Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 77.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 47 (61 mg, yield 77.7%) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11][C:12]1[S:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]>CO>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11][C:12]1[S:16][C:15]([CH:17]([OH:19])[CH3:18])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
Sodium borohydride (54 mg, 1.44 mmol) was added to a suspension of 1-[5-(2,3-dichlorophenylsulfanyl)-4-nitro-2-thienyl]ethanone (0.5 g, 1.44 mmol) in methanol (10 mL) and the resulting mixture was stirred at ambient temperature. After 90 minutes, TLC showed no starting material remaining so the reaction was quenched by addition of water (20 mL). The resulting precipitate was collected by filtration and dissolved in dichloromethane (50 mL). The organic solution was dried over magnesium sulfate (MgSO4), filtered and the solvent removed to give a yellow solid. The crude solid was re-crystallized from methanol to afford the title product as a yellow solid (0.164 g, 33% yield). 1H NMR (300 MHz, CDCl3) δ: 7.65 (2H, m), 7.40 (1H, m), 7.33 (1H, t), 4.94 (1H, q), 1.99 (1H, d, J=4.74 Hz), 1.51 (3H, d, J=6.48 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][C:8]([C:14]([O-:16])=[O:15])=[C:7]([C:17]1[S:18][CH:19]=[C:20]([CH3:22])[N:21]=1)[C:6]2=[O:23])[CH3:2].[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.C(OCC)(=O)C>[C:24]1([O:15][C:14]([C:8]2[O:9][C:10]3[C:5]([C:6](=[O:23])[C:7]=2[C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[CH:4][C:3]([CH2:1][CH3:2])=[C:12]([OH:13])[CH:11]=3)=[O:16])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCc1cc2c(=O)c(-c3nc(C)cs3)c(C(=O)[O-])oc2cc1O
Reactant: Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cc2c(=O)c(-c3nc(C)cs3)c(C(=O)Oc3ccccc3)oc2cc1O
Reaction time: 20 h
Yield: 40.9 %

Procedure:
In a 5 mL Schlenk tube 18 mg (0.054 mmol) 6-ethyl-7-hydroxy-3-[(4-methyl)-1,3-thiazol-2-yl]-4-oxo-4H-chromene-2-carboxylate 10 (Aldrich, no. R66,464-2) were suspended in 0.5 mL methylene chloride. Then 51 mg (0.54 mmol) phenol and 18 μl (0.108 mmol) triflate anhydride were added at ambient temperature. The resulting mixture was stirred for 20 hours, diluted in 10 mL of ethyl acetate and washed with water and saturated solutions of sodium bicarbonate and sodium chloride. The organic layer was separated, dried over magnesium sulfate and filtered. Evaporation of the solvent on a rotavapor yielded 9 mg of a yellow solid. This crude product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:23][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:21])[F:22])=[N:4]2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid and N-methylbenzylamine using a similar procedure to that described for Example 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][N:24]=2)=[CH:20][CH:19]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=C[C:41]2N(O)N=[N:44][C:42]=2C=1.CCN(C(C)C)C(C)C.Cl.CN.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](=[O:29])[NH:44][CH2:42][CH3:41])=[CH:25][N:24]=2)=[CH:32][CH:33]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1
Agent: CN
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(Oc2ccc(CN(CCc3ccccc3)C(=O)OC(C)(C)C)cc2)nc1
Reaction time: 72 h
Yield: 55.5 %

Procedure:
Combine 6-{4-[(tert-Butoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-nicotinic acid (0.097 g, 0.21 mmol), CH2Cl2 (5 mL), EDC (0.048 g, 0.25 mmol), HOBt (0.034 g, 0.25 mmol), Hunig's Base (92 uL, 0.53 mmol), and Methylamine Hydrochloride (0.014 g, 0.21 mmol) in a 7 mL reaction vial. After reactions shake for 72 hours, add 10% Citric acid, followed by 10% NaHCO3, and then add the organic mixture to a Celite column. Elute with CH2Cl2, concentrate, and flash chromatograph using 2:1 Ethyl acetate:Hexanes eluent to afford 55.4 mg (57% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.4 (9H, s), 2.7-2.9 (2H, m), 3.0 (3H, s), 4.2-4.4 (2H, m), 4.3-4.5 (2H, m), 6.3-6.4 (1H, br s), 6.9 (1H, d), 7.0-7.4 (9H, m), 8.1 (1H, d), 8.6 (1H, s); MS m/z 362 (M−100, Boc).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([CH:21]3[CH2:23][CH2:22]3)[C:13]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:3]=1.C(N(C(C)C)CC)(C)C>C(O)C.[C].[Pd]>[CH:21]1([N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10]([CH:2]=[CH:3][N:4]3[CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:9][CH:8]=2)[C:13]([C@@H:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[O:14])[CH2:22][CH2:23]1
Reactant: COCCCn1cc(Cl)c2ccc(CN(C(=O)[C@H]3CNCCO3)C3CC3)cc21
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COCCCn1ccc2ccc(CN(C(=O)[C@H]3CNCCO3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
10% Palladium-carbon (20 mg) was added to a solution of (2R)—N-{[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]methyl}-N-cyclopropylmorpholin-2-carboxamide (67 mg) and diisopropylethylamine (43 mg) in ethanol (3 ml) and the mixture was stirred under hydrogen atmosphere at room temperature for 8 hours. Insoluble materials were filtered and the filtrate was concentrated in vacuo. The resulted residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with NH-silica gel column chromatography (eluting solvent: ethyl acetate to ethyl acetate/methanol=10/1) to give (2R)—N-cyclopropyl-N-{[1-(3-methoxypropyl)-1H-indol-6-yl]methyl}morpholin-2-carboxamide (53 mg) as a colorless oil.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[Cl:7][C:8]1[N:9]=[C:10]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[O:24][CH2:25][CH3:26])=[O:16])[NH:11][C:12]=1[CH2:13][CH3:14]>C(OCC)(=O)C>[Cl:7][C:8]1[NH:9][C:10]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[O:24][CH2:25][CH3:26])=[O:16])=[N:11][C:12]=1[CH2:13][CH3:14]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(CC)c(Cl)[nH]1

Procedure:
Ethyl acetate and saturated sodium bicarbonate solution were added to cis(±)-4-chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (0.100 g, 0.296 mmol), and the aqueous layer was extracted with ethyl acetate. Thereafter, drying over anhydrous sodium sulfate gave cis(±)-4-{[(5-chloro-4-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidine. This and 3-{(S)-2-methoxycarbonylpyrrolidine-1-carbonyl}-3-methyl-1H-imidazol-3-ium iodide obtained in Example (151b) (0.162 g, 0.444 mmol) were dissolved in dichloromethane (5 ml), and the solution was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution, followed by extraction with ethyl acetate and further extraction with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: hexane/ethyl acetate=1/1, then methanol/ethyl acetate=0/100, 5/95, 10/90) to obtain 38 mg of the crude title compound. This was further purified by thin layer silica gel chromatography (developing solvent: methanol/dichloromethane=5/95) to obtain 24 mg of the title compound as a colorless oily substance (18%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:21][N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-3-nitro-benzaldehyde (5 g) and ammonium acetate (3.5 g) in nitromethane (4.5 mL) and acetic acid (20 mL) was heated to reflux for 3 hr, and then cooled to room temperature in an ice bath. The product precipitated as a dark solid. The dark solid was washed with water then ether/hexane (1:1) and dried overnight under vacuum to give 3.5 g of the title compound (75a) as a bright-red solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ncn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
150 mg palladium on charcoal was added to 765 mg 4-(6-methoxy-pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 90 mL methanol. The reaction was stirred 3.5 h at RT and 3 bar hydrogen. Then, the reaction was filtered and evaporated to yield 769 mg of the desired product. Rt: 1.31 min (method K), (M+H)+: 294
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32].C(O)CC>CN1C(=O)CCC1>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CN1CCCC1=O
Solvent: CCCO
Product: O=C(O)C[C@H](O)C(=O)O
Temperature: 25 °C

Procedure:
2 g of sunitinib base were suspended in 6 ml of NMP under stirring at RT. 0.673 g of Malic acid were added to the mixture and the temperature was set at 40° C. 40 ml n-propanol were dropped in 30 minutes, the suspension was cooled to 0° C., filtered and washed with 10 ml n-propanol. Dried at 70° C. under vacuum for 16 h.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH2:25][CH2:24]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:23]5[CH2:24][CH2:25][CH:26]([C:29]([N:31]6[CH2:35][CH2:34][CH2:33][CH2:32]6)=[O:30])[CH2:27][CH2:28]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: O=C(C1CCNCC1)N1CCCC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC(C(=O)N2CCCC2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperidin-4-yl(pyrrolidin-1-yl)methanone (1.2 equiv) to give 206 (M+1 478.0)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[S:17][C:18]([F:21])=[CH:19][CH:20]=2)[OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][C:18]([F:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(F)s2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(F)s2)CC1

Procedure:
From 4-[(5-fluoro-thiophen-2-yl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (968 mg) by procedure E.2. MeCN (0.6 ml) was added to the reaction mixture. Yield: 577 mg (60%). Light brown gum. MS (m/z): 336.4 ([M+Na]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[BH4-].[Na+]>C1COCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:5][OH:6]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of 3,5-dichlorobenzoyl chloride (712 mg, 3.40 mmole) in THF (6 ml) at 0° C. is added dropwise a solution of sodium borohydride (227 mg, 6.0 mmole), in N-methyl pyrrolidinone (1.5 ml) maintaining the temperature at ≤18° C. The reaction mixture is stirred for 2 hours at ambient temperature and then partitioned with 0.5 N aqueous HCl (60 ml) and EtOAc (60 ml). The layers are separated and the aqueous layer is washed with EtOAc (20 ml). The combined organic layer is washed with H2O (60 ml) and brine (40 ml), dried (Na2SO4), filtered, and concentrated to give crude product as a crystalline solid. One recrystallization from hot cyclohexane (7.5 ml) gives 2, i.e., 3,5-dichlorobenzyl alcohol (451 mg, 2.55 mmole, 75%, m.p. 77°-77.5° C.).
Reaction SMILES: S(Cl)(Cl)=O.C[N+](C)=C[Cl:8].[Cl-].O[CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])[C:13]([OH:15])=[O:14].[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH3:33])[NH:28]1>ClCCl.CCOCC.C(O)C.CN(C)C=O>[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH3:33])[NH:28]1.[Cl:8][CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])[C:13]([OH:15])=[O:14]
Reactant: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: C[N+](C)=CCl
Agent: CC1CCCC(C)N1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To magnetically stirred N,N-dimethylformamide (3 mL) cooled in ice was added slowly dropwise thionyl chloride (4.5 ml., 61.7 mmol) and the resulting cold Vilsmeier reagent was diluted with dichloromethane (30 ml.). (-)-α-Hydroxy-2-nitrobenzenepropanoic acid [3.00 g., 14.2 mmol, [α]D25 -63.04° (c 0.955, 95% ethanol)] in dichloromethane (70 ml.) was added. The resulting solution, protected from moisture, was left at room temperature (25° overnight. The solution was added to stirred ice and the mixture was stirred for 1 hour, during which time it warmed to room temperature. The dichloromethane solution was separated and washed thrice with water and dried (MgSO4). Evaporation gave a syrup which was subjected to an oil pump vacuum for 1.5 hours. The syrup was dissolved in ether and 2,6-dimethylpiperidine was added to approximate neutrality (pH 9 with pH paper). The crude titled product [2.98 g. (61%), m.p. 155°-158° C. dec.] crystallized readily. Two crystallizations (methanol-ether) with decolorization (Nuchar C-190N) gave 1.91 g. (39%) of pure product; m.p. 164°-167° C. dec., [α]D25 +42.11° (c 1.09, 95% ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@@H:14]([O:21][CH3:22])[CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][CH2:24][CH3:25]>>[CH2:24]([C:25]1[N:11]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@@H:14]([O:21][CH3:22])[CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1)[CH3:23]
Reactant: CCC
Reactant: CO[C@H]1C[C@@H](Nc2c(N)cnc3ccsc23)CC[C@@H]1CC#N
Product: CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)[C@@H](OC)C1

Procedure:
This compound was prepared according to the procedure of Example 34, steps 12, using {(1R,2S,4S)-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-methoxycyclohexyl}acetonitrile (racemic) and propane, 1,1,1-triethoxy- as the starting material. LCMS calculated for C19H23N4OS (M+H)+: m/z=355.2. Found: 355.1.
Reaction SMILES: C(=O)([O-])O.[Na+].[I:6]N1C(=O)CCC1=O.[CH2:14]([N:21]1[C:25]2[N:26]=[C:27]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([O:42][CH3:43])=[O:41])[CH:34]=3)[CH:28]=[C:29]([C:30]([OH:32])=[O:31])[C:24]=2[CH:23]=[N:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[CH2:14]([N:21]1[C:25]2[N:26]=[C:27]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([O:42][CH3:43])=[O:41])[CH:34]=3)[CH:28]=[C:29]([C:30]([OH:32])=[O:31])[C:24]=2[C:23]([I:6])=[N:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3cnn(Cc4ccccc4)c3n2)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3c(I)nn(Cc4ccccc4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.9 %

Procedure:
Sodium hydrogen carbonate (11.39 g/0.136 mol) and N-iodosuccinimide (30.51 g/0.136 mol) are added portionwise to a suspension of 1-benzyl-6-[4-fluoro-3-(methoxycarbonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (14.25 g/45.2 mmol) in 410 mL of dioxane. The reaction mixture is stirred for 24 h at ambient temperature. The reaction medium is run into a saturated aqueous solution of NaHCO3. The aqueous phase is washed with EtOAc and then acidified to pH=2-3 using a solution of KHSO4 (1 M), and extracted with EtOAc. The organic phase is washed with water, with a solution of sodium thiosulphate (0.1 M) and with a saturated aqueous solution of NaCl, dried over sodium sulphate and then concentrated to dryness to give 13.9 g of a yellow powder (yield: 70%).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH2:10][CH:9]2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C-:21]#[N:22].[K+]>O1CCCC1.O>[OH:13][CH:12]([CH:9]1[CH2:10][CH2:11][N:8]1[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:21]#[N:22]
Reactant: [C-]#N
Reactant: O=CC1CCN1C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(O)C1CCN1C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a solution of 1.4 g (5.57 mmoles) of 1-diphenylmethyl-2-formylazetidine in a mixture of 7.5 ml of tetrahydrofuran and 7.5 ml of water is added 0.91 ml (11.14 mmoles) of concentrated hydrochloric acid under cooling and then 0.724 g (11.14 mmoles) of potassium cyanide is added thereto. The mixture is stirred for 2 hours and extracted with 30 ml of ether. The aqueous layer is reextracted with 30 ml of ether. The extract and the above organic layer are combined, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 1.6 g of crude syrupy 2-hydroxy-2-(1-diphenylmethylazetidin-2-yl)acetonitrile in quantitative yield.
Reaction SMILES: [F:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:3]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(F)c2N2CCOCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(CN2CCNCC2)c1N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[3-fluoro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate (1.00 g, 2.64 mmol, 1.00 equiv), dichloromethane (20 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (2 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.600 g (crude) of 4-[2-fluoro-6-(piperazin-1-ylmethyl)phenyl]morpholine as light yellow oil. LCMS (ESI, m/z): 280 [M+H]+.
Reaction SMILES: Cl[O-:2].[Na+].[C:4]([C:7]1[C:8]([CH3:22])=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13](=[O:18])(=[O:17])[CH2:12][C:11]([CH3:20])([CH3:19])[C:10]2=[O:21])(=[O:6])C>O1CCOCC1.O>[C:4]([C:7]1[C:8]([CH3:22])=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13](=[O:17])(=[O:18])[CH2:12][C:11]([CH3:20])([CH3:19])[C:10]2=[O:21])([OH:6])=[O:2]
Reactant: CC(=O)c1ccc2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Reactant: [O-]Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1C(=O)C(C)(C)CS2(=O)=O
Temperature: 28 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
11.6 Grams (about 9.8 mmol) of a 6.3 wt % sodium hypochlorite aqueous solution was placed in a 50-ml three-necked round-bottomed flask, and cooled to 15~20° C., and then a solution of 0.83 g (2.96 mmol) of 6-acetyl-3,3,5-trimethylthiochroman-4-one-1,1-dioxide in 5 ml of dioxane was gradually added. The mixture was stirred at 15~20° C. for 30 minutes, and then stirred at room temperature (temperature-increased to 28° C.) for 3 hours, and the reaction mixture was diluted with about 50 ml of water and washed with chloroform twice. A sodium sulfite aqueous solution was added to an aqueous layer to decompose excess hypochlorite, and then the mixture was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution to give a white solid. The solid was extracted with ethyl acetate, and an organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, to give 0.68 g (yield 81%) of 6-carboxy-3,3,5-trimethylthiochroman-4-one-1,1-dioxide in the form of a white solid.