Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](Cl)=[O:34]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:34]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a solution of 0.61 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.47 g of (±)-2-chloro-2-phenylacetyl chloride in 2 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour and then diluted with 10 ml of 50% NaHCO3. The methylene chloride is evaporated and the residue is extracted with ethyl acetate. The separated organic layer is washed with saturated NaHCO3 and brine and then dried with Na2SO4 followed by filtering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with ether-hexane to give 0.98 g of pink solid. MS(CI): 456(M+H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.[N+](C1C=CC=CC=1)([O-])=O.Cl>ClCC(Cl)(Cl)Cl>[O:25]=[C:19]([C:14]1[CH:15]=[CH:16][C:11]([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:12][C:13]=1[O:17][CH3:18])[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C1CCC(=O)O1
Reactant: COc1cccc(C2CCCCC2)c1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(C2CCCCC2)ccc1C(=O)CCC(=O)O
Reaction time: 72 h

Procedure:
70 g of AlCl3 are added with stirring at -5° to 47.5 g of m-cyclohexylanisole, 26.5 g of succinic acid anhydride, 250 ml of tetrachloroethane and 62.5 ml of nitrobenzene, at such a rate that the temperature does not exceed -5°. The mixture is then stirred for 72 hours at 22°. 2N hydrochloric acid is then slowly added in the cold to the reaction solution until there is no further reaction, and the solution is then extracted twice with methylene chloride. The organic phases are extracted with 2N NaOH. The alkaline extract is acidified and extracted there times with ethyl acetate. The ethyl acetate phases are washed three times with water, dried over Na2SO4 and evaporated. The residue is crystallised twice from methylene chloridehexane. M.p. 130°-131°.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC.C1COCC1>[CH2:9]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][C:19]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:24])[CH2:18]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of phenylmagnesium bromide in ether (3 M, 2.3 mL) was added dropwise to a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (1.0 g, 4.6 mmol) in THF (20 mL) that had been cooled to 0° C. The mixture was stirred for 3 hours and a solution of saturated aqueous ammonium chloride was added and the products extracted into diethyl ether, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10-30% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.5 g) as an oil. LCMS m/z 294.4 [M+H]+. R.T.=2.59 min (Analytical Method 4).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=N[O-]
Reactant: COc1cc(N)ccc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Bromo-3-methoxyaniline (3.0 g, 14.85 mmol) was suspended in concentrated HCl (50 mL) and the mixture was cooled to 0° C. in the ice-water bath. A solution of sodium nitrite (1.23 g, 17.82 mmol) in 10 mL water was added very slowly to the reaction mixture. The mixture turned yellow, then brown with a yellow haze indicating diazotization. The diazonium salt was held at 0° C. for an hour and then a solution of tin(II) chloride dihydrate (10.05 g, 44.5 mmol) in concentrated HCl (20 mL) was added very slowly (caution, extremely exothermic). The reaction was stirred for 2 h at 0° C. then at RT overnight. The reaction was filtered and the filter cake was washed with cold H2O to afford (4-bromo-3-methoxyphenyl)hydrazine as a tan solid (3.1 g, MS: 218 [M+H+]).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Br:7])[S:5][CH:6]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Br:7][C:4]1[S:5][CH:6]=[C:2]([NH:1][C:10](=[O:11])[CH2:9][Cl:8])[N:3]=1
Reactant: Nc1csc(Br)n1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1csc(Br)n1
Yield: 29.7 %

Procedure:
The starting material was prepared as follows. 4-Amino-2-bromothiazole (15.6 g) and chloroacetyl chloride (7.6 g) were suspended in methylene chloride (100 ml) with stirring and treated with pyridine (16 ml) over 15 min., maintaining reaction temperature at 0° C. with an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate (500 ml) and stirred for 30 minutes. The mixture was separated and the organic layer washed with 2N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo and the residue recrystallised twice from carbon tetrachloride to give 2-bromo-4-chloroacetamidothiazole (5.1 g). m.p. 146°-8° C. (Found: C, 24.1; H, 1.7; N, 11.2. C5H4ClBrN2OS requires C, 23.5; H, 1.6; N, 11.0%).
Reaction SMILES: [CH2:1]([C:8]1[CH:26]=[CH:25][C:11]([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:33]([CH3:36])([CH3:35])[CH3:34].CCCCCC>O1CCCC1>[C:13]1([N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:11]2[CH:10]=[CH:9][C:8]([CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:26][CH:25]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)Cl
Reactant: c1ccc(Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C(c1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
4-benzyl-N,N-diphenylaniline (5.0 g, 14.9 mmol) was dissolved in tetrahydrofuran (80 mL) under a nitrogen atmosphere. n-Butyllithium (10.3 mL, 16.4 mmol) was slowly added to the reaction solution at −78° C., and then the reaction mixture solution was stirred at room temperature for 1 hour. Also, the reaction mixture solution with chlorotrimethylsilane (1.8 g, 16.4 mmol) added thereto was stirred at room temperature for 1 hour. The reaction mixture solution was passed through a silica gel column by using hexane as an eluant. After the solvent is removed, the residue material was dried in vacuum to thereby a white solid (5.1 g, yield: 84%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]2[CH2:36][O:35]2)=[CH:30][N:29]=1>C(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:36][C@@H:34]([C:31]1[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][CH:32]=1)[OH:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc([C@@H]2CO2)cn1
Reactant: COC(=O)c1ccc(-c2ccc(CCNCc3ccccc3)cc2)cc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccc(Cl)nc3)cc2)cc1
Yield: 70.5 %

Procedure:
A solution of methyl 4′-[2-(benzylamino)ethyl]-1,1′-biphenyl-4-carboxylate (460 mg), and 2-chloro-5-[(2R)-2-oxiranyl]pyridine (207 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chlorofor:methanol=100:1) to give methyl 4′-[2-[N-benzyl-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate (470 mg) as a colorless foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>CC(O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[C:13]([NH:18][NH2:19])[N:12]=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ncn1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CN(C(=O)OC(C)(C)C)c1cc(NN)ncn1
Temperature: 90 °C

Procedure:
A mixture of (6-Chloro-pyrimidin-4-yl)-methyl-carbamic acid tert-butyl ester (10 g, 41.1 mmol), hydrazine monohydrate (6.5 g, 130.0 mmol), and 2-propanol (50 mL) is heated to 90° C. for 4 hours. The reaction mixture is then cooled to room temperature, and concentrated. The resultant crude product is treated with a mixture of water (80 mL) and ethanol (15 mL), heated for 30 minutes, and slowly cooled to room temperature. White precipitate forms. After filtration, the undissolved solid is washed with water, dried under vacuum overnight to give (6-Hydrazino-pyrimidin-4-yl)-methyl-carbamic acid tert-butyl ester as white powder in needle form: 1H NMR 400 MHz (d6-DMSO) δ 8.23 (s, 1H), 8.19 (s, 1H), 7.14 (s, 1H), 4.29 (s, 2H), 3.23 (s, 3H), 1.49 (s, 9H); MS m/z 240.10 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH:21]([CH3:25])[CH:22]([OH:24])[CH3:23])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4].[CH3:42]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH:21]([CH3:25])[C:22]([OH:24])([CH3:42])[CH3:23])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)O)CC2)c2ncnn12
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4′-({7-butyl-4-[trans-4-(2-hydroxy-1-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.66 g), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.76 g) and acetonitrile (20 mL) was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.4 mL) was added at 0° C. The reaction mixture was warmed to 0° C., and stirred for 6 hr. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.32 g, 47%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.C[Al](C)C.CCCCCCC.[C:30]([Si:34]([CH3:55])([CH3:54])[O:35][CH2:36][C:37]1[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:39]=[C:40]([C:42](OC)=[O:43])[N:41]=1)([CH3:33])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.O>[Si:34]([O:35][CH2:36][C:37]1[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH:39]=[C:40]([C:42]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:43])[N:41]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:55])[CH3:54]
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(CO[Si](C)(C)C(C)(C)C)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a flask containing a solution of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 17.5 mmol) in toluene (20 ml), 2 M solution of trimethyl aluminium in heptane (2.62 ml, 52.6 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 10 min and a solution of methyl 2-((tert-butyldimethyl-silyloxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (0.7 g, 17.5 mmol) in toluene (20 ml) was added at 0° C. The reaction mixture was heated at 110° C. for 4 h and diluted with water. The mixture was filtered through a celite bed and the filtrate was extracted with EtOAc. The organic layer was concentrated under reduced pressure. The product was purified by flash column chromatography. Yield 400 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.05 (s, 9H), 0.05 (s, 6H), 0.82-0.84 (s, 11H), 1.14 (d, 3H), 3.47 (t, 2H), 4.26-4.40 (m, 3H), 4.74 (s, 2H), 5.38 (s, 2H), 6.94 (d, 1H), 7.73 (s, 1H), 7.83 (d, 1H), 7.99 (d, 2H), 8.10 (d, 2H). LC-MS: [M+1]=629.38.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.[CH3:31][NH:32][CH3:33]>>[F:30][C:2]1([F:1])[CH2:3][CH2:4][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:32]([CH3:33])[CH3:31])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:6][CH2:7]1
Reactant: CNC
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Product: CN(C)C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexyl methyl)-amide, and dimethylamine. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (d, J=6.2 Hz, 1H), 8.13 (t, J=5.6 Hz, 1H), 8.11-7.96 (m, 1H), 7.79-7.77 (m, 2H), 7.59 (d, J=8.6 Hz, 1H), 3.41-2.85 (m, 1H), 2.84-2.50 (m, 1H), 2.50-2.49 (m, 2H), 2.48-2.46 (m, 6H), 2.25-2.07 (m, 1H), 2.01-1.91 (m, 4H), 1.90-1.85 (m, 5H), 1.73-1.69 (m, 4H). m/z: 466.3 [M+H]+
Reaction SMILES: [NH:1]([CH2:3][C@@H:4]([OH:7])[CH2:5][CH3:6])[NH2:2].[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][C:18](=[N:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=2[F:30])SC)=O)[CH:12]=[C:11]([Cl:31])[N:10]=1>CC(O)(C)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]2[N:1]([CH2:3][C@@H:4]([OH:7])[CH2:5][CH3:6])[N:2]=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=3[F:30])[N:17]=2)[CH:12]=[C:11]([Cl:31])[N:10]=1
Reactant: CSC(=Nc1ccc(F)c(F)c1F)NC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CC[C@H](O)CNN
Solvent: CC(C)(C)O
Product: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2F)nc1-c1cc(Cl)nc(Cl)c1
Reaction time: 8 h

Procedure:
Intermediate D3 (0.143 g, 0.00137 mol) was added to a solution of intermediate D10 (0.3 g, 0.000457 mol) in t-BuOH (40 ml). The reaction mixture was stirred overnight at reflux. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography over silica gel (eluent: EtOAc/heptane gradient from 20/80 to 50/50). The desired fractions were collected and the solvent was evaporated. Yield: 0.160 g of intermediate D11 (81%; S-enantiomer).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[C:17]1([CH3:29])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:25]([C:18]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=2[CH3:29])(=[O:27])=[O:26])=[CH:4][CH:3]=1
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)n2ncc3ccc(I)cc32)c(C)c1
Temperature: 23 °C
Yield: 100 %

Procedure:
To a solution of 6-iodo-1H-indazole (7.35 g, 30.1 mmol, 1 equiv) in THF (100 mL) cooled to 0° C. under argon, was added sodium t-butoxide (2.89 g, 30.1 mmol, 1 equiv). A color change from orange to red was observed. Mesitylenesulfonyl chloride (6.60 g, 30.1 mmol, 1 equiv) was added in one portion and the ice bath was removed allowing the reaction mixture to warm to 23° C. After 40 min the mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The aqueous was extracted a total of 3 times with ethyl acetate. The combined organic material was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole as an orange solid (12.8 g, 100% yield, 2:1 mixture). 1H NMR (CDCl3) 8.51 (s, 1H), 7.95 (s, 0.66H, major isomer), 7.91 (s, 0.33H, minor isomer), 7.47 (d, 0.33H, J=8.4 Hz), 7.29 (d, 0.33H, J=8.4 Hz), 7.26 (d, 0.66H, J=8.9 Hz), 7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H), 2.15 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>CN(C)C1C=CN=CC=1.O1CCOCC1>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([O:15][CH2:16][CH3:17])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:7][CH:6]=1)[CH3:14]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1ccc(OC(=S)N(C)C)cc1)OCC
Temperature: 100 °C
Yield: 101.8 %

Procedure:
A mixture of ethyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (100.8 g, 0.423 mol), triethylamine (83.4 g, 115 ml, 0.824 mol), 4-dimethylaminopyridine (5.2 g, 42.3 mmol) and dimethylthiocarbamoyl chloride (62.6 g, 0.507 mol) in dioxane (640 ml) was stirred and heated at 100° C. for 10 h in nitrogen atmosphere. The solid was filtered off, washed with dioxane and the filtrates were evaporated in vacuo. The residue was dissolved in dichloromethane (600 ml), the solution was washed with water (3×250 ml), dried (MgSO4) and passed through column of silica gel (Fluka 60, 500 g). The column was washed with 500 ml dichloromethane, collected dichloromethane solutions were evaporated to yield 140.1 g (˜100%) of 3-(4-dimethylthiocarbamoyloxy-phenyl)-2-ethoxy-propionic acid ethyl ester as an oil, which was used to next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.Cl.C([N:43]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([NH2:43])=[O:28])=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.30 g), 1-hydroxybenzotriazole ammonia complex (0.17 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenamide as colorless crystals (0.25 g, yield 83%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 187-188° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7].Cl>O1CCOCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[S:5][C:6]=1[CH3:7]
Reactant: COc1ncc(-c2nc(C)c(C)s2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2c[nH]c(=O)[nH]c2=O)sc1C
Temperature: 25 °C

Procedure:
(5-(4,5-dimethyl-1,3-thiazol-2-yl)-2,4-bis(methyloxy)pyrimidine) (Prep14, 118 mg, 0.470 mmol) in HCl (5.87 ml, 23.48 mmol) 4M in dioxane was stirred in a closed tube at 90° C. for 1.5 hour. Then the mixture was cooled to rt and the solvent evaporated under vacuum to afford the title compound as a pale grey solid (153 mg)
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)([CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:12](=[O:14])[N:13]=1.Cl>C(O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:15][CH2:16][OH:17])([CH2:25][CH2:26][OH:27])[C:12](=[O:14])[N:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1(CCO[Si](C)(C)C(C)(C)C)SC(NC2CC3CCC2C3)=NC1=O
Agent: Cl
Solvent: CCO
Product: O=C1N=C(NC2CC3CCC2C3)SC1(CCO)CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5,5-bis(2-(tert-butyldimethylsilyloxy)ethyl)thiazol-4(5H)-one (771 mg, 1.46 mmol) in 15 mL of a 1% HCl solution in ethanol was stirred at room temperature for 3 h. The reaction mixture was then concentrated in vacuo. Flash column chromatography (silica gel, 0-8% MeOH—CH2Cl2) afforded the title compound as a colorless thin film (390 mg). MS (ESI, pos. ion) m/z: 299 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=[O:11].[N:13]1C=CC=CC=1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:13])=[O:11]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cc2ccccc2[nH]1

Procedure:
Indolyl carboxylic acid amides as starting materials may be produced by reacting an indolyl carboxylic acid chloride in absolute methylene chloride with an amine in the presence of pyridine at -10° to 0°.