Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:19])([F:20])[F:21])=[O:49])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:39])([F:40])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
0.45 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 1.6 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.41 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[C:23]([N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=O)=[N:28]1)([CH3:26])([CH3:25])[CH3:24]>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:35][C:34]4[CH:37]=[CH:38][CH:39]=[C:32]([C:29]5[N:30]=[N:31][N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:28]=5)[CH:33]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)n1nnc(-c2cccc(C=O)c2)n1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)n1nnc(-c2cccc(C=Nc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)c2)n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 691 mg (3.0 mmol) of 3-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[{3-(2-tert-butyl-tetrazol-5-yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H, analogous working-up and digestion in methanol yield 4(3-chloro-phenylamino)-3-[3(2-tert-butyl-tetrazol-5-yl)-benzylamino]1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.60 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=10.3.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:4]1.[ClH:16]>C(O)C>[ClH:16].[NH2:8][C@H:6]1[CH2:7][C@@H:3]([CH2:2][OH:1])[CH:4]=[CH:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Agent: Cl
Solvent: CCO
Product: N[C@@H]1C=C[C@H](CO)C1

Procedure:
(1S,cis)-tert-Butyl N-[4-(hydroxymethyl)-2-cyclopenten-1-yl]carbamate (part b of this example, 10.66 g, 50.0 mmol) was refluxed in absolute ethanol (25 mL) with concentrated hydrochloric acid (5.0 mL, 60 mequiv) for 2.5 hours. Evaporation of volatiles left title compound as white solid; mass spectrum (ES): 114 (M+1); 1H-NMR (DMSO-d6) δ 7.9 (m, 3H), 6.03 and 5.75 (two m, 2H), 4.11 (m, 1H), 3.41 (d, J=5.4 Hz, 2H), 2.8 (m, 1H), 2.36 (m, 1H), 1.4 (m, 1H). This solid was used immediately in the following example.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])C=CC=CC=1.[H][H]>CCOC(C)=O.C(O)(=O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:9]1=[O:28]
Reactant: [H][H]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 65.8 %

Procedure:
To a solution of 1′-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (2.10 g, 4.70 mmol) in EtOAc (100 mL) and acetic acid (0.10 mL) was added palladium on carbon (1.00 g). The reaction mixture was hydrogenated under 60 psi of hydrogen at ambient temperature for 5 days and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compound (0.87 g, 66%) as a white powder: mp 252° C. (dec.); 1H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 7.25-6.84 (m, 4H), 6.64 (s, 1H), 6.22 (s, 1H), 5.88 (s, 2H), 4.76-4.57 (dd, 2H); MS (ES+) m/z 282.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]1[O:8][CH2:7]1.[NH2:16][C:17]([CH3:36])([CH3:35])[CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(O)C>[NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@@H:6]([OH:8])[CH2:7][NH:16][C:17]([CH3:36])([CH3:35])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:33][CH:34]=1
Reactant: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Solvent: CCO
Product: CC(C)(Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1)NC[C@H](O)COc1cccc([N+](=O)[O-])c1N
Temperature: 55 °C
Yield: 61.7 %

Procedure:
A suspension of (S)-3-(2-amino-3-nitrophenoxy)-1,2-epoxypropane (5 g, 23.8 mmol) and 4-(4-(2-amino-2-methylpropyl)phenoxy)benzamide (20.3 g 71.1 mmol) in absolute ethanol (200 mL) was heated to 55° C. for 12 h. All solids went into solution at 50° C. Upon completion of the reaction, the solvent was evaporated to dryness. The residue was redissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The two organic layers were combined and washed with brine. The phases were separated and the organic layer was dried over sodium sulfate, filtered, and the solvent evaporated. Column chromatography eluting with 20% MeOH/CHCl3 gave 7.26 g (62%) of product. NMR. MS.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][CH3:13].O>C1COCC1>[CH3:11][N:12]([CH3:13])[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of benzenesulfonylchloride (10 ml; 78 mmol) in THF (100 ml) was added a 40% solution of dimethylamine in H2O (20 ml; 160 mmol) such that the reaction temperature was kept below 50° C. The reaction mixture was stirred 1 h at rt. The reaction mixture was added H2O and THF removed by evaporation. The precipitate formed was isolated by filtration and air dried to give 14 g (97%) of N,N-dimethylbenzenesulfonamide.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[NH:10][C:11](=[O:13])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19]I.O>CN(C)C=O>[CH3:19][O:13][C:11]1[N:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:16]=[CH:15][S:14][C:9]=2[N:10]=1
Reactant: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(-c2ccccc2)c2ccsc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 4.0 g of 4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 80 ml of dimethylformamide is added 0.8 g of 63% sodium hydride. The mixture is stirred at 60°C for 1 hour. The mixture is cooled to room temperature and 4.97 g of methyl iodide in 15 ml of dimethylformamide is added dropwise thereto at 10°C. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-phenylthieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 160° - 161.5°C (after recrystallization from ethanol). From the second fraction, 1-methyl-4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 256° - 257.5°C (after recrystallization from ethanol). From the third fraction, 3-methyl-4-phenyl-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystal having a melting point of 175° - 181°C (after recrystallization from ethanol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccnc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-pyridinylboronic acid to give (6-methoxy-1-pyridin-3-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 318(MH+).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](N2CCCCC2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].C[O:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH2:32][CH2:33]Cl>>[CH2:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:33][CH2:32][O:31][C:24]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=3[C:22]([OH:21])=[O:35])[CH2:9][CH2:8]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(OC)cc1OCCCl
Reactant: CCCCn1cc(N2CCCCC2)c2cccnc21
Product: CCCCn1cc(C2CCN(CCOc3cc(OC)ccc3C(=O)O)CC2)c2cccnc21
Yield: 35 %

Procedure:
This compound was prepared following the procedure described in example 4, part E and F starting with 2.5 g (9.1 mmol) of 1-butyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine and 3.3 g (13.6 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. After standard purification the overall yield was 35% (0.77 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][N:10]1[CH:18]=[C:17]2[C:12]([N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH3:20])[C:16]2=[O:19])=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][N:10]1[C:18]([B:24]([OH:29])[OH:25])=[C:17]2[C:12]([N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH3:20])[C:16]2=[O:19])=[CH:11]1)=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c2cn(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(B(O)O)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-ethyl]-carbamic acid tert-butyl ester (step 3) (1.8 g, 5.58 mmol) was dissolved in anhydrous THF (49 ml) at room temperature. The flask was then evacuated and backfilled with nitrogen (×3) and cooled to −78° C. (external). After 10 mins, LDA (0.731 M, 22.92 ml, 16.75 mmol in THF, freshly prepared by standard procedure from BuLi and diisopropylamine) was charged over 3 mins. After 15 mins at −78° C., triisopropyl borate (3.87 ml, 16.75 mmol) was charged drop wise over 2 mins and the reaction held for 2 hr at −78° C. The reaction was then quenched with saturated NH4Cl solution (10 mL) via syringe under nitrogen and diluted with water (60 mL) and EtOAc (40 mL). The layers were separated and the aqueous extracted with EtOAc (4×50 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4) and filtered under reduced pressure to afford a pale yellow solution. The solvent volume reduced by half under reduced pressure to afford a suspension of a white solid. The solid was recovered by reduced pressure filtration and dried in air, followed by heating to 50° C. under vacuum for 3 h. This afforded the title compound as a white crystalline solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(=[O:4])=[O:3].[H-].[Na+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C=O)C>[CH:29]1([CH2:28][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a 100 mL round-bottomed flask was added tert-butyl 4-{2-[(methylsulfonyl)amino]phenyl}piperidine-carboxylate (Example 1 Step d) (1.9 grams, 5.4 mmol) and DMF (Aldrich) (30 mL). The solution was magnetically stirred vigorously at 25° C. under N2 atmosphere and treated in portions with NaH as a 60% dispersion in mineral oil (Aldrich) (150 mg, 6.4 mmol). After gas evolution ceased, (bromomethyl)cyclopropane (Aldrich) (675 μL, 940 mg, 7.0 mmol) was introduced via syringe. The reaction mixture was stirred at 25° C. for 15 h. The reaction was quenched by careful addition of satd NH4Cl (150 mL) and extracted with EtOAc (400 mL). The organic layer was washed with H2O (150 mL), satd NaCl (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a yellow foam (2.2 g). MS (ESI, pos. ion) m/z: 409 (M+1); (ESI, neg. ion) m/z: 407 (M−1). Calc'd for C21H32N2O4S: 408.56.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[C:5]1([C:3](=[O:4])[CH2:2][N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1cn[nH]c1
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cn1cccn1)c1ccccc1
Reaction time: 5 h

Procedure:
To a solution of 1.5 g (9.7 mmol) of 2-chloroacetophenone in 10 mL of MeCN, 0.7 g (10.3 mmol) of pyrazole was added. After all the solids dissolved, 1.4 g (10.1 mmol) of ground K2CO3 was added and the mixture was stirred for 5 h. The reaction was diluted with EtOAc, filtered, and the solid was washed with EtOAc. The filtrate was washed with water and brine, then was dried and concentrated. The residue was chromatographed on a flash column using a gradient of 10-50% EtOAc-hexane to isolate desired product.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=3)=[CH:14][CH:13]=2)=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10])([O-])=O>CO.CN(C=O)C.[Pt]>[NH2:1][C:4]1[S:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=3)=[CH:14][CH:13]=2)=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(-c3cc(C(N)=O)c([N+](=O)[O-])s3)cc2)nn1
Agent: [Pt]
Solvent: CN(C)C=O
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(-c3cc(C(N)=O)c(N)s3)cc2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-nitro-5-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,3-triazol-4-yl)phenyl]thiophene-3-carboxamide (440 mg, 0.99 mmol) in MeOH (15 mL) was added 3% Pt/C doped with 0.6% V (64 mg, 9.9 μmmol). The reaction was stirred under a hydrogen balloon at room temperature overnight. The solution was diluted with MeOH and DMF, filtered through Celite, and evaporated. The crude was triturated with MeOH and filtered to isolate the title compound as a gray solid. The mother liquor was concentrated, triturated with CH2Cl2, and filtered to isolate additional product.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](Cl)(=[O:13])[C:10]([Cl:12])=[O:11]>C1C=CC=CC=1>[O:13]=[C:9]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]([Cl:12])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(Cl)C(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Similar to Referential Example 1, aniline hydrochloride (3.0 g) was dissolved in benzen (10 mL), and oxalyl chloride (10 mL) was added thereto under cooling with ice. The temperature of the mixture was then returned to room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, to thereby give the title compound (3.26 g, 76.6%) as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]([OH:32])=[O:31])=[O:15])[CH3:14]
Reactant: C=CC(=O)O
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)CCC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (10 ml) was added triethylamine (0.68 ml, 0.0049 mole), trimethyl silylchloride (0.61 ml, 0.0049 mole) and acrylic acid (0.175 g, 0.0024 mole). The reaction mixture was stirred at room temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water and sodium bicarbonate, dried over anhydrous sodium sulfate and the organic solvent removed on a rotavap to produce the title compound as a thick oil (0.4 g, 61% yield).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:38]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([Cl:53])[CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:3]([NH:5][C:6]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1)=[O:4].C(N(CC)CC)C.Cl[C:62]([O:64][CH3:65])=[O:63]>ClCCl>[Cl:53][C:47]1[CH:46]=[C:45]([C@@H:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:2]([NH:1][C:62]([O:64][CH3:65])=[O:63])[C:3]([NH:5][C:6]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:7]=2[CH2:8][CH2:9][C@H:10]2[O:15][CH2:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:12]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:11]2)=[O:4])[CH:50]=[CH:49][C:48]=1[O:51][CH3:52]
Reactant: COC(=O)Cl
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N)C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)[C@H](c1ccccc1)c1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the product from step 3 (80 mg, 0.1 mmol) in dichloromethane (2 mL) was added triethylamine (0.02 mL, 0.16 mmol) and methyl chloroformate (0.01 mL, 0.12 mmol). The mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (10 mL) and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=825.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH2:26]Cl)[O:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].[C:34]1(=[O:40])[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1.C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH2:26][N:38]4[C:34](=[O:40])[CH2:35][CH2:36][C:37]4=[O:39])[O:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(CCl)n1
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(CN2C(=O)CCC2=O)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 16.92 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(chloromethyl)oxazole-4-carboxamide (0.132 g, 0.327 mmol) and potassium carbonate (0.068 g, 0.490 mmol) were dissolved in dry DMF under nitrogen atmosphere. Succinimide (0.036 g, 0.359 mmol) was added and the mixture was stirred in RT for 4.5 h. DCM was added and the organic phase was washed with water. The product was triturated using diethyl ether, DCM and finally by Flash-chromatography. Yield 16.92%. %. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.83 (s, 4H), 4.29 (dd, 1H), 4.39 (dd, 1H), 4.51-4.59 (m, 1H), 4.83 (s, 2H), 6.63 (d, 1H), 7.47 (d, 1H), 7.52 (d, 1H), 7.74 (d, 1H), 7.87 (dd, 1H), 7.98 (d, 1H), 8.11 (s, 1H).
Reaction SMILES: [I-:1].[Na+].[CH3:3][CH:4]([CH3:14])[CH2:5][C:6]([O:8][CH:9](Cl)[CH:10]([CH3:12])[CH3:11])=[O:7]>C(#N)C>[CH3:3][CH:4]([CH3:14])[CH2:5][C:6]([O:8][CH:9]([I:1])[CH:10]([CH3:12])[CH3:11])=[O:7]
Reactant: [I-]
Reactant: CC(C)CC(=O)OC(Cl)C(C)C
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CC(=O)OC(I)C(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 56.5 %

Procedure:
Acetonitrile (200 ml) is warmed to 60° C. and in this solvent is dissolved 35 g of sodium iodide. To this solution is added 12 g of 1-chloro-2-methylpropyl 3-methylbutyrate as obtained by the above procedure (a), and the mixture is stirred for 40 minutes, poured into 500 ml of ice water and extracted with hexane. The extract is washed with water and then with 5% aqueous sodium thiosulfate and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 10 g of 1-iodo-2-methylpropyl 3-methylbutyrate.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[N:7]1([CH2:13][C:14]2[CH:28]=[CH:27][C:17]3[NH:18][C:19]([C:21]4[C:25]([NH2:26])=[CH:24][NH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([CH2:3][C:4]([NH:26][C:25]1[C:21]([C:19]2[NH:18][C:17]3[CH:27]=[CH:28][C:14]([CH2:13][N:7]4[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:15][C:16]=3[N:20]=2)=[N:22][NH:23][CH:24]=1)=[O:6])#[N:2]
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of cyano-acetic acid (23 mg, 0.28 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (70%, 100 mg, 0.23 mmol), TBTU (89 mg, 0.28 mmol) and DMF (2 ml) was stirred at 25° C. overnight. The mixture was then evaporated in vacuo. Flash chromatography, eluting with DCM—6% MeOH/DCM afforded 2-cyano-N-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide as a yellow solid (65 mg, 77%). (LC/MS (acidic method/final compound): Rt 4.61, [M+H]+ 366).