Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][C@@H:44]([OH:46])[CH3:45])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][C@@H:44]([OH:46])[CH3:45])[CH2:41][CH2:42]4)=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: C[C@H](O)CN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C[C@H](C)O)CC4)cc3)nn12
Yield: 55.6 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (S)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (0.205 g, 0.000870 mol) were dissolved in 2-Methoxyethanol (1.0 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 110.96 mg of (S)-1-(4-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=459.20. 1H NMR (400 MHz, DMSO, d6) δ 9.22 (s, 1H), 8.92 (s, 1H), 7.82 (dd, 1H, J=1.44, 6.16 Hz), 7.61 (d, 2H, J=8.96 Hz), 7.43 (t, 1H, J=7.36 Hz), 6.90 (m, 4H), 4.11 (m, 2H), 3.80 (s, 3H), 3.60 (m, 3H), 3.18 (m, 3H), 3.03 (m, 3H), 1.14 (d, 3H, J=6.16 Hz).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8](OC(=O)C)([CH3:11])([CH3:10])[CH3:9].CS(O)(=O)=O.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH3:31])[CH:30]=1)[NH:27][N:26]=[CH:25]2>O>[Br:21][C:22]1[CH:30]=[C:29]([CH3:31])[C:28]2[C:24](=[CH:25][N:26]([C:8]([CH3:9])([CH3:10])[CH3:11])[N:27]=2)[CH:23]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1cc(Br)cc2cn[nH]c12
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc2cn(C(C)(C)C)nc12
Temperature: 80 °C
Reaction time: 28 h

Procedure:
Toluene (150 mL), acetic acid tert-butyl ester (360 mL), and methanesulfonic acid (22 mL) were added to 5-bromo-7-methyl-1H-indazole (35.9 g), and the reaction solution was stirred at 80° C. for 28 hours. The reaction solution was cooled to room temperature, water (500 mL) was added, and extracted with toluene (500 mL) and 200 mL toluene. After separation, the organic layer was washed with water twice. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. Hexane was added to the resultant residue and the insolubles were separated by filtration. The solvent was evaporated from the filtrate under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-2-(tert-butyl)-7-methyl-2H-indazole as a light red oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:15]=[C:16]([CH3:23])[CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:41](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:40][CH3:41])([C:36]([F:39])([F:37])[F:38])[C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:15]=[C:16]([CH3:23])[CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(C(=O)N(CCc2ccc(Cl)c(Cl)c2)Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2cc(C)cc3cc[nH]c23)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
20 mg of 5-methyl-1H-indole-7-carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-amide (0.03 mmol) were dissolved in 5 ml DMF and potassium carbonate (9 mg, 0.07 mmol) and methyl iodide (3 μl, 0.05 mmol) were added. The reaction mixture was stirred over night at rt, then saturated ammonium chloride solution was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtrated and concentrated. The remaining residue was purified by silica gel filtration (hexane/EtOAc 1:1). This gave 20 mg (98%) of the title compound as a white foam. MS (ISP) 617.2 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[CH2:26]Cl>C(O)(C)C>[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[CH2:26][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CCOC(=O)c1ccc(N)c(CCl)c1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(N)c(CSc2nc3cc(OC)ccc3[nH]2)c1
Yield: 25.3 %

Procedure:
The title compound was prepared by the method of Example 1 using 1.30 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 1.80 g of ethyl 4-amino-3-(chloromethyl)benzoate hydrochloride (prepared as for Example 70) instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 10% sodium hydroxide instead of sodium carbonate and 1,2-dichloroethane instead of dichloromethane. The 1,2-dichloroethane extract was dried over sodium sulfate, filtered, and concentrated in vacuo to a gum. Recrystallization from diethyl ether-hexane gave 650 mg of the title compound: m.p. 140-146° C. Anal. Calc'd. for C18H19N3O3S: C, 60.49; H, 5.36; N, 11.76; S, 8.90. Found: C, 60.27; H, 5.44; N, 11.39; S, 8.70.
Reaction SMILES: C[C:2](=[CH:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3](O)=O.C([N:14]([CH2:17]C)CC)C.C(Cl)(=O)[O:20]CC.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH3:3][C:2]1[NH:14][C:17](=[O:20])[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[CH:6]=1
Reactant: CC(=Cc1cccs1)C(=O)O
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc2sccc2c(=O)[nH]1

Procedure:
To a mixture of 8.2 g of 2-methyl-3-(2-thienyl)acrylic acid and 9.5 ml of triethylamine in 45 ml of acetone was added dropwise 7.2 ml of ethyl chlorocarbonate over a period of 30 minutes under ice-cooling with stirring. After being stirred for 1 hour, a solution of 5.1 g of sodium azide in 10 ml of water was added dropwise over 30 minutes, and then stirred for 1 hour. The reaction mixture was poured into water and extracted with benzene. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. Drying agent was removed by filtration, and the solvent was removed under reduced pressure, and then 15 ml of diphenylether was added to the residue. The resultant solution was added dropwise to a mixture of 14 ml of tri-n-butylamine and 35 ml of diphenylether at 200° C. When addition was complete, the reaction mixture was allowed to cool and the crystalline precipitate was washed with diethyl ether to give 6.2 g of 6-methylthieno[3,2-c]pyridin-4(5H)-one as a pale yellow powder.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([F:25])[F:24])[CH:17]=2)=[CH:10][C:9]=1[CH3:26])([O-])=O>O.C(O)C.[Fe]>[F:25][CH:23]([F:24])[O:22][C:18]1[CH:17]=[C:16]([S:15][C:11]2[CH:10]=[C:9]([CH3:26])[C:8](=[CH:13][C:12]=2[CH3:14])[NH2:5])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(OC(F)F)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(Sc2cccc(OC(F)F)c2)c(C)cc1N
Temperature: 60 °C

Procedure:
7.7 ml of glacial acetic acid (0.135 moles) are added to a solution of 30 g of 2-nitro-5-(3-difluoromethoxyphenylthio)-p-xylene (0.092 moles) in H2O (40 ml) and ethanol (400 ml); 34.7 g of Fe in powder form (0.621 moles) are carefully added to the reaction mixture kept under stirring at 60° C. The temperature is brought to 90° C. and the mixture is kept under stirring for 1.5 hours. When the reaction is completed (GC and TLC analyses), the mixture is cooled to room temperature; the solid is filtered on a celite bed. The ethanol is concentrated at reduced pressure. The crude product obtained is washed with a saturated solution of sodium bicarbonate and extracted with ethyl acetate.
Reaction SMILES: [C:1]1([P:7](=O)([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.II.C(P(CCCC)CCCC)CCC>C(#N)C.C1COCC1>[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: II
Solvent: C1CCOC1
Solvent: CC#N
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
100 mg (0.359 mmol) of triphenylphosphine oxide were treated with 9 mg I2 (35 μmol) and tributylphosphine 180 μL (0.72 mmol) in acetonitrile/THF (1:1 v/v) 1 mL. The mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere before it was quenched with H2O (100 μL). The reaction mixture was diluted with ethyl acetate (10 mL) and was washed with portions of sat. NaHCO3 (3×5 mL). The organic fraction was dried with Na2SO4, filtered and the solvent evaporated under vacuum. The resulting residue was recrystallized from methanol, the resulting crystals were filtered, washed and dried in vacuum, giving 88 mg (0.334 mmol, 93%) of triphenylphosphine.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:31]=[CH:30][C:20]([CH2:21][N:22]3[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]3)=[CH:19][C:18]=1[F:32])=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O.CC(O)=O>[F:32][C:18]1[CH:19]=[C:20]([CH2:21][N:22]2[CH2:23][CH:24]([C:26]([OH:28])=[O:27])[CH2:25]2)[CH:30]=[CH:31][C:17]=1[C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:16][CH:15]=2
Reactant: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4[nH]3)c(F)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4[nH]3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 1-(4-(5-benzyl-1H-indol-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate (0.090 g, 0.21 mmol) in THF (1.0 mL) and water (1.0 mL) was added lithium hydroxide (0.025 g, 1.1 mmol). The solution was stirred at rt for 1 h, or until starting material was no longer observed by LCMS. The solvent was removed under reduced pressure, and 0.5M phosphate buffer (3.0 mL, pH 6.0) was added (pH was ca. 9-10). The mixture was acidified with 1N HCl to pH 6.0 and sonicated for 5 min. The aqueous solution was extracted with EtOAc (3×15 mL), and the separated organic extracts were dried over MgSO4, filtered and concentrated to afford a brown oil. The oil was dissolved in AcOH (3.0 mL), and the excess AcOH was removed under reduced pressure. Ether (15 mL) was added, and the resulting precipitate was collected by filtration. The brown solids were washed with water (10 mL) and chloroform (15 mL) to afford title compound as a yellow solid [hS1P1 EC50=1336 nM]. MS (ESI) m/z: Calculated: 414.1; Observed: 415.1 (M++1).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16].[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:23].Cl>CCCCCC.O1CCCC1>[OH:23][C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)([CH3:21])[CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
19.9 ml (31.89 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 6.7 ml (31.89 mmol) of hexamethyldisilazane in 50 ml of tetrahydrofuran at 0° C., and the mixture was stirred for 15 min and then cooled to −78° C. 3.12 ml (31.89 mmol) of ethyl acetate were added, the mixture was stirred for 1 h and, after addition of 5.00 g (26.57 mmol) of 4-trifluoromethylacetophenone, dissolved in 20 ml of tetrahydrofuran, stirred at −78° C. for a further hour. 1N hydrochloric acid was added to the reaction solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8/2) to result in 7.14 g (97% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:23])[NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=[C:11]([O:24][CH3:25])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:43][CH2:44][CH3:45])[C:37]=1[N:38]1[CH:42]=[CH:41][CH:40]=[CH:39]1)[CH:33]=O)[CH3:28].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:10]=[C:11]([O:24][CH3:25])[CH:12]=[C:13]([C:15](=[O:23])[NH:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:33][C:32]3[CH:35]=[C:36]([O:43][CH2:44][CH3:45])[C:37]([N:38]4[CH:42]=[CH:41][CH:40]=[CH:39]4)=[C:30]([O:29][CH2:27][CH3:28])[CH:31]=3)[CH2:21][CH2:22]2)[CH:14]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCN(Cc3cc(OCC)c(-n4cccc4)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 2-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-2-methyl-propionic acid ethyl ester [example 66b)] was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound yellow oil. MS: 608.4 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:18])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].[Li+].[OH-]>C1COCC1.O>[O:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:19])=[O:2])=[O:7])[C:9]1=[O:18]
Reactant: COC(=O)CNC(=O)c1cc2ccccc2oc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cc2ccccc2oc1=O
Temperature: 25 °C

Procedure:
A solution of coumarin-3-carbonylamino-acetic acid methyl ester (312 mg, 1.19 mmol), in THF (12 ml) under Ar atmosphere, at 0° C. (ice bath), a solution of LiOH in H2O (0.2 M) was added dropwise. The reaction mixture was stirred vigorously at room temperature until total conversion was observed by TLC (2 hours). The solution was partially concentrated and Et2O was added (10 ml). The organic layer was washed with NaHCO3 (10 ml, sat) and the combined aquous layers were acidified with 10% KHSO4 (pH=3-4) and extracted with ether (3×20 ml). The organic layer was concentrated at reduced pressure to afford 8G9C1 (280 mg, 95%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:36]1[CH2:40][CH2:39][N:38]=[C:37]1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH:48][CH3:49])=[CH:43][CH:42]=1.Cl>ClCCCl>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:48]([CH2:47][C:44]3[CH:45]=[CH:46][C:41]([C:37]4[NH:38][CH2:39][CH2:40][N:36]=4)=[CH:42][CH:43]=3)[CH3:49])=[O:22])[CH:16]=2)[CH3:13])(=[O:10])=[O:11])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)cc1Cl
Reactant: CNCc1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCCN4)cc3)co2)c(C)cc1Cl
Reaction time: 2 h

Procedure:
5-({[(4-chloro-2,5-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (28 mg, 0.08 mmol) was dissolved in DCE (1 mL) and CDI (26 mg, 0.16 mmol) was added. The reaction was stirred for 2 h. The activated acid solution in DCE was added to a vial containing 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (41 mg, 0.16 mmol) and TEA (0.022 mL, 0.16 mmol). The reaction was stirred at ambient temperature for 18 h, then partitioned between saturated aqueous NaHCO3 (1 mL) and DCE (3×1 mL). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude product was purified using prep method A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1)=[O:15])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:32]1([C:38]2[S:39][CH:40]=[C:41]([C:43](O)=[O:44])[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:43]([C:41]1[N:42]=[C:38]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:39][CH:40]=1)=[O:44])=[O:15])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1)C(O)CF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)c1csc(-c2ccccc2)n1)C(O)CF
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
A stirred solution of [3S/R,4S/R,(2S)]-5-fluoro-4-hydroxy-3-[2-piperidinecarboxamido]-pentanoic acid tert-butyl ester (520 mg, 1.63 mmol), in DMF (9.7 ml) at room temperature was treated with DIPEA (311 μl, 1.80 mmol). The resulting mixture was allowed to stir for 30 min before being treated with 2-phenyl-thiazole-4-carboxylic acid (335 mg, 1.63 mmol) and TBTU (524 mg, 1.63 mmol). The mixture was stirred at room temperature for 16 hr and then diluted with ethyl acetate. The resulting solution was washed with 2 N HCl, saturated aq. NaHCO3, saturated aq. NaCl, dried (Na2SO4), filtered and concentrated to reveal an oil. The residue was purified by flash chromatography (60% ethyl acetate in hexane) to afford the sub-title compound as a colorless oil (463 mg, 56%): 1H NMR (400 MHz, CDCl3) δ 1.10-1.85 (15H, m), 2.22-2.89 (3H, m), 3.09-4.78 (6H, m), 5.20-5.43 (1H, m), 7.40-7.56 (3H, m), 7.81-8.11 (3H, m).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH3:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CS(C)=O>O.[N+](C1C=CC=C([N+]([O-])=O)C=1)([O-])=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH2:12])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)O)cc1
Agent: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Solvent: CS(C)=O
Solvent: O
Product: C=Cc1ccc(CC(C)C)cc1
Temperature: 160 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To 6 g of α-(4-isobutylphenyl)ethyl alcohol were added 12 g of dimethyl sulfoxide and 0.1 g of m-dinitrobenzene as a polymerization inhibitor. The mixture was stirred at 160° C. for 8 hours. The resultant reaction liquor was cooled, diluted with water and then subjected to extraction with benzene. After the resulting organic layer was dried with magnesium sulfate, the solvent was distilled off. The residue thus obtained was distilled to give 4.2 g of 4-isobutylstyrene having the following physical properties.
Reaction SMILES: ClC1C=C(CCCNC(=O)/C=C2\OC(C)(C)OC\2=O)C=CC=1Cl.[NH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].[O:41]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:43]1[CH2:52][CH2:53][C:54](O)=[O:55]>>[O:41]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:43]1[CH2:52][CH2:53][C:54]([NH:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:55]
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Agent: CC1(C)OC(=O)/C(=C/C(=O)NCCCc2ccc(Cl)c(Cl)c2)O1
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCN1C(=O)c2ccccc2C1=O
Yield: 97.3 %

Procedure:
By appropriate application of the method used to synthesize Intermediate 5, tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (400 mg, 1.6 mmol) and 3-(1,3-dioxoisoindolin-2-yl)propanoic acid (388 mg, 1.8 mmol) were combined to provide Intermediate 7A (700 mg, 87% yield). HPLC/MS (Method C) RT=2.80 min, [M+H]+ 450.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:18])[C:13]=1[O:14][CH2:15][C:16]#[CH:17])[C:5]([O:7]CC#C)=[O:6].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:18])[C:13]=1[O:14][CH2:15][C:16]#[CH:17])[C:5]([OH:7])=[O:6]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOc1c(F)cc(C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To 10 ml of ethanol were added 2.2 g of 2-propynyl 3,5-difluoro-4-(2-propynyloxy)benzoate and 6 ml of a 15% aqueous sodium hydroxide solution, and the resulting mixture was stirred at 50° C. for 1 hour. Thereafter, the reaction mixture which had been allowed to cool to near room temperature was concentrated under reduced pressure, and hydrochloric acid was added to the residue to make the mixture acidic. The precipitated crystals were collected by filtration, and dried, and 1.8 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid was obtained.
Reaction SMILES: NC1C=C(N2C3C4C=CC=CC=4SCC=3C([C:21](=[O:34])[CH:22]([C:32]#[N:33])[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=N2)C=CC=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>CN(C)C=O>[C:32]([CH:22]([CH:21]=[O:34])[C:23]([NH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:24])#[N:33]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2cccc(N)c2)c2c1CSc1ccccc1-2
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: N#CC(C=O)C(=O)Nc1ccccc1
Temperature: 0 °C

Procedure:
3-[1-(3-amino-phenyl)-1,4-dihydro-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide (1.9 g) dissolved in dimethylformamide (25 ml) is reacted with acetic anhydride (5 ml) in the presence of pyridine (5 ml) at room temperature for 20 hours. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water: crystallization from dimethylformamide-ethanol gives 1.6 g of 3-[1-(3-acetylamino-)phenyl)-1,4-dihydro-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:24](=O)[CH2:25][C:26]#[N:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[N:1]=[C:24]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:25]([C:26]#[N:27])=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCC(=O)C1CCCCC1
Reactant: Nc1cc(F)c(Cl)cc1C(=O)c1ccccc1
Product: N#Cc1c(C2CCCCC2)nc2cc(F)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-4-fluoro-phenyl)-phenyl-methanone (prepared as described in example 105 step D) and 3-cyclohexyl-3-oxo-propionitrile (prepared as described in example 110 step A). Off-white solid. MS (ESI): 365.4 (M+H)+.