Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1C=CC(C(=O)CBr)=CC=1.[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:21])[CH2:19]Cl)=[CH:16][CH:15]=1)#[N:13].C(C1C=CN=CC=1)#N.[Cl:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[Cl-:1].[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:21])[CH2:19][N+:36]2[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: Clc1ccncc1
Reactant: N#Cc1ccc(C(=O)CCl)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: N#Cc1ccncc1
Product: N#Cc1ccc(C(=O)C[n+]2ccc(Cl)cc2)cc1
Product: [Cl-]

Procedure:
Employing the procedure of Example II but replacing 4-chlorophenacyl bromide with a substantially equimolecular amount of 4-cyanophenacyl chloride and replacing 4-cyanopyridine with a substantially equimolecular amount of 4-chloropyridine there is obtained N-(4-cyanophenacyl) 4-chloropyridinium chloride, a solid soluble in water.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([NH:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[O:19])(=[O:7])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CCN
Product: CCON=C1C[C@@H](C(=O)NCCN(CC)CC)N(C(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 84% purity by LC/MS. MS(ESI+): m/z=375.2.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)=[CH:12][CH:11]=1.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[NH:23][C:25](=[S:26])[NH:24][C:19]=3[CH:18]=2)=[CH:14][CH:15]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(Cc2ccc(N)c(N)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cc2ccc3[nH]c(=S)[nH]c3c2)cc1

Procedure:
To a solution of 0.51 g (5.0 mmoles) of triethyl amine, 1.14 g (5.0 mmoles) of 4-[(4-methoxyphenyl)-methyl]-o-phenylene-diamine and 35 ml of chloroform a solution of 0.58 g (5.0 mmoles) of thiophosgene and 10 ml of chloroform are added dropwise.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10](SCC)([F:12])[F:11].Cl[C:24]1C=CC=C(C(OO)=O)[CH:25]=1.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([S:34]([CH2:24][CH3:25])(=[O:38])=[O:36])([F:12])[F:11]
Reactant: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (850 mg, 2.39 mmol) in dichloromethane (100 ml), 85% m-chloroperbenzoic acid (1.4 g, 5.75 mmol) was added at room temperature, followed by stirring at room temperature for 12 hours. After the completion of the reaction, a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added and the resulting mixture was stirred. The dichloromethane solution was separated and after washing with water, dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether--ethyl acetate, whereby 2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (718 mg, yield: 78%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]#N)=[CH:8]2.[OH-:15].[K+].Cl.[OH2:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([OH:18])=[O:15])=[CH:8]2
Reactant: COc1cccc2cc(C#N)ccc12
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1cccc2cc(C(=O)O)ccc12
Temperature: 70 °C
Yield: 94 %

Procedure:
A solution of 5-methoxy-2-naphthonitrile (455 mg, 2.5 mmol) and KOH (460 mg, 8.2 mmol) in 95% ethanol (5 mL) is heated to reflux for 24 hours. The reaction mixture is allowed to cool, diluted with water then acidified to pH<2 with concentrated HCl. The resulting precipitate is collected by filtration, washed with water and dried by heating at 70° C. under vacuum to give 5-methoxy-2-naphthoic acid as a white solid (471 mg, 94%). HRMS (EI) calculated for C12H10O3: 202.0630, found 202.0627.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(OC)(C)C>O.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at reflux temperature for 2 h. After this time the raw material was not observed by HPLC. MTBE (58 ml) was dripped into the solution over 2 h. The solution was cooled slowly to room temperature and was stirred overnight. The product was isolated by filtration under nitrogen, washed with MTBE (50 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.78 g (91.3%) of fluvastatin sodium Form B.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6]C)=O.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:4](=[O:6])[CH2:3][CH:2]([OH:1])[CH2:8][CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: CC=CC=CCCC(O)CC(=O)OC
Product: CC=CC=CCCC(O)CC(=O)NCC(C)C
Temperature: 90 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Methyl 3-hydroxy-6,8-decadienoate (g) (86.1 g, 0.43 mol) and isobutylamine (95.3 g, 1.3 mol) were put into a 500-ml flask, followed by stirring at 90° C. for 24 hours. After isobutylamine was recovered under a reduced pressure, heptane (700 ml) was added thereto, followed by cooling to 0° C. A white solid thus precipitated was filtered and dried under a reduced pressure. Thus, N-isobutyl-3-hydroxy-6,8-decadienamide (h) was obtained (85.2 g, 0.35 mol, yield 82%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:33]([O-:36])([O-:35])=[O:34].[Na+:37].[Na+]>C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:33]([O-:36])(=[O:35])=[O:34])[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:37]
Reactant: O=S([O-])[O-]
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1n(CCCCCCCS(=O)(=O)[O-])c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reaction time: 20 h
Yield: 23.4 %

Procedure:
A solution of 1,4,5-triphenyl-3-(7-bromoheptyl)imidazol-2-one (2.0 g) in ethanol (10 ml) was refluxed with a solution of sodium sulphite (0.55 g) in water (5 ml) for 20 hours. More sodium sulphite (0.2 g) was added and refluxing continued for a further 20 hours. The mixture was evaporated to dryness, boiled in ethanol, filtered hot and evaporated to an oil. This was taken up in a small volume of ethanol, excess diethyl ether added and the precipitated solid filtered off and chromatographed on silica gel (dichloro-methane/methanol 5:1). The resulting oil in methanol/water 1:1 was passed down an Amberlyst 15 ion exchange resin (Na form) and evaporated to a solid. This was taken up in ethanol and precipitated with diethyl ether giving sodium 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptane-sulphonate (0.49 g), 23%) as a white solid, m.p. 160° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.[F:10][C:11]([F:29])([F:28])[C:12]1[CH:27]=[CH:26][C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][Cl:25])[CH:19]=2)=[CH:14][CH:13]=1>C(O)C>[ClH:25].[ClH:25].[F:29][C:11]([F:10])([F:28])[C:12]1[CH:27]=[CH:26][C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:1][C:2]3[NH:6][C:5]4=[CH:7][S:8][CH:9]=[C:4]4[N:3]=3)[CH:19]=2)=[CH:14][CH:13]=1
Reactant: Sc1nc2cscc2[nH]1
Reactant: FC(F)(F)c1ccc(COc2ccnc(CCl)c2)cc1
Solvent: CCO
Product: Cl
Product: FC(F)(F)c1ccc(COc2ccnc(CSc3nc4cscc4[nH]3)c2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
0.625 g (4 mmol) of 2-mercaptothieno[3,4-d]imidazole are added at 25° C. to 1.35 g (4 mmol) of the title compound from Example 4 in 50 ml of ethanol, and the mixture is stirred at 60° C. for 1.5 hours. The reaction mixture is concentrated in vacuo, and the residue is treated with acetone, filtered off with suction, washed with acetone and dried in vacuo, m.p. 180°-182° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:20])[CH:3]=1.[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:20])[CH:3]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1C
Reaction time: 8 h

Procedure:
Methyl-3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-2-methylbenzoate (from Step 1) (42.0 g, 154 mmol) was stirred briskly at room temperature with 2,4-difluorobenzyl bromide (19.7 ml, 154 mmol) and K2CO3 (31.8 g, 231 mmol) in 250 ml of N,N-dimethylformamide. After stirring overnight, the reaction was poured into 1 L of cold water. The solution was extracted 3 times with ethyl acetate and the organic layers were dried over MgSO4, and evaporated. The product was carried on to the next step as a crude oil (60.4 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J=7.85, 1.28 Hz, 1H), 7.45-7.34 (m, 2H), 7.27-7.23 (m, 1H), 6.94-6.84 (m, 2H), 5.98 (d, J=2.68 Hz, 1H), 5.92 (dd, J=2.69, 0.81 Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.81 (s, 3H); LC/MS, tr=2.96 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 400 (M+H). ES-HRMS m/z 400.1341 (M+H calcd for C22H19F2NO4 requires 400.1355).
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:26][C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([CH:37]=O)[CH:36]=1)[O:33][C:32]([CH3:40])([CH3:39])[CH2:31][C:30]2([CH3:42])[CH3:41]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[Br:26][C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([CH:37]=[CH2:1])[CH:36]=1)[O:33][C:32]([CH3:40])([CH3:39])[CH2:31][C:30]2([CH3:42])[CH3:41]
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=Cc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Yield: 72 %

Procedure:
A solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7 g, 20 mmol) and (11.8 mL, 19 mmol) of a 1.6M solution of n-butyl lithium in hexanes] was added 6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Intermediate 30, 0.52 g, 1.75 mmol). After 1 h the reaction mixture was diluted with hexane, washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil (0.37 g, 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28](Cl)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([Sn](CCCC)(CCCC)[C:44]([O:46][CH2:47][CH3:48])=[CH2:45])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[N+:1]([C:4]1[CH:38]=[CH:37][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:44]([O:46][CH2:47][CH3:48])=[CH2:45])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(Cl)cc(C#N)nc3c2)nn1)C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C(OCC)c1cc(C#N)nc2cc(Cn3cc([C@](CC)(OC(=O)c4ccc([N+](=O)[O-])cc4)C(F)(F)F)nn3)ccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-1-{1-[(4-chloro-2-cyanoquinolin-7-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-(trifluoromethyl)propyl 4-nitrobenzoate (900 mg, 1.65 mmol), tributyl (1-ethoxyvinyl)tin (0.6 ml, 1.73 mmol) in dioxane (6 mL) was added lithium chloride (210 mg, 4.96 mmol) and Pd(PPh3)4 (95 mg, 0.083 mmol). The reaction mixture was stirred at 100° C. overnight then cooled to room temperature. The solution was then diluted with ethyl acetate, washed with sat. sol. of ammonium chloride, brine and dried over magnesium sulfate. The crude material was purified on silica gel (eluting solvent: 3% acetone in CH2Cl2) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.52 (s, 1H), 8.42 (d, 2H), 8.39 (d, 1H), 8.30 (d, 2H), 8.05 (d, 1H), 7.95 (s, 1H), 7.75 (dd, 1H), 6.02 (s, 2H), 4.75 (dd, 2H), 4.12 (q, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.40 (t, 3H), 1.15 (t, 3H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:15][N:16]([C:19]([CH3:29])([CH3:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:17]=2[OH:18])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH3:37][O:38][CH2:39]Cl>CN(C)C=O.C(OCC)C>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:15][N:16]([C:19]([CH3:28])([CH3:29])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[C:17]=2[O:18][CH2:37][O:38][CH3:39])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COCCl
Reactant: CCCCCCc1ccc(-c2c(C(=O)OCC)nn(C(C)(C)Cc3ccc(C)cc3)c2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCc1ccc(-c2c(C(=O)OCC)nn(C(C)(C)Cc3ccc(C)cc3)c2OCOC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
152 mg (0.329 mol) of ethyl 4-(4-hexylphenyl)-5-hydroxy-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylate was dissolved in 1.6 mL of N,N-dimethylformamide, mixed with 26 mg (0.65 mmol) of 60 wt % sodium hydride (suspended in mineral oil) and 0.050 mL (0.66 mmol) of chloromethyl methyl ether under cooling with ice successively and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with 1 M hydrochloric acid, with saturated aqueous sodium hydrogen carbonateand with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product (crude yield 174 mg).
Reaction SMILES: Cl.[CH3:2][C:3]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C(OCC)=O)[C:4]([O:6]CC)=[O:5]>>[CH3:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(Cc1ccncc1)C(=O)OCC
Agent: Cl
Product: CC(Cc1ccncc1)C(=O)O
Yield: 100.3 %

Procedure:
Next, 6 N hydrochloric acid (96.8 ml, 581 mmol) was added to diethyl 2-methyl-2-(4-pyridylmethyl)malonate (17.2 g, 64.6 mmol), and the mixture was refluxed overnight. The reaction mixture was allowed to stand, then washed with hexane (100 ml) to remove sodium hydride oil contained in diethyl 2-methyl-2-(4-pyridylmethyl)malonate and concentrated under reduced pressure. The resulting crystals were filtered off with ethyl acetate to give 2-methyl-3-(4-pyridyl)propionic acid (10.7 g, 82%) as pale pink crystals.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=2[C:4](=[O:14])[NH:3][CH:2]=1.[CH3:15][O:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH3:26])=[O:24])[C@H:18]1[CH2:27][C:28](=[O:31])[CH2:29]Br>>[O:14]=[C:4]1[N:3]([CH2:29][C:28](=[O:31])[CH2:27][C@H:18]2[C@H:17]([O:16][CH3:15])[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][CH3:26])=[O:24])[CH:2]=[N:1][C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]1=2
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2c1oc1ccccc12
Product: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(oc3ccccc32)c1=O

Procedure:
According to the method of Example 1, 1.22 g (0.0066 mole) of benzofuro[3,2-d]pyrimidin-4(3H)-one [S. S. Sangapure and Y. S. Agasimundin, Indian J. Chem., 14B, 688-691 (1976)] and 0.0066 moles of methyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate were combined to give the title compound: yield 0.627 g (23%); 1H-nmr (CDCl3) delta 1.2-2.1 ppm (multiplet, 4H, CH3OCHCH2CH2CH2N), 2.7-3.2 (multiplet, 2H, NCH2), 2.9 (doublet, 2H, COCH2CH), 3.3 (singlet, 3H, CHOCH3), 3.7 (singlet, 3H, CO2CH3), 4.0 (broad doublet, 1H CHOCH3), 4.9 (broad triplet, 1H, CH2CHNCO), 5.2 (singlet, 2H, NCH2CO), 7.3-7.7 (multiplet, 3H, aromatic H), 8.0 (doublet, 1H, aromatic H), 8.2 (singlet, 1H, N=CH--N).
Reaction SMILES: IC1SC=CC=1.C[O-].[O-]CC.[O-:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[C:20]1[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=1>>[O:12]([C:20]1[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)s1
Reactant: [O-]c1ccccc1
Agent: CC[O-]
Agent: C[O-]
Agent: Ic1cccs1
Product: O=C(O)c1ccc(Oc2ccccc2)s1

Procedure:
The latter compounds are alternatively prepared by reaction of 2-iodothiophene with methoxide, ethoxide or phenoxide, followed by carbonylation according to Sice [J. Am. Chem. Soc. 75, 3697 (1953)], or by alkylation of 5-hydroxythiophene-2-carboxylic acid by the method of Gronowitz [Ankiv Kemi 12, 239 (1958); Chem. Abstr. 52, 20115].
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([S:21]([CH3:23])=[O:22])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)(=O)=O.[S:26]1[C:30](B(O)O)=[CH:29][C:28]2[CH:34]=[CH:35][CH:36]=[CH:37][C:27]1=2.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[S:26]1[C:30]([C:7]2[C:8]([S:21]([CH3:23])=[O:22])=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]3)=[CH:29][C:28]2[CH:34]=[CH:35][CH:36]=[CH:37][C:27]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CCCC(C)n1ccc2c(S(C)=O)c(OS(=O)(=O)C(F)(F)F)ccc21
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: [K+]
Solvent: Cc1ccccc1
Product: CCCC(C)n1ccc2c(S(C)=O)c(-c3cc4ccccc4s3)ccc21
Temperature: 90 °C
Yield: 68 %

Procedure:
To a deaerated solution of 4-(methylsulfinyl)-1-(pentan-2-yl)-1H-indol-5-yltrifluoromethanesulfonate 17) (0.40 g, 1.0 mmol) and benzo[b]thiophen-2-ylboronic acid (18) (0.35 g, 2.0 mmol), and Pd(PPh3)4 (60 mg, 0.05 mmol) in toluene (10 mL) was added aqueous K2CO3 (2M, 6.0 mL). The mixture was heated at 90° C. for 4 h. Toluene (20 mL) was added and the organic phase was washed with water (20 mL) and then concentrated to dryness in vacuo. The residual was purified by silica gel column chromatography (2:1 hexanes/ethyl acetate) to give 5-(benzo[b]thiophen-2-yl)-4-(methylsulfinyl)-1-(pentan-2-yl)-1H-indole (19) (0.26 g, 68%) as a yellow oil. 1H NMR (500 MHz, CD2Cl2): δ 7.88 (d, J=8.0, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.40 (m, 4H), 7.35 (d, J=3.5, 1H), 7.2 9s, 1H), 4.62 (m, 1H), 3.00 (d, 3H), 1.88 (m, 2H), 1.57 (m, 3H), 1.24 (m, 2H), 0.93 (m, 3H). Mass (ESI, M+H): 382.7. See also Im, G-Y. J., et al., J. Am. Chem. Soc., 132:17933 (2010).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCOCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Temperature: 110 °C
Yield: 67.8 %

Procedure:
To a stirred solution of 4-nitrobenzoyl chloride (6.23 g, 33.9 mmol) and N-phenyl piperazine (4.71 ml, 30.8 mmol) in anhydrous dioxane (250 ml) at 0° C. was added triethylamine (4.73 ml, 33.9 mmol) and the mixture was then stirred at reflux (110° C.) for 5 hours. The reaction was allowed to cool then quenched with water (100 ml) and the resulting aqueous mixture was extracted with ethyl acetate (2×75 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated to yield crude product as a yellow oil. Pure product was obtained by crystallisation from a mixture of 40% ethyl acetate in petrol to afford the title compound as a white crystalline solid (6.5 g, 62%). HPLC retention time 6.9 min. Mass spectrum (ES+) m/z 312 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1>C(O)(=O)C.[Fe]>[NH2:9][C:7]1[CH:6]=[C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(N)cc(NS(C)(=O)=O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
N-(3-Methoxy-5-nitrophenyl)methanesulfonamide (3 g, 11.82 mmol) was treated with iron powder (3.3 g, 59.09 mmol) in acetic acid (120 ml) and stirred at 40° C. for 2 h. The crude was then filtered over Celite and the solvent was removed in vacuum. A mixture of a solution of sodium bicarbonate 4% and ethyl acetate was added and the resulting mixture was filtered over Celite. The organic phase was washed with water and brine, dried over magnesium sulphate and the solvent was remove to give 2.53 g (86% yield) of the title compound as a dark solid, that was used in the next step without further purification. Purity 87%.