Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH2:13]([S:15][C:16]1[C:17]([C:22](O)=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:14].CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C1C=CC2N(O)N=NC=2C=1.N1C=CC=CC=1>[CH2:13]([S:15][C:16]1[C:17]([C:22]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: CCSc1cccnc1C(=O)O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CCSc1cccnc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of 0.35 g of 4-trifluoromethoxyaniline, 0.36 g of 3-ethylsulfanylpicolinic acid, 0.46 g of EDCI hydrochloride, 0.02 g of HOBt and 3 mL of pyridine was stirred at room temperature overnight. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 0.60 g of 3-ethylsulfanyl-N-(4-trifluoromethoxyphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 18).
Reaction SMILES: [H-].[Na+].C(C1C=CC(OC2C=CC(C(NC3C=CC(C(F)(F)F)=CC=3)=O)=CN=2)=CC=1)(=O)C.[Cl-].[NH4+].[F:34][C:35]([F:67])([F:66])[C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2[CH:46]=[CH:47][C:48]([O:51][C:52]3[CH:57]=[CH:56][C:55]([C:58]([CH3:65])=[CH:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:54][CH:53]=3)=[N:49][CH:50]=2)=[O:44])=[CH:38][CH:37]=1>C1COCC1>[F:66][C:35]([F:34])([F:67])[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]([C:45]2[CH:46]=[CH:47][C:48]([O:51][C:52]3[CH:57]=[CH:56][C:55]([CH:58]([CH3:65])[CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:54][CH:53]=3)=[N:49][CH:50]=2)=[O:44])=[CH:40][CH:41]=1
Reactant: CCOC(=O)C=C(C)c1ccc(Oc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cn2)cc1
Agent: CC(=O)c1ccc(Oc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cn2)cc1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)c1ccc(Oc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride (0.133 g, 3.3 mmol) in THF (6 mL) was added dropwise triethylphosphono acetate (0.53 mL, 2.7 mmol) under ice cooling, and the resulting solution was stirred for 1 hour at room temperature. To the reaction solution was added a solution of 6-(4-acetylphenoxy)-N-[4-(trifluoromethyl]phenyl]nicotinamide (0.53 g, 1.3 mmol) in THF (6 mL), and the resulting solution was stirred for 10 hours at 60° C. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.57 g of the intermediate product ethyl 3-(4-{5-[4-(trifluoromethyl)phenyl-carbamoyl]pyridin-2-yloxy}phenyl)-2-butenoate. 10% palladium-carbon (0.057 g) was suspended in a mixed solvent consisting of ethanol (8 mL) and dioxane (2 mL), and to this suspension was added ethyl 3-(4-{5-[4-(trifluoromethyl)phenylcarbamoyl]pyridin-2-yloxy}phenyl)-2-butenoate (0.57 g, 1.2 mmol). The resulting product was subjected to catalytic reduction at atmospheric pressure and room temperature. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 0.56 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@:29]([OH:44])([C@H:36]([S:38][CH:39]([CH2:42]O)[CH2:40][OH:41])[CH3:37])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[O:41][CH2:40][C@H:39]([S:38][C@H:36]([CH3:37])[C@:29]([C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[F:21])([OH:44])[CH2:30][N:31]4[CH:35]=[N:34][CH:33]=[N:32]4)[CH2:42][O:17]3)=[CH:12][CH:11]=2)=[CH:19][CH:20]=1)#[N:2]
Reactant: N#Cc1ccc(CNC(=O)c2ccc(C=O)cc2)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)NCc3ccc(C#N)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 1(2), a reaction was carried out using N-(4-cyanobenzyl)-4-formylbenzamide, obtained in Example 26(1) (200 mg, 0.76 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (237 mg, 0.66 mmol) and p-toluenesulfonic acid monohydrate (151 mg, 0.79 mmol) and the reaction mixture was treated using a similar procedure to that described in Example 1(2) to afford the trans isomer of the title compound (137 mg, yield 34%) as a white solid and the cis isomer (82 mg, yield 21%) as a white solid. The trans isomer was recrystallized from tetrahydrofuran-hexane to give white powdery crystals and the cis isomer was recrystallized from ethyl acetate to give white powdery cryatals.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1.C(=O)([O-])[O-:28].[K+].[K+].NC1C2C(=CC(Cl)=CC=2)NC=1C(=O)C1C=CC=C(C#N)C=1>C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:25])=[O:28])[CH:19]=1
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C#N)c2)c(N)c2ccc(Cl)cc21
Reactant: O=C([O-])[O-]
Agent: N#Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1

Procedure:
A mixture of 3-amino-6-chloro-2-(3-cyanobenzoyl)-1-(ethoxycarbonyl)indole (step 1, 10.4 g, 28 mmol) and potassium carbonate (20 g, 140 mmol) in ethanol (100 ml) and water (100 ml) was heated at reflux for 4 h. The mixture was cooled and concentrated, and the residue partitioned between water (100 ml) and ethyl acetate (250). The organic layer was dried (MgSO4) and concentrated. The residual oil was purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to give; 3-Amino-6-chloro-2-(3-cyanobenzoyl)indole (Example 127):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+]([O-])=O)=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([O:24][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[CH2:23][CH2:22][CH:21]=[O:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)ccc2CCC=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-2-fluoro-1-nitrobenzene (2 g, 11.40 mmol) and 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester in 40 mL of anhydrous DMF, add NaH (0.55 g, 22.79 mmol) at 0° C. in portions. Stir the mixture at room temperature for 1 h, then, pour into ice-water, extract with EtOAc (3×50 mL), dry over MgSO4 and evaporate to afford the compound pure enough to use in the following step without further purification (yellow solid, 4.15 g). Follow a procedure similar to preparation 49 substituting 3-(5-chloro-2-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert butyl ester for 1-(5-chloro-2-nitro-phenyl)-pyrrolidine to prepare the title compound.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.[OH-].[Li+]>C(O)C.O1CCCC1>[CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccccc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.2 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (9.85 g) synthesized in Example A16 was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase:hexane/ethanol (500/500), flow rate: 60 mL/min, column temperature: room temperature). The fraction containing an optically active form having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (4.85 g, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (20 mL) and tetrahydrofuran (20 mL) was added 1N lithium hydroxide (22 mL), and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (4.41 g, 97%, 99.9% ee) as a white solid. The obtained white solid (50 mg) was crystallized from ethanol/water to give ethanol-containing crystals (41 mg). The ethanol-containing crystals (35 mg) were recrystallized from diethyl ether to give colorless crystal (18 mg) free of solvent.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:10])[O:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccccc21
Yield: 100.7 %

Procedure:
A mixture of 1-isobenzofuranone (150 g) and N-bromosuccinimide (199.05 g) in carbon tetrachloride (3000 ml) is irradiated with a 500 W photospot lamp for 3 hr, cooled and filtered. The filtrate is evaporated to give 3-bromo-1-isobenzofuranone (240 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[CH3:8][N:9](C)/[CH:10]=[C:11](\[C:16]([F:19])([F:18])[F:17])/[CH:12]=[N+:13](C)C.Cl.[Br:22][C:23]1[CH:28]=[C:27](C)[C:26](NN)=[C:25]([CH3:32])[CH:24]=1.C[O-].[Na+]>O1CCCC1>[Br:22][C:23]1[CH:28]=[C:27]([CH3:26])[C:8]([N:9]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[N:13]2)=[C:25]([CH3:32])[CH:24]=1
Reactant: Cc1cc(Br)cc(C)c1NN
Reactant: CN(C)/C=C(/C=[N+](C)C)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1-n1cc(C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
(Z)—N-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-N-methyl methanaminium hexafluorophosphate (3000 mg, 8.819 mmol) and 1-(4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (2480 mg, 9.84 mmol) were suspended in tetrahydrofuran. The suspension was cooled to 0° C. Sodium methoxide (551 mg, 9.7 mmol) was added as a solid in one portion. The ice bath was removed and the mixture warmed to room temperature and stirred for 48 hours. Trifluoroacetic acid (3 mL) was then added at room temperature. The reaction was heated to 80° C. for 5 hours, diluted with ethyl acetate and washed with saturated sodium bicarbonate twice. The combined aqueous washings were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-20% ethyl acetate in heptane), gave 1-(4-bromo-2,6-dimethylphenyl)-4-(trifluoromethyl)-1H-pyrazole as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.93 (s, 1H), 7.71 (s, 1H), 7.31 (s, 2H), 1.99 (s, 6H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([Br:14])[S:11][C:10]=12)=[O:5].[H-].C([Al+]CCCC)CCC.C1(C)C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[Br:14][C:12]1[S:11][C:10]2=[C:6]([CH:4]=[O:5])[N:7]=[CH:8][N:9]2[CH:13]=1
Reactant: CON(C)C(=O)c1ncn2cc(Br)sc12
Agent: CCCC[Al+]CCCC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ncn2cc(Br)sc12
Reaction time: 3 h
Yield: 38.7 %

Procedure:
A solution of N-methoxy-N-methyl-2-bromoimidazo[5,1-b]thiazole-7-carboxamide (54 mg, 0.19 mmol) in dichloromethane (5 ml) was cooled to −78° C. A solution of dibutylaluminium hydride in toluene (1.01 M solution; 0.4 ml, 0.42 mmol) was added dropwise to the cooled solution, and the mixture was stirred at the same temperature for 3 hr. After the completion of the reaction, a saturated aqueous potassium sodium tartrate solution was added thereto, the mixture was stirred at room temperature for one hr, and the mixture was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (17 mg, 39%) as a white solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(Cl)(=O)C.CS(O[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](=[NH:24])[NH2:23])=[CH:16][CH:15]=1)(=O)=O>C(OCC)C>[C:1]([O:4][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](=[NH:23])[NH2:24])=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Solvent: CC(=O)Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C=CC(=N)N)cc1

Procedure:
To a mixture of 8 ml of glacial acetic acid and 8 ml of acetyl chloride, was added 2.0 g of 4-(β-amidinoethenyl)phenol methanesulfonate. The mixture was heated with stirring under reflux for one hour. After cooling, the reaction mixture was mixed with ethyl ether to precipitate a white solid substance which was recrystallized from ethanol to yield 1.8 g of colorless needle crystals of 4-(β-amidinoethenyl)phenyl acetate methanesulfonate.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C@@H:9]([OH:17])[CH2:10][C:11](=[O:16])[C:12]=1[CH2:13][C:14]#[CH:15].[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@@H:23]([C:24]([O:17][C@H:9]2[CH2:10][C:11](=[O:16])[C:12]([CH2:13][C:14]#[CH:15])=[C:8]2[CH3:7])=[O:25])[C:22]1([CH3:27])[CH3:28]
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C#CCC1=C(C)[C@@H](OC(=O)[C@@H]2[C@@H](C=C(Cl)Cl)C2(C)C)CC1=O
Yield: 78.3 %

Procedure:
3.4 Grams of pyridine was added to a mixture of 5.0 g of (S)-2-methyl-4-oxo-3-(2-propynyl)-cyclopent-2-enyl alcohol, 8.0 g of (1R)-trans-3-(2, 2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride and 50 ml of toluene under ice-cooling. The resulting mixture was allowed to react at room temperature for 12 hours. Thereafter, about 50 ml of a saturated aqueous ammonium chloride solution was added to the resultant reaction solution, which was then extracted with three 50-ml portions of diethyl ether. The combined diethyl ether layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography followed by recrystallization from a mixed solvent of hexane and ethyl acetate to obtain 8.9 g (yield: 78%) of (S)-2-methyl-4-oxo-3-(2-propynyl)-cyclopent-2-enyl (1R)-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (the present compound).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][CH:19]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([I:20])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc(-c2cc(C3CC3)n3nccc3n2)cc1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 91.6 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine (1.08 g, 4.0 mmol) and N-iodo-succinimide (0.90 g, 4.0 mmol) in N,N-dimethylformamide (8 mL) was stirred at 20° C. for 40 min. The heterogeneous mixture was partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give 5-(4-chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine (1.45 g, 92%) as a yellow solid. MS (ISP) 395.8 [(M+H)+]; mp 189-190° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:35]4[CH:36]=[CH:37][C:38]([C:40]5[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=5)=[CH:39][C:34]4=[N:33][CH:32]=3)=[CH:27][CH:26]=2)=[O:22])[N:8]([CH2:10][CH2:11][O:12][Si](C(C)(C)C)(C)C)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:35]4[CH:36]=[CH:37][C:38]([C:40]5[CH:41]=[CH:42][C:43]([S:46]([CH3:49])(=[O:47])=[O:48])=[CH:44][CH:45]=5)=[CH:39][C:34]4=[N:33][CH:32]=3)=[CH:29][CH:30]=2)=[O:22])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCO[Si](C)(C)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCO)n1
Yield: 77.4 %

Procedure:
In a round bottomed flask dissolve 1-{5-tert-butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-yl}-3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-urea (0.26 g, 0.37 mmol) in THF (5 mL) under N2, Add TBAF (0.41 mL of a 1M solution in THF, 1.1 equiv.) via syringe and stir the reaction at room temperature for 20 minutes. Load the reaction directly onto a silica column and purify (EtOAc to 5% MeOH: DCM to 10% 2 M NH3 in MeOH: DCM) to give a pale yellow solid (0.168 g, 77%). MS (ES), m/z 587 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:14][S:15]([C:18]1[C:19]2[CH:20]=[CH:21][NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:17])=[O:16])[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13].CC(SCC[NH2+]C(CN)=O)=O.C([O-])(C(F)(F)F)=O.C1C(=O)N([Cl:53])C(=O)C1>CN(C=O)C.CC#N>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:14][S:15]([C:18]1[C:19]2[C:20]([Cl:53])=[CH:21][NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:17])=[O:16])[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13]
Reactant: COC(=O)C(CCn1cccc1C#N)NS(=O)(=O)c1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(=O)SCC[NH2+]C(=O)CN
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)C(CCn1cccc1C#N)NS(=O)(=O)c1cccc2[nH]cc(Cl)c12
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A solution of 0.20 g (0.52 mmol) of 4-(2-cyano-pyrrol-1-yl)-2-(1H-indole-4-sulfonylamino)-butyric acid methyl ester (from the synthesis of I-102) and 0.070 g (0.52 mmol) of NCS in 1 mL of DMF is stirred overnight, and then diluted with MeCN and purified by preparative HPLC to provide 0.15 g (0.36 mmol; 69%) of 2-(3-chloro-1H-indole-4-sulfonylamino)-4-(2-cyano-pyrrol-1-yl)-butyric acid methyl ester. This material is stirred in 1.4 mL of THF with 1.4 mL of 1M NaOH for 3 h, and then 2N HCl is added until the pH is 3. The mixture is extracted with EtOAc, and the extract washed with brine, dried over Na2SO4, filtered, and concentrated to provide 0.12 g (85%) of I-103 as a tan powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:22])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[C:16](Br)[C:15]=2[CH:14]=[C:13]([F:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu][C:24]#[N:25]>CN(C)C=O.[Cu]I>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:22])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[CH:14]=[C:13]([F:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(Cc1cc(F)cc2c(Br)coc12)NC(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(Cc1cc(F)cc2c(C#N)coc12)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 16 h
Yield: 5.8 %

Procedure:
A mixture of 0.20 gm (0.54 mMol) N-tert-butoxycarbonyl 1-(3-bromo-5-fluorobenzofur-7-yl)-2-aminopropane, 0.95 gm (5 mMol) copper(I) iodide, and 0.43 gm (4.78 mMol) copper(I) cyanide in 10 mL dimethylformamide was purged with nitrogen for 15 minutes. The mixture was then heated at 120° C. An additional equivalent of copper(I) iodide and copper(I) cyanide were added and the reaction continued at 120° C. for about 16 hours. After cooling to room temperature the reaction mixture was diluted with dichloromethane and then silica gel was added. The solvents were removed under reduced pressure and the dry silica gel remaining was loaded on the top of a silica gel column. The column was then eluted with a gradient of hexane containing from 17% to 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.010 gm (6%) of the desired compound.
Reaction SMILES: Cl[CH:2]([CH2:15]Cl)[CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[Na]>C1(C)C=CC=CC=1>[CH2:4]([Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[CH2:3][CH:2]=[CH2:15]
Reactant: CCO[Si](CCC(Cl)CCl)(OCC)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Product: C=CCC[Si](OCC)(OCC)OCC
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A mixture of 578.6 g 3,4-dichlorobutyl triethoxysilane (2.0 moles) and 750 ml toluene is combined at reflux temperature within 2 hours with 92.0 g molten sodium in a heatable (approximately 130° C.) dropping funnel. In order to complete the reaction, the mixture is subsequently agitated for 30 minutes more at 120° C. After the workup already described in b), 417.3 g crude product =95.4% of theory are obtained which yield 366.0 g 3-butenyl triethoxysilane as a main fraction in the subsequent vacuum fractionation, corresponding to 83.7% of theory.