Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].BrC(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH:18]([CH3:20])[CH3:19])[CH:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c2[nH]ccc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)Br
Product: COC(=O)c1ccc(C)c2c1ccn2C(C)C
Temperature: 70 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A cooled (ice/water bath) solution of methyl 7-methyl-1H-indole-4-carboxylate (260 mg, 1.374 mmol) in DMF (20 mL) was added sodium hydride (43.4 mg, 1.718 mmol). After 10 minutes 2-iodopropane (0.151 mL, 1.512 mmol) was added and the reaction was stirred for 16 h. LCMS showed reaction only 10% complete. Added sodium hydride (43.4 mg, 1.718 mmol) followed by 2-iodopropane (0.151 mL, 1.512 mmol). After 2 hours LCMS showed reaction was 15% compete. Added more sodium hydride (43.4 mg, 1.718 mmol) and let stir for 5 minutes, then added more 2-bromopropane (0.142 mL, 1.512 mmol). Heated to 70° C. for 16 h. LCMS showed reaction 50% complete. Concentrated reaction mixture. Added DCM and washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (Biotage; 0% to 100% DCM:Hex; 25 g-HP-silica gel column) to give 137 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.60 (m, 6H), 2.78 (s, 3H), 3.94-4.02 (m, 3H), 5.17 (dt, J=13.20, 6.66 Hz, 1H), 6.96 (d, J=7.83 Hz, 1H), 7.28 1H, 7.40 (d, J=3.28 Hz, 1H), 7.81 (d, J=7.58 Hz, 1H). MS(ES) [M+H]+ 232.1
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]#[CH:18])[CH:8]=[CH:9][C:2]1=2.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C:17]#[CH:18])[CH:8]=[CH:9][C:2]1=2
Reactant: BrCc1ccccc1
Reactant: C#CCNCCOCCc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN(CCOCCc1ccc2sccc2c1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
In 3 ml of N,N-dimethylformamide is dissolved 0.60 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-(2-propynyl)amine, to which are added 0.40 g of benzyl bromide and 0.35 g of potassium carbonate. The mixture is stirred at ambient temperature for one hour. Water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography (eluent: chloroform:methanol=10:1 to 7:1) to obtain 0.67 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-benzyl-N-(2-propynyl)amine as an oily product.
Reaction SMILES: [NH3:1].[CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[S:18](F)(=[O:20])=[O:19])([CH3:4])[CH3:3]>>[CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[S:18]([NH2:1])(=[O:20])=[O:19])([CH3:4])[CH3:3]
Reactant: CC(C)c1cc(S(=O)(=O)F)c(C(C)C)cc1C(F)(F)F
Reactant: N
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C(F)(F)F

Procedure:
A mixture of ammonia, 25 parts, and 2,5-diisopropyl-4-trifluoromethylbenzenesulfonyl fluoride, 7 parts, is heated for 4 hours at 100° in a Hastelloy-lined bomb. After removal of the ammonia, the crude product is stirred with water, filtered and dried. Pure product, m.p. 171°-174°, is obtained after vacuum sublimation.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CO)C(=O)O
Product: O=C(O)[C@@H](CO)NCc1ccccc1

Procedure:
The title compound was prepared from D-serine and benzaldehyde according to Method W and was obtained as a white solid (88%) that was used crude. δH (DMSO-d6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (1H, t, J 5.8 Hz). Not all exchangeable protons were observed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1Br.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>CN(C=O)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH2:15][CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(C)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1cc(C)ccc1C(=O)OC
Temperature: 120 °C
Yield: 88.7 %

Procedure:
To a solution of 2-bromo-4-methyl-benzoic acid methyl ester (1.330 g, 5.81 mmol) in 5 mL DMF and 50 mL acetonitrile are added allyl tri-n-butyl tin (2.12 g, 6.39 mmol), PdCl2(PPh3)2 (0.203 g, 0.29 mmol), and lithium chloride (0.493 g, 11.6 mmol). The resulting mixture is heated to 120° C. for 8 hours. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is dissolved in dichloromethane and purified via chromatography eluting with 10% ethyl acetate in hexanes to give 0.980 g (89%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 7.79-7.76 (d, 1H), 7.05 (s, 1H), 7.05-7.03 (d, 1H), 6.03-5.92 (m, 1H), 5.01 (dd, 1H), 4.99-4.98 (dd, 1H), 3.84 (s, 3H), 3.72 (dd, 1H), 3.70 (dd, 1H), 2.33 (s, 3H).
Reaction SMILES: S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]=O)=[N:11]1.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([NH2:29])=[C:24]([NH2:30])[CH:23]=1>CN(C)C=O>[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]2[NH:29][C:19]([C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10][N:11]=3)=[N:30][C:24]=2[CH:23]=1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: Cc1cc(N)c(N)cc1C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3n[nH]c4ccccc34)[nH]c2cc1C
Temperature: 20 °C
Yield: 25.8 %

Procedure:
389 mg of sodium metabisulphite are added, at a temperature in the region of 20° C., to a solution of 300 mg of 1H-indazole-3-carboxaldehyde and 279 mg of 4,5-dimethyl-1,2-phenylenediamine in 3 ml of dimethylformamide. The reaction mixture is refluxed for 4 hours and then cooled to a temperature in the region of 20° C. and filtered through paper. The collected filtrate is concentrated under reduced pressure. The brown lacquer obtained (340 mg) is purified by preparative LC-MS. 138.8 mg of 5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole are thus obtained in the form of a beige-coloured powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([Cl:9])[N:6]=[C:5](Cl)[N:4]=1.C([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=C.[CH:20](N(CC)C(C)C)(C)[CH3:21]>CC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[CH2:21])=[CH:18][CH:19]=2)[N:6]=[C:7]([Cl:9])[N:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CNc1ccccc1
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Product: C=Cc1ccc(Nc2nc(Cl)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 16.4 g (0.1 mole) 2-methoxy-4,6-dichloro-s-triazine in 150 ml of acetone being stirred at 0°-5° C. was added dropwise over a 1/2 hr. period a solution of 11.9 g (0.1 mole) of vinylaniline and 12.9 g (0.1 mole) of N,N-di-iso-propylethylamine. After stirring at room temperature for 2 hr., the solution was poured into 1 l of ice water to isolate the product. The crude product was collected by filtration and dried in vacuo at room temperature to give 24.9 g. Recrystallization was effected by dissolution in 75 ml. of hot benzene followed by addition of ligroin to the cloud point. Yield=20.5 g (78%) (mp 118°-122°).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10])[CH2:2]2.[Br:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCOC(C)=O>[Br-:27].[CH2:28]([N+:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([C:9]([O:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[O:10])[CH2:2]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: O=C(OC(c1cccc(F)c1)c1cccc(F)c1)C1CN2CCC1CC2
Solvent: CCOC(C)=O
Product: O=C(OC(c1cccc(F)c1)c1cccc(F)c1)C1C[N+]2(Cc3ccccc3)CCC1CC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a solution of bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (90 mg, 0.25 mmol, prepared as in example 4) in EtOAc (3 ml), (bromomethyl)benzene (30.0 μl, 0.25 mmol) was added, and the reaction was stirred at room temperature overnight. The solvent was removed, and the crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain 1-benzyl-3-((bis(3-fluorophenyl)methoxy)carbonyl)-1-azoniabicyclo[2.2.2]octane bromide (50 mg, racemic mixture).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH:21]([CH3:23])[CH3:22])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:33]>C(#N)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH:21]([CH3:23])[CH3:22])=[C:18]([NH2:33])[N:19]=2)=[N:6]1
Reactant: N
Reactant: CC(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
900 mg (5.138 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-isopropyl-1,2,4-triazin-5-ol were admixed with 12 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 173 ml of concentrated aqueous ammonia solution (25% strength). The reaction mixture was stirred for 2 h at RT and for 6 h at 50° C. After cooling, concentration on a rotary evaporator was carried out.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4]OOC.[CH3:8]CN(C(C)C)C(C)C.[CH:17]1([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18]1.C(Cl)CCl>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:8])[C:21]([CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:23]
Reactant: CONOOC
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CCC1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CON(C)C(=O)C1CCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
To an ice-cooled suspension of N,O-dimethoxyhydroxylamine hydrochloride (1.95 g, 20 mmol) in DCM (50 mL) was added DIPEA (7.0 mL, 40.0 mmol) and cyclobutanecarboxylic acid (1.9 mL, 20 mmol). After stirring for 5 min, EDC (4.2 g, 22.0 mmol) was added and the reaction mixture was stirred overnight while allowing it to warm to room temperature. The mixture was diluted with DCM (50 mL) and was transferred to a separatory funnel. The organic layer was washed with saturated aqueous NaHCO3 (2×50 mL), water (1×50 mL), brine (50 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, eluted with petrol-EtOAc 0-40%) gave the title compound (1.9 g, 67%) as an oil. MS: [M+H]+=144.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].CC1C=C(C=C(C)C=1[N+]([O-])=O)C(O)=O.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[CH3:29])=[O:6]
Reactant: Cc1ccccc1CN
Reactant: Cc1cc(C(=O)Cl)cc(C)c1[N+](=O)[O-]
Agent: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1CNC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dimethyl-4-nitrobenzoyl chloride in tetrahyrofuran, generated from 7.0 g of 3,5-dimethyl-4-nitrobenzoic acid by standard procedures, was added to 4.3 g of 2-methylbenzyl amine and 5.0 ml of triethylamine in tetrahydrofuran. The reaction was stirred at ambient temperature overnight, chilled, and filtered. The filtrate was evaporated in vacuo and the residue therefrom was dissolved in chloroform, washed sequentially with 1N hydrochloric acid, 1N sodium hydroxide, water, and a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated in vacuo. Crystallization from methanol/water provided 4.7 g of the desired title product, m.p. 202°-203° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Mg]Cl)(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(C(O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1.CC(O)=O.O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]([C:4](=[O:6])[CH2:3][C:1]#[N:2])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: N#CCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.52 g (30 mmol) of cyanoacetic acid in 80 mL of dry THF was stirred at −78° C. as 24.6 mL (49.2 mmol) of 2.0 M i-PrMgCl in THF was added. After 1 h, a solution of 3.00 g (10 mmol) 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid (Maybridge, cat. no. JFD 01929) and 1.93 g (12 mmol) of 1,1′-carbonyldiimidazole in 20 mL of THF was added. The reaction mixture was allowed to warm to rt. After 16 h, the mixture was poured into 300 mL of water and the pH lowered to 4 with conc. AcOH. The mixture was then extracted with EtOAc, dried over MgSO4 and concentrated. Purification on silica gel using 1:1 EtOAc-hexanes as eluant afforded 4-(2-cyanoacetyl)-4-phenylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[CH3:17].[OH-:19].[Na+].Cl>ClCCl.O.C(O)=O>[C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]([CH3:8])[CH:5]=[O:7])(=[O:19])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccccc1C(C)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=CO
Product: CC(=O)c1ccccc1N(C)C=O
Temperature: 25 °C
Reaction time: 1.83 h

Procedure:
A mixture of acetic anhydride (147.2 ml) and formic acid (98%, 100.3 ml) was stirred at 50°-60° for 110 minutes and then cooled to ambient temperature. 2'-(Methylamino)acetophenone (100 g) was added in portions over a period of 30 minutes whilst maintaining the temperature below 30°. The mixture was stirred at ambient temperature for 90 minutes and then cooled to 0°. Water (512 ml) was added over a period of 20 minutes, followed by aqueous sodium hydroxide (specific gravity 1.5, 288 ml) added over a period of 85 minutes whilst maintaining the temperature below 10°. The reaction mixture was transferred to a separating funnel, dichloromethane (200 ml) was added, followed by hydrochloric acid (2M) to pH 9, and the dichloromethane layer separated. The aqueous layer was further extracted with dichloromethane (2×200 ml). The combined dichloromethane extracts were washed with aqueous sodium chloride (6M, 200 ml) and then dried over magnesium sulphate to give a solution of 2'-acetyl-N-methylformanilide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)([N:29]1C=CN=C1)=O.N>ClCCl.C1COCC1.ClCCl.CO>[CH3:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:15][CH2:16]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([NH2:29])=[O:6]
Reactant: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (6.2 g, 17.4 mmol) in anhydrous dichloromethane (170 mL), 1,1′-carbonyldiimidazole (7.07 g, 43.6 mmol) was added at 0° C. under N2 atmosphere. The reaction mixture was allowed to stir at room temperature for 2 h. Where upon a solution of ammonia in THF (≈4M) was added slowly at 0° C. under N2 atmosphere. The reaction mixture was allowed to stir at room temperature overnight. After the completion of the reaction as monitored by the TLC, solvent was removed in vacuo. Residue obtained was diluted with dichloromethane/methanol (150 mL, 9:1 by volume), and washed with water. Aqueous layer was again extracted in dichloromethane/methanol (3×50 mL). The combined extract was washed with brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford the pure product 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzamide. Yield (6.0 g, 97%; and yellow solid).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](/[C:7](/[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2OCC2C=CC=CC=2)=[CH:8]\[C:9]([O:11][CH2:12]C)=[O:10])=[N:4][CH:3]=1.[Mg].Cl.[CH3:31][OH:32]>>[CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:32][CH2:31][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:19][CH:20]=2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:3]=1
Reactant: CO
Reactant: CCOC(=O)/C=C(/Cc1ccccc1OCc1ccccc1)c1ncc(C)s1
Agent: Cl
Agent: [Mg]
Product: COC(=O)CC(Cc1ccc(OCc2ccccc2)cc1)c1ncc(C)s1

Procedure:
Ethyl (±)-3-(5-methylthiazol-2-yl)-4-(benzyloxyphenyl)crotonate (0.99 mmole, crude) was dissolved in MeOH (5 mL), and magnesium turnings (120 mg, 4.95 mmole) were added at RT. After 72 hr the mixture was poured into 10% HCl (75 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the crude title compound. This was used without purification: MS (ES) m/e 382 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[N:29]O)[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH2:29])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=NO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -40 °C

Procedure:
4-[2,4-Bis(tert-butyldimethylsilyloxy)phenyl]cyclohexanone oxime (120 mg) was dissolved in anhydrous methanol (10 ml) with stirring. The solution was cooled to −40° C., and nickel chloride hexahydrate (133 mg) was added. Stirring was continued for 10 min before sodium borohydride (42 mg) was added in one portion. The reaction mixture was stirred at −40° C. for 20 min and water (0.5 ml) was added. The reaction mixture was allowed to warm to room temperature with stirring. Silica gel was added and the solvent removed in vacuo. Purification via flash column chromatography (SiO2 eluting with CH2Cl2:MeOH:NH4OH, 44:50:6 v/v) afforded the desired product as a pale brown oil (83 mg, 71%) and a mixture of diastereoisomers. δH (CD3OD): 0.22 (6H, s), 0.27 (6H, s), 1.02 (9H, s), 1.08 (9H, s), 1.24-1.40 (1H, m), 1.42-1.57 (1H, m), 1.57-1.68 (1H, m), 1.71-1.90 (4H, m), 1.99-2.07 (1H, m), 2.84-2.98 (1H, m), 4.28-4.40 (1H, m), 6.34 (1H, d), 6.44 (1H, t), 7.04 (0.5H, d), 7.16 (0.5H, d); m/z (ES+) 436 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1C(=O)OC(C)(C)[O:8][C:7]1=[O:15].O.C(OCC)(=O)C>CN(C=O)C>[OH:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([CH2:5][CH2:6][C:7]([OH:15])=[O:8])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1c(O)cccc1CC1C(=O)OC(C)(C)OC1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(O)cccc1CCC(=O)O
Temperature: 90 °C
Reaction time: 15 h
Yield: 71.4 %

Procedure:
To a solution of 5-(3-hydroxy-2-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (100 mg) in DMF (10 mL) was added water (1.0 mL), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The mixture was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (50 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1C(O)=O.NC1C=CC=CC=1.O.Cl>CO>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Agent: Cl
Solvent: Nc1ccccc1
Solvent: CO
Solvent: O
Product: Oc1ccnc2c(-c3ccc(Sc4ccccc4)cc3)cnn12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 9.32 g of 7-hydroxy-6-carboxy-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine and 68 ml of aniline was heated and stirred at 80° C. for 1.5 hours to react. To the reaction mixture, 300 ml of water was added, and while ice-cooling, hydrochloric acid was added to adjust the pH to 1 to 2. Adding 100 ml of methanol, the mixture was stirred for 30 minutes while ice-cooling, and the precipitate was filtered, washed in cold water-methanol (3:1), and dried, and the title compound was obtained (8.17 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][CH:8]([CH2:12]C)[C:9]([OH:11])=[O:10])[CH2:3]1>CCOC(C)=O.CCCCCC>[OH:1][C@H:2]1[CH:6]=[CH:5][C@H:4]([O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH2:3]1
Reactant: CCC(O[C@H]1C=C[C@@H](O)C1)C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(O[C@H]1C=C[C@H](O)C1)C(=O)O
Yield: 89 %

Procedure:
Compound 15 was subjected to general procedure J. Yield=89%. TLC: Rf=0.31 (25% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ1.30 (t, 3H), 2.35 (m, 2H), 4.10 (s, 2H), 4.25 (q, 2H), 4.90 (m, 1H), 6.05 (m, 1H), 6.20 (m, 1H), 6.30 (m, 1H), 8.20 (d, 2H), 8.30 (d, 2H). Subsequent subjection of the product to general procedure E gave compound 30. Yield=91%. TLC: Rf=0.18 (50% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ2.00 (m, 1H), 2.25 (m, 1H), 3.75 (s, 3H), 4.05 (s, 2H), 4.80 (m, 1H), 5.05 (m, 1H), 6.05 (s, 2H).