Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=C(Cc1ccccc1)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)Cc3ccccc3)cc2)cc1
Yield: 26 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-(phenyl-acetamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(phenyl-acetamido)-ethyl]-4' -hydroxy-biphenyl and ethyl 2-bromo-2methyl-propionate analogous to Example 1. Yield: 26% of theory; m.p. <20° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C[Si](C)(C)[O:40][NH2:41]>C1COCC1>[OH:40][NH:41][C:13](=[O:15])[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=CCCCCc1ccccc1
Reactant: C[Si](C)(C)ON
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=CCCCCc1ccccc1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
7-Phenylhept-2-enoic acid (7 g; 34 mmol) is dissolved in dry THF and cooled to 0° C. Diphenylphosphinic chloride (ClP(O)Ph2) (7.1 mL; 37 mmol) is added followed by dropwise addition of triethylamine (4.7 mL; 34 mmol). After 45 min at 0° C., a mixture of O-(trimethylsilyl)hydroxylamine (TMSONH2) (4.3 g; 37 mmol) and triethylamine (4.7 mL; 34 mmol) is added dropwise at 0° C. The bath is removed and the reaction is allowed to stir at 20° C. for 2 hours. The reaction is then filtered and the solid is extracted with EtOAc (500 mL). The EtOAc is washed with 60 mL 1 N HCl, 50 mL brine and dried (MgSO4). The resulting solution is concentrated in vacuo to yield a white solid which is purified by tituration with Et2O to obtain 7-phenylhept-2-enoic acid hydroxyamide (3.9 g; 18 mmol). MS (EI) m/e 219 (M+). Anal. (C13H17NO2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:6]=1[C:7]([O:9]CC)=O.[CH:18]([NH2:20])=O>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:5]1[C:6]2[C:7]([OH:9])=[N:20][CH:18]=[N:1][C:2]=2[S:3][CH:4]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(-c2ccccn2)csc1N
Product: Oc1ncnc2scc(-c3ccccn3)c12
Temperature: 180 °C
Reaction time: 4 h

Procedure:
A 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 2-amino-4-(pyridin-2-yl)thiophene-3-carboxylate (10 g, 40.27 mmol, 1.00 equiv) and formamide (100 mL). The resulting solution was stirred for 4 h at 180° C. The reaction mixture was cooled to 20° C. with a water/ice bath. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 5×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×100 mL of brine. The organic layers combined was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (30:1-10:1). Purification resulted in 4 g (43%) of 5-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-ol as a yellow solid. MS: m/z 249 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH:10]=[CH2:11])=[CH:4][CH:3]=1.[OH2:13].[C:14]([OH:18])(=[O:17])[CH:15]=O>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:13])/[CH:11]=[CH:15]/[C:14]([OH:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=CC(=O)O
Reactant: C=CC(=O)Cc1ccc(F)cc1
Reactant: O
Solvent: CC(=O)O
Product: O=C(O)/C=C/C(=O)/C=C/c1ccc(F)cc1

Procedure:
A solution of 21.5 g (131 mmol) of (E)-4-(4-fluorophenyl-but-3-en-2-one and 12 g (131 mmol) of glyoxylic acid monohydrate in 32 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/ether yielded (E,E)-6-(4-fluorophenyl)-4-oxo-2,5-hexadienoic acid of melting point 160°-162°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][CH:10]=[C:4]2[CH:3]=1.C([Li])CCC.[F:23][C:24]([F:38])([F:37])[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1)=[O:26]>C1COCC1>[F:38][C:24]([F:23])([F:37])[C:25]([C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][CH:10]=[C:4]2[CH:3]=1)([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1)[OH:26]
Reactant: Fc1ccc(-c2ncc3cc(Br)ccn23)cc1
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C(O)(c2ccn3c(-c4ccc(F)cc4)ncc3c2)C(F)(F)F)c2ccccc21
Reaction time: 0.02 h
Yield: 34.1 %

Procedure:
To a chilled (−78° C.) solution of 7-bromo-3-(4-fluorophenyl)imidazo[1,5-a]pyridine (58 mg, 0.2 mmol) in anhydrous THF (1 mL) was added n-butyllithium (0.1 mL of a 2.5 M solution in hexanes, 2.5 mmol). After 1 minute, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (68 mg, 0.3 mmol) in 1 mL of THF was added. After 5 minutes, the reaction mixture was quenched with 50 mL of brine solution and extracted with three 25 mL portions of methylene chloride. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-70% ethyl acetate to afford 30 mg of the title compound as a light yellow solid. MS m/z 440 (MH+).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[C:12]([CH3:26])[C:13]([NH:16][NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH3:25])=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:9][C:10]1[CH:11]=[C:12]([CH3:26])[C:13]2[N:14]([C:18]([C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])=[N:17][N:16]=2)[CH:15]=1
Reactant: Cc1cc(F)cnc1NNC(=O)[C@@H]1CCCN1C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(F)cn2c([C@@H]3CCCN3C)nnc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Hexachloroethane (141 mg, 0.587 mmol) was added portionwise at RT to a stirred mixture of Intermediate 105c (74 mg, 0.293 mmol), triethylamine (166 μL, 1.17 mmol) and triphenylphosphine (154 mg, 0.587 mmol) in THF (5 mL). The reaction mixture was stirred at 80° C. for 2 h, then cooled to RT and filtered. The filtrate was concentrated in vacuo and the resultant residue was purified by SCX cartridge. The cartridge was washed with 10% MeOH in DCM and the product eluted with 10% (2M NH3 in MeOH) in DCM. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM, to afford the title compound (59 mg, 86%) as a colourless oil. 1H NMR (400 MHz, CDCl3): 1.88-2.12 (3H, m), 2.15-2.53 (5H, m), 2.69 (3H, s), 3.28 (1H, t, J=7.8 Hz), 4.01-4.15 (1H, m), 6.97 (1H, d, J=8.4 Hz), 8.50 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:45])[CH2:40][CH2:41][CH2:42][NH:43][CH3:44]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:43]([CH2:42][CH2:41][CH2:40][N:39]([CH3:45])[CH3:38])[CH3:44])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CNCCCN(C)C
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(N(C)CCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N,N,N′-trimethyl-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) 1.70 (m, 2H), 2.04 (m, 2H), 2.20 (s, 6H), 2.36 (s, 3H), 2.89-3.21 (m, 3H), 3.36-3.70 (m, 2 H), 6.36 (d, J=8.4 Hz, 1H), 7.16 (m, 1H), 7.27 (m, 2H), 7.50 (m, 2H), 7.59 (m, 2 H), 8.01 (s, 1H), 8.13 (m, 1H).
Reaction SMILES: [CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:24].OO>CO>[CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:24])[C:11]([CH3:17])([CH3:18])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: CCCCN(C(C)=O)C1CC(C)(C)NC(C)(C)C1
Agent: OO
Solvent: CO
Product: CCCCN(C(C)=O)C1CC(C)(C)N(O)C(C)(C)C1
Reaction time: 2 h

Procedure:
To a stirred 50° C. solution of 13.3 g of N-butyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)acetamide, 0.075 g of sodium tungstate-dihydrate and 0.075 g of ethylenediamine-tetraacetic acid in 25 mL of methanol is added 35 mL of 30% aqueous hydrogen peroxide over a three hour period. After the addition is complete, the reaction mixture is stirred another two hours. The reaction mixture is then partitioned between diethyl ether and water. The organic phase is washed with water, 1% aqueous hydrogen chloride and then water. After drying over anhydrous magnesium sulfate and concentrating, the title compound is obtained as a red solid. After crystallization from hexane, the compound melts at 84-85° C.
Reaction SMILES: C[O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[CH:55]([C:58]1[O:59][C:60]([CH3:66])=[C:61]([C:63]([OH:65])=O)[N:62]=1)([CH3:57])[CH3:56]>C(Cl)Cl>[Cl:53][C:48]1[CH:47]=[C:46]([CH:51]=[CH:50][C:49]=1[Cl:52])[CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C@H:36]2[CH2:35][O:34][C:30]3=[CH:31][C:32]4[CH2:33][C@@H:24]([C:22]([NH:21][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([O:12][C:13]6[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=6[CH3:20])=[CH:8][CH:7]=5)[C:3]([OH:54])=[O:2])=[O:23])[N:25]([C:63]([C:61]5[N:62]=[C:58]([CH:55]([CH3:56])[CH3:57])[O:59][C:60]=5[CH3:66])=[O:65])[CH2:26][C:27]=4[CH:28]=[C:29]3[O:37]2)=[CH:39][CH:40]=1
Reactant: Cc1oc(C(C)C)nc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3nc(C(C)C)oc3C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 2-isopropyl-5-methyl-oxazole-4-carboxylic acid (according to a procedure in Synthesis, Vol. 10, pp. 1569-71 (2005)) in DCM (3.0 mL) according to General Procedure A and directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (8.5 mg). LCMS (m/z) 906.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (27, 2.45 g, 8.77 mmol) in 68 mL of tetrahydrofuran, sodium hydride (0.4208 g, 10.52 mmol) is added and the reaction is stirred at room temperature for 30 minutes. 4-Methyl-benzenesulfonyl chloride (28, 1.838 g, 9.643 mmol) is added and the reaction stirred at room temperature overnight. Water is added and the reaction is extracted with ethyl acetate, resulting in some precipitate that is removed by filtration. The aqueous layer is separated and extracted with ethyl acetate. The organic layers are combined, washed with water, then brine and dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue is suspended in ethyl acetate, sonicated for 30 minutes, and the solid collected by filtration to provide the desired compound (29, 3.325 g). MS (ESI) [M+H+]+=433.8.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:14]([C:15](=O)[CH3:16])=[CH:13][C:12]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:11]1)(C)(C)C>Cl.O1CCOCC1>[CH3:16][C:15]1[C:14]2[N:10]([N:11]=[C:12]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH2:9][CH2:8][N:7]=1
Reactant: CC(=O)c1cc(COc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1=NCCn2nc(COc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
[2-(5-Acetyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (0.2 g, 0.56 mmol) was dissolved in a 4M solution of HCl in 1,4-dioxane (2.12 mL) under nitrogen. The mixture was stirred at room temperature for 30 minutes and then the solvents evaporated in vacuo. The residue was basified with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 4-methyl-2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine (135 mg, 99% yield) as a brown solid that was used without further purification.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])C.CCOCC>C(O)C>[C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:15]([NH:14][C:8]3([C:6]([OH:7])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:16])[CH2:22][CH2:21]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1(NC(=O)N2CCN(Cc3ccccc3)CC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCN(Cc2ccccc2)CC1
Yield: 42 %

Procedure:
600 ml of 1N aqueous sodium hydroxide solution was added to a solution of 7.62 g (20 mmol) of 1-[[(4-phenylmethyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid ethyl ester in 300 ml of ethanol, and the mixture was heated under reflux for 2 hours. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.90 g (42%) of the title compound.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:58][NH2:59]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:59][N:58]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:32][CH:31]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: O=C(O)C(CCCCCl)c1ccc(OCC(F)(F)F)cc1
Reactant: NN
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)(F)F)cc3)n2)ccc1-n1cnc(Cl)c1

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (1.50 g, 3.53 mmol, from preparation A) and 6-chloro-2-(4-(2,2,2-trifluoroethoxy)phenyl)hexanoic acid (1.43 g, 4.42 mmol, from preparation AW) were coupled [N-methylmorpholine (2.00 mL, 17.7 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.556 mL, 17.7 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(4-(2,2,2-trifluoroethoxy)phenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown foamy solid. LC-MS (M+H)+ 569.3. The crude product was used in the next step without purification.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17]([OH:19])=O)=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:35]=[CH:36][CH:37]=[N:38]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C=O.C1(N)CC1>C(OCC)(=O)C>[CH:37]1([NH:38][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:14]([C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][N:6]=[CH:7]4)[CH:15]=2)[CH2:35][CH2:36]1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(C(C)C)nncc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C(C)C)nncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 10-mL round-bottom flask was charged with 3-(1-isopropylphthalazin-6-yl)-4-methylbenzoic acid (32 mg, 0.10 mmol), HATU (60 mg, 0.157 mmol), and N,N-dimethylformamide (0.5 mL), followed by cyclopropylamine (0.03 mL, 0.52 mmol). The resulting golden yellow mixture was stirred at RT for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, then dried (MgSO4) and concentrated in vacuo. CombiFlash purification (20% to 70% ethyl acetate in Hexane) afforded the title compound as an off-white amorphous solid. MS (ES+): 346.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].[Cl:43]C1C=CC(Cl)=CC=1S(Cl)(=O)=O>>[Cl:43][C:6]1[CH:7]=[CH:2][C:3]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]4[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=3)[NH:25][CH:24]=[C:23]4[CH:32]3[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:39])=[O:40])[CH2:34][CH2:33]3)[CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[CH:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5ccc(Cl)cc5)c4)cc23)CC1
Yield: 13 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting (2E,4E)-5-chloro-2,4,6-heptatriene-2-sulfonyl chloride (80 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 7.5 mg the title compound (13%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22](C)(C)[O:23][SiH2]C(C)(C)C)=[CH:17][CH:16]=4)=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:12][C:11]2[C:10]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][CH:16]=4)=[N:9][NH:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]nc(-c3cc4cc(C(C)(C)O[SiH2]C(C)(C)C)ccc4[nH]3)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]nc(-c3cc4cc(CO)ccc4[nH]3)c2s1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indol-2-yl]-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [192 mg, 0.435 mmol, Intermediate (28)] is dissolved in tetrahydrofuran (10 mL) and treated with tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.52 mL) and stirred overnight. The reaction mixture is diluted in ethyl acetate and washed with water, brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel cartridge (50% ethyl acetate in heptane then ethyl acetate) to obtain solid. Recrystallization from ethyl acetate and heptane afforded 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid methyl ester [90 mg, 73%, Example 40] as beige solid; 1H NMR [(CD3)2SO)]: δ 13.66 (1H, s), 11.60 (1H, s), 7.92 (1H, s), 7.51 (1H, s), 7.38 (1H, d, J=8.2 Hz), 7.10 (1H, d, J=8.2 Hz), 6.68 (1H, s), 5.75 (1H, br s, OH), 4.54 (2H, s, —CH2OH), 3.90 (3H, s, —CO2CH3); LC/MS 328 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([C:29]([NH2:32])([CH3:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:32][C:29]([CH3:31])([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:33])[F:34])[CH:24]=3)[CH3:30])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 53.3 mg (0.262 mmol) of 1-methyl-1-[(3-trifluoromethyl)-phenyl]ethylamine from Example 1A are placed in 2 ml of dimethylformamide and treated with 38.6 mg (0.286 mmol) of HOBt. After 10 mins' stirring, 59.4 mg (0.310 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1). 97 mg (85% of theory) of the target compound are thus obtained.