Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[S:6])[NH2:5].[CH3:12]OS(OC)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([S:6][CH3:12])=[NH:5]
Reactant: COS(=O)(=O)OC
Reactant: NC(=S)c1c(F)cccc1Cl
Solvent: Cc1ccccc1
Product: CSC(=N)c1c(F)cccc1Cl
Yield: 87 %

Procedure:
Into a 25-mL three-necked round bottom flask equipped with a magnetic stirrer was added 2-chloro-6-fluorobenzthioamide (1.89 g, 10.0 mmol) and toluene (10 mL). Dimethylsulfate was added dropwise and the mixture was allowed to stir at reflux using a Dean Stark trap. The solids were removed via filtration and washed with small portions of toluene to give methyl 2-chloro-6-fluorobenzthioimidate as a light yellow solid: 2.7 g (87% yield): 1H NMR (DMSO-d6) δ7.7 (m, 1H), 7.5 (m, 2H), 3.3 (s, 3H), 2.7 (s, 3H); 98% pure by HPLC analysis.
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:20]3[N:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)[CH2:15]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.[ClH:45]>O1CCOCC1>[ClH:45].[ClH:45].[C:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:20]3[N:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[CH2:15]2)=[CH:40][CH:41]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(C(=O)c4ccccc4)cc3)C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(Cc2ccc(C(=O)c3ccccc3)cc2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (111 mg) in dioxane (2 mL) was added 1N sodium hydroxide (0.6 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O (10 mL) and acidified with 1N hydrochloric acid (to pH 1). A resulting mixture was extracted with CHCl3, and the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylic acid dihydrochloride (97 mg).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH:8]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reaction time: 0.25 h

Procedure:
To a solution of pyridine (9.5 g, 0.12 mol) in dichloromethane (150 mL) was added chromium trioxide (6.0 g, 0.06 mol). The internal reaction temperature was not allowed to exceed 20° C. during the addition. After 15 minutes, the stirred mixture was charged with a solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 10 mmol) in dichloromethane (30 mL). After 15 minutes, the solution was decanted from the reaction vessel which was washed with dichloromethane (200 mL). The organics were combined, washed with 5% aqueous sodium hydroxide (3×100 mL), then washed with 5% hydrochloric acid (100 mL), then washed with 5% aqueous sodium bicarbonate (100 mL), and finally washed with 5% aqueous sodium chloride (100 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford tert-butyl 3-formylpyrrolidine-1-carboxylate that was used without additional purification.
Reaction SMILES: COC(=O)[NH:4][C:5]1[C:10]([F:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13].O.[OH-].[Na+]>CO>[Cl:13][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[C:10]([F:11])[C:5]=1[NH2:4]
Reactant: COC(=O)Nc1c(Cl)ccc(C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)c(N)c1F
Temperature: 25 °C

Procedure:
N-(2-chloro-5-methyl-6-fluorophenyl)-carbamic acid methyl ester (39 g, 0.18 mmol) is dissolved in MeOH (150 mL), water (150 mL) and 30% NaOH solution (150 mL). The reaction mixture is heated to reflux temperature for 3 days and then cooled to room temperature. The reaction is concentrated by rotary evaporator to remove most of the methanol and then partitioned between Et2O (500 mL) and water (500 mL). The aqueous phase is extracted again with Et2O (250 mL) and the combined organic layers washed with brine (500 mL), dried and concentrated by rotary evaporator. The crude product is purified by bulb-to-bulb distillation to give 2-chloro-5-methyl-6-fluoroaniline as a colorless oil (b.p. 120–131° C. at ˜20 mm of Hg), which forms a white crystalline solid upon storage at 4° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:7]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[CH2:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]2)=[CH:18][CH:19]=1
Reactant: COC(=O)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1
Temperature: 100 °C
Reaction time: 12 h
Yield: 105.4 %

Procedure:
1-(4-Bromo-phenyl)-5-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (5.3 g, 13.5 mmol) prepared in Step 3 and a solution of potassium hydroxide (2.0 g, 35.6 mmol) in distilled water (25.0 mL) were added to methanol (25.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.4 g of the titled compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19]([Cl:26])[C:18]=1[CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([Si:44](Cl)([CH3:46])[CH3:45])([CH3:43])([CH3:42])[CH3:41].Cl>C(Cl)Cl>[Si:44]([O:30][CH2:29][CH:28]([OH:31])[CH2:27][C:18]1[C:19]([Cl:26])=[N:20][C:21]2[N:22]([N:23]=[CH:24][CH:25]=2)[C:17]=1[N:7]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)[C:6](=[O:32])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:45]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(O)CO)c(Cl)nc3ccnn23)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(O)CO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To a methylene chloride (3.6 mL) solution containing tert-butyl[5-chloro-6-(2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (500 mg, 1.08 mmol), triethylamine (300 μL, 2.16 mmol), tert-butylchlorodimethylsilane (195 mg, 1.30 mmol) and N,N-dimethylpyridine (13 mg, 0.108 mmol) were added. After the reaction mixture was stirred at room temperature for 5 hr, 1 mol/L hydrochloric acid was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography to obtain the title compound (503 mg).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15](O)=[O:16])=O)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C(O)C>[CH:1]1([C:4]([NH:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]3[CH2:13][CH2:14][C:15](=[O:16])[NH:21][N:22]=3)=[CH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)C2CC2)cc1
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(NC(=O)C3CC3)cc2)=NN1
Yield: 68.1 %

Procedure:
2.0 g (7.7 millimoles) of 3-(p-cyclopropylcarbonylaminobenzoyl)-propionic acid, 0.45 g (9.0 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 6 hours. The product is filtered off at 10° C. and recrystallized from dimethylformamide/water, giving 1.35 g (68% of theory) of 6-(p-cyclopropylcarbonylaminophenyl)-4,5-dihydro-3(2H)-pyridazinone, as colorless crystals, identical with the compound from Example 1.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[OH:16][CH:17]1[CH2:21][CH:20]([CH3:22])[NH:19][CH2:18]1>>[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:19]3[CH:20]([CH3:22])[CH2:21][CH:17]([OH:16])[CH2:18]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC1CC(O)CN1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Product: CC1CC(O)CN1S(=O)(=O)c1cccc2cnccc12

Procedure:
In substantially the same manner as in Example 11, 2.64 g of 5-isoquinolinesulfonyl chloride hydrochloride was reacted with 2.0 g of 3-hydroxy-5-methylpyrrolidine to obtain 1-(5-isoquinolinesulfonyl)-3-hydroxy-5-methylpyrrolidine.
Reaction SMILES: C(OC(=O)[N:7]([C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]=O)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=2)=[O:26])=[CH:20][CH:19]=1)[CH3:8])(C)(C)C.C(O)(=O)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C([BH3-])#N.[Na+]>C(O)C>[CH3:8][NH:7][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:49]3[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]3)=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:29]=2)=[O:26])=[CH:22][CH:23]=1
Reactant: CN1CCNCC1
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
In 2 mL of ethanol, 40 mg (0.07 mmol) of (9-{4-[3-(4-formyl-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)-methyl-carbamic acid tert-butyl ester was dissolved, and 15 μL of acetic acid and 20 mg (0.20 mmol) of 1-methylpiperazine were added thereto, and the mixture solution was stirred at room temperature for 30 minutes. To the reaction solution, 10 mg (0.26 mmol) of sodium cyanoborohydride was further added and the resulting solution was stirred at room temperature for one hour. The reaction solution was concentrated and partitioned between water and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, concentrated under reduced pressure and purified by a silica gel column (ethyl acetate:methanol=4:1). The obtained intermediate was dissolved in 1 mL of trifluoroacetic acid and stirred for one hour. The reaction solution was concentrated and partitioned between a saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution, concentrated under reduced pressure, and purified by trituration with ethyl acetate to obtain 27.4 mg (70%) of a target product as a white solid.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([CH:36]2[CH2:41][CH2:40][N:39]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=3)[CH2:38][CH2:37]2)=[O:35])=[CH:32][CH:33]=1
Reactant: O=S(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCC(S(=O)c2ccc(F)cc2)CC1
Yield: 66.2 %

Procedure:
4-[[7-(Trifluoromethyl)-4-quinolyl]amino]benzoyl chloride hydrochloride (14.7 g) was added slowly to a stirred mixture of 4-[(4-fluorophenyl)sulfinyl]piperidine hydrochloride (10.0 g) and triethylamine (26.4 ml) in dry methylene chloride (440 ml) at room temperature. The resultant mixture was stirred at the same temperature for 3 hours, and concentrated to dryness in vacuo. Water was added to the residue and the precipitated powder was collected by filtration, washed with water, and dried to give a powder. The powder was washed with methylene chloride to give 4-[(4-fluorophenyl)sulfinyl]-1-[4-[[7-(trifluoromethyl)-4-quinolyl]amino]benzoyl]piperidine (13.60 g) as colourless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:18]([CH3:19])=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1.[Li]CCCC.[C:33](C#N)(=[O:37])[O:34][CH2:35][CH3:36]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:18]([CH3:19])=[CH:17][C:16]2[C:12](=[C:13]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: COc1ccc(-c2cc3cn(COCC[Si](C)(C)C)nc3cc2C)c(F)c1
Reactant: CCOC(=O)C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c2cc(-c3ccc(OC)cc3F)c(C)cc2nn1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a solution of 5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (650 mg, 1.68 mmol) in THF (10 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.74 mL, 1.85 mmol) dropwise via syringe. The reaction was stirred at −78° C. for 10 minutes, warmed to room temperature for 5 minutes, and cooled back to −78° C. A solution of ethyl cyanocarbonate (188 mg, 1.90 mmol) in THF (1 mL) was added via syringe. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with aqueous NH4Cl solution and diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc/heptane) to provide the title compound (448 mg, 58% yield). MS (ES+) 459.3 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.69 (s, 1H), 7.22 (t, J=8.54 Hz, 1H), 6.81 (dd, J=8.42, 2.32 Hz, 1H), 6.75 (dd, J=11.34, 2.32 Hz, 1H), 6.20 (s, 2H), 4.49 (q, J=7.07 Hz, 2H), 3.89 (s, 3H), 3.66-3.72 (m, 2H), 2.29 (s, 3H), 1.44 (t, J=7.07 Hz, 3H), 0.93-1.00 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[C@@H:7](O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N12CCCN=C1CCCCC2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[C@H:7]([F:27])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@@H](O)C1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@H](F)C1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
Process B: (3S,4R)-3-Bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (561 mg) was dissolved in toluene (20 mL). To this solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) was added and perfluoro-1-octanesulfonylfluoride (0.93 mL) was then added dropwise while the mixture was chilled in an ice water bath. After stirred at 2° C. for 1 hour, the reaction mixture was poured on a silica gel pad and was eluted with ethyl acetate (100 mL). The eluate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-3-bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine as a yellow oil (447 mg).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([Cl:16])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)SCC(CC(C)C)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(Acetylthio)methyl]-4-methylpentanoic acid (6.0 g) is combined with the thionyl chloride (5 ml). The reaction mixture is allowed to exotherm to 45° C. It is stirred at room temperature for about 16 hours and the acid chloride product is then vacuum distilled yielding 5.1 g, boiling point 80°-90° C. at 10 mm of Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[S:28]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:19])=[S:28]
Reactant: Cc1ccccc1N=C=S
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccccc1C
Temperature: 80 °C
Reaction time: 96 h
Yield: 51.3 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol), 2-methylphenyl isothiocyanate (0.55 mL, 4.11 mmol, and ethyl acetate 20 mL) was allowed to stand at room temperature. After 4 days, the reaction was heated to 80° C. for 3 hours then allowed to stand at room temperature for an additional 5 days. Filtration afforded the product (0.804 g); m.p. 172-174° C.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[C:5](=[CH:15][C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:3]=[CH:2]1.[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:23][C:2]1[S:1][C:10]2[CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[C:5](=[CH:15][C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:3]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3sccc32)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Nc1cccc(C=C2c3ccccc3CCc3sc(Cl)cc32)c1
Reaction time: 1 h
Yield: 22 %

Procedure:
Add 2.2 equiv of n-BuLi-hexanes dropwise to a solution of 3-(9,10-dihydro-1-thia-benzo[f]azulen-4-ylidenemethyl)-phenylamine in THF (0.1 M) at 0° C. under Ar. Stir the resultant dark solution for 1 h before adding 2.5 equiv of hexachloroethane in THF. Stir for 2 h, quench with excess water, and acidify to neutral pH. Extract the aqueous layer with diethyl ether (3×) and then dry (MgSO4) and concentrate the combined organic layers under reduced pressure. Purify the crude residue by column chromatography (0% to 2% to 20% EtOAc:hexanes) to give title compound as an oil (22%) along with recovered starting material: HPLC (ISO80-20A) t=1.903 (90%). MS (APCI): 338 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7](Cl)=[O:8].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([NH2:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:28][C:7]([C:6]2[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:3][C:2]=2[CH3:1])=[O:8])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
2-Methyl-5-phenyl-furan-3-carbonyl chloride (0.025 g) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine (0.024 g) and N,N-diisopropylethyl-amine (0.018 mL) in dichloromethane (5 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×5 mL) and basic (dilute NaHCO3, 2×5 mL) workup followed by washing with brine (saturated NaCl, 2×5 mL), drying over MgSO4, and concentration. The crude compound was purified by passing through a silica gel plug eluting with hexanes/ethyl acetate (2:1) to afford the title compound (0.035 g, 82% yield). ES-MS negative Q1 (m/z) 412.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].[CH3:29][NH:30][C:31](=[S:34])[NH:32][NH2:33].O>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:33][NH:32][C:31]([NH:30][CH3:29])=[S:34])=[O:23]
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)O)nc2ccc(F)cn12
Reactant: CNC(=S)NN
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=S)NNC(=O)c1ccccc1-c1nc2ccc(F)cn2c1Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
3.1 200 mg (0.533 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoic acid, 56 mg (0.533 mmol) of 4-methyl-3-thiosemicarbazide and 125 mg (0.650 mmol) of DAPECI are dissolved in 1 ml of DMF and stirred at RT for 2 hours. The mixture is subsequently added to water, the precipitated solid is filtered off with suction and dried, giving 117 mg (47%) of 1-{2-[3-(2,6-dimethylphenylamino)-6-fluoro-imidazo[1,2-a]pyridin-2-yl]benzoyl}-4-methyl-3-thiosemicarbazide as solid; MS-FAB (M+H+)=463.7; Rf (HPLC, polar method): 1.69 min. This is employed in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cc(F)cc(F)c2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of tert-butyl 3-(3,5-difluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (3.38 g, 11.3 mmol) in dichloromethane (100 mL), was added trifluoroacetic acid (10 mL). The mixture was stirred for 1 h at ambient temperature after which the solvent was evaporated. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (1.04 g). MS m/z (rel. intensity, 70 eV) 199 (M+, bp), 141 (52), 127 (52), 114 (36), 113 (63).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([Br:25])=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:26][C:13]([F:12])([F:27])[C:14]1[C:15]([Br:25])=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Br
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Br)c1cc(Cl)ccc1O
Yield: 14.5 %

Procedure:
Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)-2-bromoaniline as the raw materials, the same operation as the example 16 gave the title compound.