of chloroform was added over 5 minutes to a cooled (0 degrees) mixture of 2.34 g (0.012 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.1 g (0.060 mole) of sodium bicarbonate and 25 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-70:30) gave 3.3 g of [(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (IV-102) as a yellow thick oil.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1.C1CCN2C(=NCCC2)CC1>>[C:1]1([CH:7]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: COC(=O)/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of methyl (2E)-3-phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol) was slowly added to a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 μL, 0.003 mol). The reaction was stirred at room temperature over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel using EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (500 mg, 70%) as a semisolid residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1.C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
A solution of 3,4,5-trimethoxyaniline (500 mg, 2.8 mmol) in pyridine (5 mL) was treated with 4-methoxybenzenesulfonyl chloride (564 mg, 2.8 mmol) in THF (5 mL), stirred at room temperature for 18 hours, concentrated, redissolved in THF (1 mL), treated with water with stirring, and filtered to provide 820 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:11]3[NH:12][N:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[C:33]([N:12]1[C:11]2=[C:20]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]2[CH2:15][CH2:14][N:13]1[CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)CN1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCN1CC(C)C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-2-isobutyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (70 mg, 0.199 mmol) and pyridine (31 mg, 0.398 mmol) in N-methyl-2-pyrrolidone (1.2 ml) was added acetyl chloride (19 mg, 0.239 mmol) in N-methyl-2-pyrrolidone (0.3 ml) at ambient temperature. The reaction mixture was stirred for 1 hour, then aqueous saturated sodium bicarbonate and ethyl acetate were added thereto. The organic phase was separated, and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol; 100/1~40/1). The fractions containing the object compound were concentrated in vacuo and the obtained oil was crystallized from diisopropyl ether to give 1-acetyl-7-(4-fluorophenyl)-2-isobutyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo-[5,1-c][1,2,4]triazine (57.0 mg).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][CH:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].[CH3:43]I>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:43])[CH:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3c[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1H-indol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (90 mg, 0.156 mmol) was dissolved in DMF (1 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 8 mg, 0.20 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then methyl iodide (10 μl, 0.16 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2% MeOH) to afford 56 mg (61%) of 2-(6-chloro-1-methyl-1H-indol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-difluorophenylacetic acid (20 g, Fluorochem) in c.H2SO4 (150 ml) was stirred at -15° C. and c.HNO3 (75 ml) added dropwise over 1 hour at a temperature of from -5° to -10° C. The mixture was stirred for a further 1/2 hour at -10° C. and then poured into ice-water (1.0 l). The latter was extracted with ether (×3) and the combined extracts washed with water (×2), dried over MgSO4, and evaporated under reduced pressure to give a solid which was crystallised and then recrystallised from ether/hexane (1:4 v/v) to give 20.8 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.[NH:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:28](O)=[O:29])=[CH:27][C:22]=2[N:21]=[CH:20]1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:28]([C:26]3[CH:25]=[CH:24][C:23]4[NH:19][CH:20]=[N:21][C:22]=4[CH:27]=3)=[O:29])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1nn(-c2ccccc2)c2cc(N)ccc12
Product: COc1nn(-c2ccccc2)c2cc(NC(=O)c3ccc4[nH]cnc4c3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 66 reacting 3-methoxy-1-phenyl-1H-indazol-6-ylamine and 1H-Benzoimidazole-5-carboxylic acid.
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]2.[C:16]([CH:20]1[CH2:24][CH:23](OC)O[CH:21]1OC)(=[O:19])[CH2:17][CH3:18]>>[C:16]([C:20]1[CH:24]=[CH:23][N:2]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:12]=2[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]3)[CH:21]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)C1CC(OC)OC1OC
Reactant: [NH3+]c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Agent: [Cl-]
Product: CCC(=O)c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2Cl)c1

Procedure:
14.2 mmol of 6-ammonio-7-chloro-2,3(1H,4H)-quinoxalinedione chloride were reacted with 14.2 mmol of 3-propionyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[F:16].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:14][CH:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:16])[CH:4]=1)[OH:15])[C:10]([O:12][CH3:13])=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)c(F)c1
Reactant: NCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(4-chloro-3-fluorophenyl)(hydroxy)methyl]prop-2-enoate (69.1 g) and triethylamine (47.3 mL) in methanol (706 mL) was added benzylamine (37.1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (58.2 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:18]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.[Cl:27][CH:28]([Cl:47])[C:29]([N:31]1[C@H:35]([CH2:36][F:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=2)[O:33]C1(C)C)=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1(C)C=CC=CC=1.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>[NH2:18][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([C:41]3[CH:42]=[CH:43][C:38]([C@@H:34]([OH:33])[C@H:35]([NH:31][C:29](=[O:30])[CH:28]([Cl:27])[Cl:47])[CH2:36][F:37])=[CH:39][CH:40]=3)=[CH:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: NC1(c2ccc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A mixture of tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (252 mg, 0.7 mmol), 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (250 mg, 0.56 mmol), Cs2CO3 (365 mg, 1.12 mmol) in dioxane (4 mL) and water (1 mL) is bubbled with nitrogen gas for 2 minutes. Pd(PPh3)4 (64 mg, 0.056 mmol) is added and the resulting reaction mixture heated at 80° C. for 4 hours. After cooling to room temperature, the reaction is diluted with water (10 ml) and extracted with ethyl acetate (3×10 mL). Combined organic extracts are dried over Na2SO4 and concentrated. Crude compound dissolved in DCM (3 mL) and stirred with TFA (0.6 mL) at room temperature for 1 hour. Reaction is diluted with toluene (10 mL) and concentrated to a syrup. Crude compound is basified slowly using saturated aq. NaHCO3, saturated with NaCl, and extracted with ethyl acetate (3×30 mL). Combined extracts dried over Na2SO4 and concentrated. Solid dissolved in DMF (2 mL) and purified using HPLC eluting from 5 to 95% water/acetonitrile to give the title compound (90 mg): 1HNMR (400 MHz, DMSO-d6) δ: 1.16-1.28 (m, 2H), 1.31-1.41 (m, 2H), 4.15-4.36 (m, 1.5H), 4.38-4.47 (m, 0.5H) 4.55-4.62 (m, 0.5H), 4.65-4.74 (m, 0.5H), 4.90 (bs, 1H) 5.98 (bs, 1H), 6.54 (bs, 1H), 7.41-7.53 (m, 4H), 7.64 (d, 2H, J=8.0 Hz), 7.72 (d, 2H, J=8.0 Hz), 8.63 (d, 1H, J=8 Hz), 8.66-8.79 (bs, 3H), m/z (Cl) 411 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:28])[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([CH2:17][CH2:16][C:15]([NH:13][N:14]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:28])=[CH:19][CH:20]=1
Reactant: NNC(=O)CCc1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: O=C(CCc1ccc(C(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1)NN=C1C(=O)Nc2ccc(Br)cc21
Temperature: 100 °C
Yield: 82 %

Procedure:
A suspension of 5-bromo-1H-indole-2,3-dione (67 mg, 0.30 mmol and) and 4-(3-hydrazino-3-oxopropyl)benzohydrazide (0.03 mg, 0.13 mmol) in acetic acid (2 mL) was heated at 100° C. for 80 min. The reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration, washing with AcOH (3×1 mL) and with AcOH/water (2×1 mL) and water (3×1 mL) and drying in vacuo at 70° C. for 4 hrs gave 68 mg of the title compound in a 79% yield as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15].O.C(OCC)(=O)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:21]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[C:18]=2[C:19]#[N:20])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
1-BOC-piperizine (piperazine-1-carboxylic acid tert-butyl ester, 20.0 g, 107.4 mmol) was added to a solution of 2,6-dinitrobenzonitrile (10.277 g, 53.2 mmol) in dry DMF (200 ml). After stirring at 50° C. overnight, the reaction mixture was cooled to room temperature and poured into a mixture of water/ethyl acetate. The organic fraction was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting brown residue was purified by flash chromatography to give 4-(2-cyano-3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as an orange solid (12.172 g, 69%). MS: (M+H)+277.1.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:6]([O:8]CC)=O.[CH3:15][N:16]([CH3:30])[S:17]([C:20]1[CH:25]=[C:24]([N:26]=[C:27]=[O:28])[CH:23]=[CH:22][C:21]=1[Cl:29])(=[O:19])=[O:18]>O1CCCC1>[CH3:15][N:16]([CH3:30])[S:17]([C:20]1[CH:25]=[C:24]([N:26]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:27]2=[O:28])[CH:23]=[CH:22][C:21]=1[Cl:29])(=[O:19])=[O:18]
Reactant: CN(C)S(=O)(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To 30 ml of dried tetrahydrofuran (THF) cooled to -5° C. was added, under nitrogen, 3.6 g of sodium hydride as a 60% dispersion mineral oil. To the stirred slurry was added a solution of 10 g of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 30 ml of THF over a period of 30 minutes. After stirring at -5° C. for 1 hour, the reaction mixture was cooled to -65° C. and a solution of N, N-dimethyl-2-chloro-5-isocyanatobenzenesulfonamide (Example A-4 above) in 30 ml of THF was added dropwise maintaining the temperature below -60° C. The mixture was stirred at -65° C. for 2 hours and allowed to warm to room temperature. After stirring for 17 hours, solvent was removed using a rotary evaporator. About 50 ml of water was added to the residue. The resulting mixture was filtered to remove a small amount of undissolved solid and the filtrate was acidified with hydrochloric acid. The resulting precipitate was filtered to give 13 g of the title compound as a beige solid, m.p. 281°-283° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][OH:11])=[CH:2]1.[CH3:12]O>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][O:11][CH3:12])=[CH:2]1
Reactant: CO
Reactant: OCc1c[nH]c2ccccc12
Solvent: O
Product: COCc1c[nH]c2ccccc12

Procedure:
Relatively pure 1H-indole-3-methanol (I3C™ from Designed Nutritional Products, Orem, UT, US) in a water solution was prepared for HPLC analysis. One sample was diluted with water and the other was diluted with methanol. By the time the partial methanol solution could be injected into the HPLC, the reaction with methanol had taken place to form 1H-indol-3-yl methoxy methane, the methyl ether of 1H-indole-3-methanol, and two peaks of about the same magnitude were observed. The same solution when diluted with water showed only one peak.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Product: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccc(OC)c(OC)c2)c1

Procedure:
The preparation took place in analogy with Example 15a), starting with 300 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 242 mg of 3-methoxybenzoyl chloride. The following was obtained: 53 C20H21N3O4 (367.41) MS (ESI) 368 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]([F:46])([F:45])[C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:45])[F:46])[CH:36]=3)(=[O:43])=[O:42])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (42 mg, 0.094mmol) in anhydrous CH2Cl2 (5 ml) was added 3-(Trifluoromethyl)benzene sulfonyl chloride (22.5 μl, 0.14 mmol) and diisopropylethylamine (32.7 μl, 0.19 mmol). The reaction stirred at room temperature overnight, was diluted with EtOAc and washed with sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (48.5 mg, 79%). Calcd for C33H35F6NO4S (M+H) 655.69, Found 656.2.