Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([CH2:9][C:10](O)=[O:11])#[N:8].[CH2:13]([O:15][C:16]([C:18]1[C:22]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)=[CH:21][S:20][C:19]=1[NH2:31])=[O:17])[CH3:14]>C(Cl)Cl.CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1[C:22]([C:23]2[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:21][S:20][C:19]=1[NH:31][C:10](=[O:11])[CH2:9][C:7]#[N:8])=[O:17])[CH3:14]
Reactant: CCOC(=O)c1c(-c2cc(C)cc(C)c2)csc1N
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2cc(C)cc(C)c2)csc1NC(=O)CC#N
Temperature: 25 °C

Procedure:
To a stirred suspension of PCl5 (0.74 g, 3.5 mmol) in CH2Cl2 (10 mL) was added a solution of cyanoacetic acid (0.3 g, 3.5 mmol) in CH2Cl2 (5 mL) and DMF (1 mL) dropwise via syringe at room temperature and the reaction mixture was heated at reflux for 1 hour. The reaction was cooled to room temperature and a solution of 2-Amino-4-(3,5-dimethyl-phenyl)-thiophene-3-carboxylic acid ethyl ester (0.78 g, 2.8 mmol) in CH2Cl2 (5 mL) was added via canula over 5 minutes. The reaction was then heated at reflux for 2.5 h, cooled to 0° C. and quenched by slow addition of sat. aq. Na2CO3 (10 mL) until basic (pH 9–10). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers were washed with water (25 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a yellow solid. MS (ESI) m/e 341.0 (M−H); 1H NMR (300 MHz, CDCl3): δ ppm 12.02 (s, 1H), 7.26 (s, 1H), 6.97 (s, 1H), 6.91 (s, 2H), 6.67 (s, 1H), 4.15 (q, 4H, J=7.12), 3.68 (s, 2H), 2.33 (s, 6H), 0.98 (t, 3H, J=7.12).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH:8]([S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11])=[CH2:9].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCOCC1>[CH:8]([S:10]([CH2:13][CH2:14][N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])(=[O:12])=[O:11])=[CH2:9]
Reactant: O=C1C=CC(=O)N1
Reactant: C=CS(=O)(=O)C=C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CS(=O)(=O)CCN1C(=O)C=CC1=O
Temperature: 45 °C
Yield: 84.8 %

Procedure:
In a 50 mL round bottom flask, a mixture of 0.5 g of maleimide, 0.61 g of divinylsulfone and 10 g of 1,4-dioxane was heated to 40-50° C. and stirred. To the reaction solution was added 0.67 g of 40% aqueous tetrabutylammonium hydroxide solution. Subsequently, the mixture was stirred at 40-50° C. for 3 more hours. After stopping stirring, the reaction solution was cooled to room temperature and precipitated and dispersed in 100 mL of methanol. The resultant precipitate was filtered, redispersed in a large volume of clean water, filtered again and washed to remove salt. Then, the product was redispersed in 50 mL of methanol, filtered and dried to obtain 0.94 g of N-vinylsulfonylethylmaleimide (yield=61%)
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[NH:26]1[C:27]2[C:23](=[C:22]([NH:21][C:2]3[C:3]4[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]5[O:18][C:14]([CH3:13])=[CH:15][CH:16]=5)=[N:7][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: Cc1ccc(CN)o1
Reactant: Nc1cccc2[nH]ccc12
Product: Cc1ccc(CNc2ccc3c(Nc4cccc5[nH]ccc45)cccc3n2)o1

Procedure:
The title compound, MS: m/e=369.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 4-aminoindole.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].[CH2:7](O)[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:8]1[O:9][C:4]([CH2:3][CH2:2][Br:1])([CH3:5])[O:6][CH2:7]1
Reactant: CC(=O)CCBr
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(CCBr)OCCO1

Procedure:
A mixture of 75 g of 4-bromo-2-butanone, 40 g of ethylene glycol, 250 mg of p-toluenesulfonic acid acid and 500 ml of toluene is refluxed for about 4-6 hours under a Dean-Stark water trap. The mixture is cooled, poured into ethyl acetate and dilute potassium carbonate solution. The organic layer is separated, washed with water, dried over sodium sulfate, stripped of solvent and the residue is distilled under reduced pressure to give the title product.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=1[F:52]>>[Cl:44][C:45]1[C:46]([F:52])=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc(Cl)c(F)c1
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Cl)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-chloro-3-fluorophenol, the title compound was obtained (33%): 1H NMR (300 MHz, CDCl3) δ 9.80 (s, 1H), 7.52-7.41 (m, 2H), 7.23 (t, 1H), 6.96 (d, 1H), 6.84 (d, 1H), 6.80 (d, 1H), 4.15 (s, 1H), 3.79-3.58 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 346 (M−17), 386 (M+23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-].[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate (Intermediate 40, Step 5) (2.24 g, 5.19 mmol) in MeOH (20 mL) was added palladium hydroxide, (20 wt % Pd (dry basis) on carbon, wet, degussa type) (0.365 g, 2.60 mmol). The resulting mixture was then stirred at rt under H2 (1 atm) overnight. The mixture was next filtered through Celite® brand filter agent and the Celite® filter agent was washed with a solution of MeOH/EtOAc (1:1, 3×20 mL). The combined filtrates were concentrated and dried to give the desired product as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:20]([Cl:21])=[CH:19][C:17]([NH2:18])=[C:16]([F:22])[CH:15]=1.CCN(C(C)C)C(C)C.[CH:32]1([C:35]([N:37]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43]([NH:45][NH2:46])=[O:44])[CH2:38]2)=[O:36])[CH2:34][CH2:33]1>ClCCl>[Br:13][C:14]1[C:20]([Cl:21])=[CH:19][C:17]([NH:18][C:2]([NH:46][NH:45][C:43](=[O:44])[CH2:42][C@@H:39]2[CH2:40][CH2:41][N:37]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH2:38]2)=[O:4])=[C:16]([F:22])[CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)c(Br)cc1F
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1cc(Cl)c(Br)cc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a round bottom flask was added triphosgene (2.66 mmol) and dichloromethane (20 mL) under nitrogen, and the solution was cooled to −78° C. In a separate vial, 4-bromo-5-chloro-2-fluoroaniline (6.83 mmol) was dissolved in dichloromethane (20 mL) and Hunig's base (17.1 mmol) was added. This solution was slowly added to the cooled solution and then the reaction was allowed to warm to room temperature. After 10 min, analysis by LCMS indicated desired intermediate formation. The reaction was cooled again to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (3.98 mmol) in dichloromethane (5 mL) was added slowly. The reaction was allowed to warm to room temperature and stirred for 30 min. Analysis by LCMS indicated desired product formation. The reaction was poured into a separatory funnel and partitioned with saturated aq sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to an oil. The residue was purified by silica gel chromatography (0-15% isopropanol/ethyl acetate). The desired fractions were combined and concentrated to afford the title product as an oil (1.12 g, 60%). MS(ES)+ m/e 461.1, 463.0 [M+H]+.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[NH:15]1[C:12]2[CH:13]=[CH:14][C:9]([C:1]3[CH:6]=[CH:5][C:4]4[NH:7][C:22]([C:21]5[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=5)=[N:8][C:3]=4[CH:2]=3)=[CH:10][C:11]=2[N:16]=[C:22]1[C:21]1[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: Oc1ccc(-c2nc3cc(-c4ccc5[nH]c(-c6ccc(O)cc6)nc5c4)ccc3[nH]2)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
A mixture of biphenyl-3,3′,4,4′-tetraamine (214 mg, 2.0 mmol), 4-hydroxybenzaldehyde (489 mg, 4.0 mmol) and Na2S2O5 (380 mg, 2.00 mmol) in IMS-H2O (3:1, 20 mL) was heated under microwave irradiation for 160° C. for 10 min, then 180° C. for 10 min. The mixture was filtered and washed with IMS. H2O was added to the filtrate, and the resulting white precipitate was filtered, and washed with water and Et2O. Column chromatography of the crude solid (EtOAc to 95:5 EtOAc-MeOH) afforded the product as a yellow solid (50 mg, 6%).
Reaction SMILES: CC(C)=O.C(=O)=O.[CH3:8][C:9]1[N:10]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:12][N:13]=1.CN(C)CCN(C)CCN(C)C.C([Li])CCC.[Cl:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[CH:54]=[O:55]>O1CCCC1.C(OCC)(=O)C>[Cl:50][C:51]1[CH:52]=[C:53]([CH:54]([OH:55])[CH2:8][C:9]2[N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:11]=[CH:12][N:13]=2)[CH:56]=[CH:57][CH:58]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
To a stirred, cooled (−78° C., acetone/dry ice bath) solution of 2-methyl-1-tritylimidazole (1 g; CAS 23593-68-2) in tetrahydrofuran (THF) (15 ml) under an argon atmosphere was added pentamethyldiethylene-triamine (0.64 ml). n-butyllithium solution (2.0 ml; 1.6 M in hexanes) was then added dropwise over a period of 10 min. The reaction mixture soon turned to a dark red compact slurry. The mixture was then stirred at a temperature between −40° C. and −50° C. for 6 hours. After cooling again to −78° C., a solution of 3-chlorobenzaldehyde (0.86 g) in THF (5 ml) was added dropwise for 5 minutes. The mixture was stirred overnight, slowly warming up to room temperature. The clear yellow solution was diluted with ethyl acetate (30 ml) and washed with H2O. The aqueous phase was back extracted with ethyl acetate (EtOAc). The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient CH2Cl2→CH2Cl2/methanol 92:8) to give 1-(3-chloro-phenyl)-2-(1-trityl-1H-imidazol-2-yl)-ethanol (1.04 g) as light yellow amorphous solid. MS (ISP): 243.3 ([Trt]+)
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([OH:18])(C)C.CS(C)=O.Br>C(Cl)Cl>[OH2:3].[CH3:12][O:11][C:9](=[O:10])[C:8]1[C:7](=[CH:6][CH:5]=[C:4]([C:1](=[O:3])[CH:2]=[O:18])[CH:13]=1)[OH:14]
Reactant: CC(C)O
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: Br
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)C=O)ccc1O
Product: O
Temperature: 15 °C
Yield: 85 %

Procedure:
To a 3-neck flask immersed in an oil bath containing a solution of 40 g (0.206 mole) methyl 5-acetylsalicylate in 6 ml methylene chloride is charged with 82 ml of isopropanol. The solution is distilled to remove excess methylene chloride. When the internal temperature reaches 77° C., 126 ml (1.77 mole or 8.6 equivalents) of DMSO is added to the reaction mixture and the temperature of the mixture is increased to a temperature of 85° to 90° C. Then 33 ml (0.29 mole or 1.4 equivalents) or HBr (aqueous, 48%) is added to the mixture over a period of 20 minutes (exothermic), and the bath temperature is maintained at 95° to 100° C. As the addition of HBr nears completion distillation is initiated and dimethysulfide and isopropanol are distilled off. The mixture is stirred and the volume of the distillate monitored. After distillation of 82 ml of solvent, 20 ml of IPA is added slowly to maintain a steady rate of distillation. After the reaction completed as determined by high performance liquid chromatography (HPLC), the reaction mixture is quenched with 70 ml of 2.4N H2SO4, the temperature of the reaction mixture is allowed to drop to 75° C. and residual isopropanol is distilled off under vacuum. After a total of 165 ml distillate is collected, the title compound begins to precipitate. A mixture of 30 ml of acetonitrile (CH3CN) and 70 ml of water is added slowly at 75° C. with stirring. After 30 minutes of stirring, the reaction mixture is cooled to 15° C. over a period of 90 minutes to complete the precipitation. The reaction mixture is filtered and the cake is washed with three 300 ml portions of water. The cake is dried in a draft oven at 50° C. for 16 hours to give 39.5 g of the title compound (85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([CH2:26][S:27][C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][S:27][C:28]2[NH:30][C:16]([CH3:17])=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:29]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COc1ccc(CSC(=N)N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 79.5 %

Procedure:
A solution of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, methyl ester (5.0 g, 0.02 mole) in 20 ml of dimethylformamide under argon at room temperature was treated with S-(4-methoxybenzyl)thiopseudourea, hydrochloride (4.65 g, 0.02 mole) and sodium acetate (1.64 g, 0.02 mole). The mixture was then heated at 65±5° C. for 3 hours. Upon cooling, ethyl acetate was added and a small amount of solids were filtered. The filtrate was washed with water (twice), aqueous sodium bicarbonate and saturated brine. The aqueous washes were extracted with fresh ethyl acetate. The combined filtrate and washings were dried (magnesium sulfate) and concentrated in vacuo to give about 9 g of crude product. Crystallization from acetone-isopropyl ether gave 6.8 g of product, melting point 125°-127.5° C., tlc, silica gel, ethyl acetate/hexane (1:1), Rf =0.48.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]([OH:15])=O)[CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][CH:51]=1)[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[C:47]([C:33]1[C:34]2[S:38][C:37]([NH:39][C:40]([CH:42]3[CH2:43][CH2:44]3)=[O:41])=[N:36][C:35]=2[CH:45]=[CH:46][C:32]=1[O:31][C:30]1[CH:29]=[C:28]([NH:27][C:13]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])[CH:51]=[CH:50][CH:49]=1)#[N:48]
Reactant: Cn1ncc(C(=O)O)c1-c1ccccc1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid (55 mg, 0.271 mmol) in tetrahydrofuran (10 mL) were added oxalyl chloride (58 μL, 0.676 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (80 mg, 0.228 mmol) produced in Example 3(vi) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (82 mg, 67%) as a white powder.
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:20][C:21]1[C:22]2[O:29][CH:28]=[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:23]=2[N:24]=[CH:25][N:26]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](O)=[O:43].Cl.C(N=C=NCCCN(C)C)C>O.C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:13]=[CH:12][C:11]=1[NH:20][C:21]1[C:22]2[O:29][CH:28]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)=[O:43])[CH2:32][CH2:31]3)[C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(C(=O)c5ccccn5)CC4)coc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Under an argon atmosphere, anhydrous methylene chloride (0.5 mL) and triethylamine (10 μL, 0.069 mmol) were added to N-[2-fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (10 mg, 0.023 mmol), picolinic acid (3.3 mg, 0.028 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9 mg, 0.046 mmol) and N,N-dimethylaminopyridine (0.3 mg, 0.002 mmol), followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, the reaction liquid was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=20:1) to give the titled compound (3.3 mg, 35%) as a yellow oily substance.
Reaction SMILES: [C:1]1([N:7]2[C:11]([N:12]3[CH2:16][CH:15]4[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH:14]4[CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]1([N:7]2[C:11]([N:12]3[CH2:13][CH:14]4[CH:15]([CH2:17][NH:18][CH2:19]4)[CH2:16]3)=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nnnn3-c3ccccc3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-n2nnnc2N2CC3CNCC3C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg) was dissolved in 10% TFA solution in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 24 hours. After removal of solvents, the residue, crude 2-(1-phenyl-1H-tetrazol-5-yl)octahydropyrrolo[3,4-c]pyrrole, was used in the further reactions without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:47])[CH2:26][C@@H:27]([C:42](OCC)=[O:43])[N:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[BH4-].[Li+].CO.O>C1COCC1>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:28]([CH:29]([CH3:31])[CH3:30])[C@H:27]([CH2:42][OH:43])[CH2:26][CH:25]([F:47])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C@H:6]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:5][C:3]([O:2][CH3:1])=[O:4])(=[O:33])=[O:34])=[CH:40][CH:39]=1
Reactant: CCOC(=O)[C@H](CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)N[C@H](C(=O)NCCC(F)C[C@@H](CO)N(C(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of the material from Step 7 (23 mg, 0.034 mmol) in THF (343 μL) at 0° C. were added a solution of 2 M lithium borohydride in THF (69 μL, 0.137 mmol) and methanol (6 μL, 0.137 mmol). The reaction mixture was stirred at room temperature for 2 hours. TLC showed not complete reaction. Additional 2 equiv of lithium borohydride was added, stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 100:0) to afford 18 mg of the title compound as a colorless foam. LCMS (M+1)=629. 1H NMR (Acetone-d6): δ 7.60 (d, J=8.34 Hz, 1H), 7.53 (d, J=8.34 Hz, 1H), 7.46-7.36 (m, 4H), 7.33-7.24 (m, 4H), 7.23-7.15 (m, 2H), 7.16-7.08 (m, 1H), 6.77 (d, J=8.34 Hz, 2H), 6.38 (d, J=9.19 Hz, 1H), 5.52-5.44 (m, 1H), 4.97 (t, J=10.18 Hz, 1H), 4.49-4.38 (m, 1H), 4.35-4.12 (2×b, 1H), 3.94-3.83 (m, 2H), 3.81-3.67 (m, 2H), 3.50 (s, 3H), 3.42 (q, J=7.00 Hz, 1H), 3.29-3.03 (2×b, 1H), 2.98-2.88 (m, 1H), 2.17-2.05 (m, 1H), 1.88-1.71 (m, 1H), 1.45-1.24 (m, 2H), 1.20 (d, J=7.00 Hz, 3H), 1.10 (d, J=7.00 Hz, 3H).