Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:32][CH2:33][N:34]1[C:39](=[O:40])[CH:38]=[CH:37][C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:35]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCCCCC>[O:40]=[C:39]1[N:34]([CH2:33][CH2:32][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[N:35]=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:37]=[CH:38]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=c1ccc(-c2ccccc2)nn1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1c2ccccc2C(=O)N1CCn1nc(-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of phthalimide (1.0 g, 6.8 mmol), Ph3P (1.9 g, 7.2 mmol), 2-(2-hydroxyethyl)-6-phenylpyridazin-3(2H)-one (1.2 g, 5.5 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (1.4 mL, 7.2 mmol) dropwise. The resulting hot, clear solution was stirred at room temperature. After 3 h, hexane (40 mL) was added. The slurry was filtered and the solid was washed with ether (6×15 mL) to give the product as a white (2.1 g). MS (ESI pos. ion) calc'd for C20H15N3O3: 345.1; found: 346.4 (MH+). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.03 (dd, 2 H) 4.39 (t, 2 H) 6.99 (d, J=9.78 Hz, 1 H) 7.26 (t, J=7.43 Hz, 2 H) 7.34 (t, J=7.34 Hz, 1 H) 7.50 (d, J=7.24 Hz, 2 H) 7.72-7.82 (m, 4 H) 7.97 (d, J=9.78 Hz, 1 H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>C1C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[C:10]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[Cl:35])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(I)nn2C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1c(-c1ccccc1Cl)nn2C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 6-(2,4-difluorophenoxy)-3-iodo-4-methyl-5-oxo-4,5-dihydro-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester (18 mg) in benzene (1.3 mL) and methanol (0.26 mL) was added I M aqueous solution of sodium carbonate (76 μL, 2 eq), 2-chlorophenylboronic acid (12 mg, 2 eq), and Pd(PPh3)4 (13 mg, 0.3 eq). The mixture was purged with argon, heated at reflux for 2 hours, cooled to room temperature, and diluted with ethyl acetate (35 mL) and water (25 mL). The organic layer was separated, washed with brine (1×25 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product ((M+H)+=488) which was used without purification for the following step.
Reaction SMILES: ClC1C(NC2C=CC=CC=2S(C(C)C)(=O)=O)=NC(NC2C=C3C(CN([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)C3=O)=CC=2OC(C)C)=NC=1.C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C=O)C>[CH2:53]([O:52][C:50]([N:22]1[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23]1)=[O:51])[CH3:54]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 446-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.O.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[S:19]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[C:18]1[C:17]([O:21][CH3:22])=[O:20]
Reactant: O=Cc1cnccc1Cl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cnccc2s1
Temperature: 45 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 4-chloropyridine-3-carboxaldehyde (D-1) (1.4 g, 10 mmol) dissolved in DMF (10 mL) and water (1 mL) were added K2CO3 (1.66 g, 12 mmol) and methyl thioglycolate (1.07 mL, 12 mmol) portion-wise. The reaction mixture was stirred at 45° C. overnight and then quenched with cold water. The flask was placed on ice to enhance precipitation. The precipitate was collected by filtration and air-dried to afford the title compound (1.23 g). MS (m/z): 194 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:30])[CH3:29].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:28](=[O:30])[CH3:29])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(F)cc1F
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)c(F)cc3F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2,4-difluorophenyl}carbamate (3.94 g, 10.0 mmol) and N,N-dimethylpyridine-4-amine (1.22 g, 10 mmol) in pyridine (20 mL) was added dropwise acetyl chloride (0.94 g, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (4.36 g, quantitatively) as a pale-yellow amorphous.
Reaction SMILES: [CH3:1][N:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]([C:5]1[C:10]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])COC)=[CH:9][C:8]([Cl:29])=[CH:7][N:6]=1)=[O:4].Cl>O.O1CCOCC1>[CH3:1][N:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]([C:5]1[C:10]([NH:11][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:9][C:8]([Cl:29])=[CH:7][N:6]=1)=[O:4]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1

Procedure:
5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-phenylamide (132 mg, 0.24 mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) and heated at 85° C. (oil bath) for 7 h. LCMS indicated complete reaction; the reaction was concentrated and the residue was neutralized (pH 7) with aqueous sodium bicarbonate and the aqueous layer was extracted with EtOAc (3×80 mL). The extracts were dried (MgSO4), filtered, and chromatographed on silica gel using ethyl acetate-hexane gradient (0:100 to 50:50) to provide 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid N-methyl-N-phenylamide. MS m/z: 504.1 (M+H).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([CH:28]([CH3:30])[CH3:29])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([CH:28]([CH3:30])[CH3:29])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(C)[C@H](N)C(=O)N(C)C
Product: COc1ccccc1C1(N[C@H](C(=O)N(C)C)C(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.92 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.99 g of the compound obtained in Step 82-2 as starting materials, respectively 1.07 g (Isomer A, pale yellow solid) and 1.73 g (Isomer B, colorless solid) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=12>CN(C=O)C.CCOCC>[N:1]1[NH:2][N:3]=[N:17][C:16]=1[C:13]1[CH:14]=[CH:15][N:10]2[CH:9]=[CH:8][N:7]=[C:11]2[CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccn2ccnc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1cn2ccc(-c3nn[nH]n3)cc2n1
Temperature: 80 °C
Yield: 330 %

Procedure:
Sodium azide (97 mg, 1.45 mmol) was added to a stirred mixture of NH4Cl (82 mg, 1.53 mmol) and imidazo[1,2-a]pyridine-7-carbonitrile (200 mg, 1.4 mmol) in dry DMF (5 ml) at RT under N2. The reaction was stirred and heated at 80° C. in a sealed vial for 10 hours. [3 identical reactions were run in parallel] After cooling to RT the reaction mixtures were combined and diluted with Et2O. The solid was collected by filtration and dried to give the title compound (860 mg) as a light brown solid. [presumably contains NaCl] 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, dd), 8.02 (1H, s), 7.94 (1H, s), 7.57 (1H, d), 7.54 (1H, dd).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.Cl[C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[C:35](=[O:41])[C:34]1=[O:42])=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:42]=[C:34]1[C:35](=[O:41])[N:36]([CH2:39][CH3:40])[CH2:37][CH2:38][N:33]1[C:31]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=[O:32]
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(C(=O)NCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)n2)C(=O)C1=O

Procedure:
Crude 4-(3-aminopropyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in CH2Cl2 and treated with 4-dimethylaminopyridine and a solution of 1-chlorocarbonyl-4-ethylpiperazine-2,3-dione in CH2Cl2. Work-up by chromatography gave 4-[3-(2,3-dioxo-4-ethylpiperazine-1-carbonylamino)propyl]-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 1.25 (t, 3H); 1.85 (quintet, 2H); 2.25-3.7 (m, 6H); 4.05 (q, 2H); 6.25 (s, 1H); 7.05-7.5 (m, 15H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:15][C@H:16]([OH:32])[C@@H:17]([NH:25]C(=O)C(F)(F)F)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:15][C@H:16]([OH:32])[C@@H:17]([NH2:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cnccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cnccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
11.75 g (21 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane are suspended in 500 ml of methanol and, at 60° C., 105 ml of a 1 M K2CO3 solution in water are added. The mixture is stirred at 75° C. for about 3 hours; the methanol is evaporated off and the residue is extracted with ethyl acetate. The organic phase is washed once each with water and brine and concentrated. The title compound is obtained in the form of orange-brown crystals, which can be recrystallised from ethyl acetate/petroleum ether. M.p.: 146-148° C. TLC: Rf =0.08 (methylene chloride/methanol 10:1). HPLC20-100 : tRet =11.23.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:18])[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:19]O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:19])([CH3:18])[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C(=O)N(C)c1cccnc1Cl
Reactant: OO
Solvent: CC(=O)O
Product: Cc1ncccc1C(=O)[N+](C)([O-])c1cccnc1Cl
Temperature: 110 °C

Procedure:
A mixture of N-(2-chloro-3-pyridinyl)-N-methyl-2-methylnicotinamide (1.86 g) and H2O2 (30%, 5 mL) in acetic acid (10 mL) was heated at 110° C. for 75 minutes. The solvents were evaporated under reduced pressure. Chromatography of the residue over basic alumina (chloroform/ethanol) gave N-(2-chloro-3-pyridinyl)-N-methyl-2-methylnicotinamide N-oxide as an oil which crystallized on trituration with isopropyl ether/ethyl acetate, (1.42 g).
Reaction SMILES: [OH:1][C:2]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)([CH3:7])[C:3]([NH:5][NH2:6])=O.[F:14][C:15]1[C:16]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[N:24]2)=[N:17][CH:18]=[C:19]([F:21])[CH:20]=1.S(=O)(=O)(O)O.N>ClCCl>[F:14][C:15]1[C:16]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([NH:28][C:29]3[S:30][C:3]([C:2]([C:8]4[S:9][CH:10]=[C:11]([CH3:13])[N:12]=4)([OH:1])[CH3:7])=[N:5][N:6]=3)=[N:24]2)=[N:17][CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: Cc1csc(C(C)(O)C(=O)NN)n1
Reactant: Fc1cnc(Cn2ccc(N=C=S)n2)c(F)c1
Agent: N
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1csc(C(C)(O)c2nnc(Nc3ccn(Cc4ncc(F)cc4F)n3)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
A mixture of Intermediate 107, 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanohydrazide (63 mg, 0.313 mmol), and Intermediate 96, 3,5-difluoro-2-[(3-isothiocyanato-1H-pyrazol-1-yl)methyl]pyridine (79 mg, 0.313 mmol) in dichloromethane (anh) (3 mL) was stirred at room temperature overnight. Reaction mixture was concentrated, residue was treated with sulfuric acid (2 mL, 0.364 mmol) and stirred at room temperature during 1 h. Resulting mixture was neutralized with 32% NH3 (aq) under ice-bath until pH was basic. Mixture was partitioned between DCM (3×15 mL) and water (15 mL). Organic phase was separated, dried over magnesium sulfate and concentrated. Residue was purified by preparative HPLC using SUNFIRE column (C18, 3.5 μm, 19×150 mm) and linear gradient 25% to 75% water (0.1% HCOOH)-(0.1% HCOOH). Appropriate fractions were collected to give 1-[5-({1-[(3,5-difluoro-2-pyridinyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol (50 mg, 0.109 mmol, 30.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.83 (s, 1H), 8.46 (d, 1H), 7.93-7.98 (m, 1H), 7.74 (d, 1H), 7.27 (s, 1H), 7.21 (m, 1H), 5.96 (d, 1H), 5.37 (d, 2H), 2.29 (d, 3H), 1.97 (s, 1H). [ES+MS] m/z 436 (MH+).
Reaction SMILES: [C:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:8]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])[CH3:9]>>[C:8]([N:11]1[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])[CH3:9]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=CC1=CCCC1
Product: CCOC(=O)C1(C(=O)OCC)C2CCCC2CN1C(C)=O

Procedure:
The title compound was prepared from cyclopenten-1-aldehyde (1 equiv.) and diethyl 2-acetamidomalonate using the procedure by Chung et al (J. Org. Chem. 1990, 55, 270). MS (ESI) 298 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:5]([C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7])[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)N1C(=O)OCC1Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of the compound of example 50 (2.40 g, 6.07 mmol) in anhydrous THF (60 mL) was cooled to −78° C. A solution of NaHDMS in THF (1M, 6.7 mmol, 6.7 mL) was injected over 10 minutes. The reaction mixture was stirred for an additional 20 minutes, after which time, a solution of tert-butyl bromoacetate in anhydrous THF (5 mL) was slowly injected. After stirring for 1 h at −78° C., and 3 h at −48° C., the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times using ethyl acetate. The recombined organic layer was extracted successively with brine, saturated sodium hydrogen carbonate, brine and water. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude material was flashed using 20% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 300 MH: 1.40, 1.41(2s, 9H); 1.74–1.92(m, 5H); 2.45–2.95(m, 4H); 3.31(m, 1H); 3.69, 3.73(2 s, 3H); 4.11(m, 2H); 4.50, 4.66(2 m, 1H); 7.25(m, 10H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)=[C:14]([CH3:21])[CH:13]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COC(=O)c1c[nH]nc1C
Product: COC(=O)c1cn(-c2ccc(F)cc2C)nc1C
Yield: 67.7 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.25 g) synthesized in Example 1(3) and 4-fluoro-2-methylphenylboronic acid (13.9 g) and in the same manner as in Example 17(1), the title object compound (7.5 g, 68%) was obtained as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[K+].[CH2:12](Cl)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>C(O)C>[C:13]([C:12]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=1)(=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: O=Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccccc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
24.4 g of salicylaldehyde and 300 ml of ethanol are mixed with 11.6 g of potassium hydroxide. The resulting suspension is agitated at room temperature until the potassium hydroxide is completely dissolved. Subsequently, 31 g of phenacyl chloride are added in portions to the solution, and the batch is heated under stirring in a reflux condenser for 2 hours. The crystals precipitated while cooling down to room temperature are filtered by suction, washed with water, and recrystallized from methanol. Another fraction may be obtained by evaporating the mother liquor. Yield: 70%, colourless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>>[Si:24]([O:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:12][CH:13]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccc(CO)cc2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cc([N+](=O)[O-])ccc2F)cc1
Yield: 98 %

Procedure:
6.0 g (98% yield was prepared by the method of Example 19E from 4.2 g 4-(2-fluoro-5-nitrophenyl)benzyl alcohol, 2.5 g imidazole and 3.5 g t-butyldimethylsilyl chloride. The oil was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([CH:11]=O)=[CH:9][N:10]=1.[NH2:13][C:14]1[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][CH3:24])[N:17]=[C:16]([C:25]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:26])[CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:13][C:14]1[C:19]([C:20]#[N:21])=[C:18]([O:22][CH2:23][CH3:24])[N:17]=[C:16]([C:25]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:11][C:8]3[S:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:10][CH:9]=3)[CH2:31][CH2:30]2)=[O:26])[CH:15]=1
Reactant: O=Cc1cnc(-c2cccs2)s1
Reactant: CCOc1nc(C(=O)NCC2CCNCC2)cc(N)c1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4cccs4)s3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.4 %

Procedure:
The compound prepared in Example 333 (31 mg) and the compound prepared in Example 334 (48 mg) were combined in dichloroethane (1.6 mL) and acetic acid (0.054 mL) was added. Sodium triacetoxyborohydride (0.101 g) was then added. The reaction mixture was stirred at ambient temperature for 17 hours. It was then treated with saturated sodium bicarbonate and extracted with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=98:2) to obtain the title compound (24 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5](Cl)[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Br:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:21]3[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]3)[C:4]=2[CH:3]=1
Reactant: Clc1nccc2sc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3sc(Br)cc23)CC1
Temperature: 100 °C
Reaction time: 144 h
Yield: 24.8 %

Procedure:
2-Bromo-4-chlorothieno[3,2-c]pyridine (5.0 g, 20.24 mmol) and K2CO3 (13.97 g, 101.2 mmol) was stirred in DMSO (20 mL) followed by addition of tert-butyl piperazine-1-carboxylate (4.14 g, 22.26 mmol). The reaction mixture was stirred at 100° C. for 6 days. The reaction mixture was filtered to eliminate the carbonate and addition of water (50 mL) and ethyl was followed. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash chromatography using ethyl acetate/hexanes (2/8) as eluent to give 2 g of the desired product, yield 25%, 99% pure. 1H NMR (270 MHz, CDCl3) δ 1.48 (s, 9H), 1.52-1.63 (m, 1H), 3.42-3.47 (m, 4H), 3.61-3.64 (m, 4H), 7.22 (dd, J=5.4, 1 Hz, 1H), 7.35 (d, J=1 Hz, 1H), 8.04 (d, J=5.4 Hz, 1H). m/z=398.91 (M+H), bromide pattern.