Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[OH:20])=[N+:4]=[N-:5].[CH3:21]I.O>CN(C)C=O>[N:3]([CH2:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][C@H:8]1[O:20][CH3:21])=[N+:4]=[N-:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN=[N+]=[N-])[C@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 60% sodium hydride (0.58 g) in dimethylformamide (10 ml) was added dropwise a solution of cis-4-azidomethyl-1-tert-butoxycarbonyl-3-hydroxypiperidine (3.4 g) in dimethylformamide (50 ml), and the resulting mixture was stirred at room temperature for 1 hr. Methyl iodide (1.24 ml) was added to the mixture with stirring, and the resulting mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 1.5 g of cis-4-azidomethyl-1-tert-butoxycarbonyl-3-methoxypiperidine.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8])[CH:2]=[CH2:3].S(O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=O)(=O)C.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][CH:6]([O:9][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][O:8][CH2:32][CH:31]=[CH2:30])[CH2:2][CH2:3][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: C=CCOCC(O)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOCC(COCCCCCCCC/C=C\C/C=C\CCCCC)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 2.5 °C
Reaction time: 40 h

Procedure:
In a 2000 mL round bottom flask equipped with a large magnetic stir bar, 3-allyloxypropane-1,2-diol (5.94 g, 45 mmol), and tetrabutylammonium hydrogen sulfate (6 g, 18 mmol) were added. A solution of linoleyl mesylate (33.8 g, 98 mmol) in toluene (150 mL) was also made and added. The mixture was cooled to 0-5° C. with an ice bath. 50% sodium hydroxide (70 mL) was then slowly added, rinsing in with deionized water (20 mL). The resulting mixture is stirred at room temperature, under nitrogen for 40 hours. Deionized water (200 mL) and isopropyl acetate (200 mL) were added and the mixture stirred vigorously for a further 10-15 min. The mixture was transferred to a 1000-mL separating funnel and allowed to separate. The aqueous phase was removed and the organic phase washed with saturated sodium chloride solution (2×150 mL). The organic phase was dried with magnesium sulfate (40 g), filtered, and concentrated to obtain a neat orange oil. The oil was purified by column chromatography. Final yield: 19.5 g (69%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[C:29]([Cl:41])[N:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>ClC(Cl)C.O>[Cl:41][C:29]1[N:28]=[C:27]([N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][NH:18][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N+:11]([O-:13])=[O:12])[CH2:22][CH2:23]2)[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: COc1cc2nc(Cl)nc(N3CCC(CCN)CC3)c2cc1OC
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nc(Cl)nc(N3CCC(CCNC(=O)c4cc(C)ccc4[N+](=O)[O-])CC3)c2cc1OC
Temperature: 100 °C
Yield: 136.5 %

Procedure:
To 2.5 g (11.8 mmol) of 5-methyl-2-nitrobenzoic acid was added 10 ml of thionyl chloride, followed by heating at 100° C. for 1.5 hours. The solvent was evaporated under reduced pressure, and 50 ml of dichloromethane was added to the residue to prepare Solution A. In dichloroethane was dissolved 2.5 g of 4-(2-aminoethyl)-1-(2-chloro-6,7-dimethoxy-4-quinazolinyl)piperidine obtained by the method described in Chem. Pharm. Bull., 38, 3014-3019 (1990) and the literature cited therein. To this solution was added 9.7 ml of triethylamine, and after stirring at room temperature, Solution A was added dropwise to the mixture. The resulting mixture was subjected to reaction at room temperature for 30 minutes and then was added dropwise to water, followed by extraction with dichloromethane. The organic layer was washed and dried, and the solvent was evaporated under reduced pressure. The residue was washed with a solvent mixture of ethanol and ether to give 5.0 g (yield: 83%) of Compound m as white crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH:28]([O:30][CH3:31])[CH3:29])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:32].Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1>CN(C=O)C.[Cl-].[NH4+]>[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH:28]([O:30][CH3:31])[CH3:29])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:32][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COC(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3c(Cl)cc(C#CC(C)OC)c4c3OCO4)c2cc1OC
Temperature: 0 °C

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.7 ml) in tetrahydrofuran (1.0M, 1.7 mmol) was added over 5 minutes to a stirred mixture of 5-chloro-7-(3-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.211 g) and 4-chloro-6,7-dimethoxyquinazoline (0.170 g) in DMF (7.0 ml) cooled to 0° C. under a nitrogen atmosphere; the resultant mixture was stirred for 1 hr at ambient temperature. The reaction mixture was diluted with saturated aqueous ammonium chloride (70 ml) and extracted with ethyl acetate (3×30 ml). The organic extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and isohexane as eluent. There was thus obtained the title compound as a racemate and in a solid form (0.200 g). NMR Spectrum: (DMSOd6) 1.41 (d, 3H), 3.35 (s, 3H), 3.92 (s, 6H), 4.39 (q, 1H), 6.15 (s, 2H), 7.13 (s, 1H), 7.18 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.50 (s, 1H);
Reaction SMILES: [CH2:1]=[C:2]1O[C:4](=[O:5])[CH2:3]1.[Cl:7][C:8]1[C:9]([OH:21])=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14].CO>CS(O)(=O)=O>[Cl:7][C:8]1[C:9]([OH:21])=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[C:12]2[C:13]=1[O:14][C:4](=[O:5])[CH:3]=[C:2]2[CH3:1]
Reactant: COC(=O)CCc1ccc(O)c(Cl)c1O
Reactant: C=C1CC(=O)O1
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CCc1cc2c(C)cc(=O)oc2c(Cl)c1O
Yield: 64.3 %

Procedure:
Diketene (0.7 ml, 9.1 mmol) was added dropwise to a stirred solution of 5a (1.0 g, 4.3 mmol) in 7 ml of methanesulfonic acid. The resultant solution was heated at 70° C. for 5 min and cooled. Methanol (20 ml) was added and the reaction was heated to boiling; this treatment esterified small amount of free acid formed during the cyclization step. Methanol was evaporated and water was added to precipitate the product. The crude material was chromatographed on silica eluting with ethyl acetate. Concentration of the pure product fractions and drying under vacuum afforded 0.82 g (64%) of the desired product as a pale yellow solid. 1H NMR (DMSO-d6): δ 10.45 (s, 1H), 7.50 (s, 1H), 6.24 (s, 1H), 3.59 (s, 3H), 2.93 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].[K+].[Br-]>>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCn1c(=O)c2[nH]c(C)nc2n(CCCC)c1=O
Agent: [Br-]
Agent: [K+]
Product: CCCCn1c(=O)c2c(nc(C)n2S(=O)(=O)CCCCl)n(CCCC)c1=O
Yield: 71 %

Procedure:
The title compound was prepared according to the procedure of example 3 except that 1,3-dibutyl-8-methyl-3,7-dihydro-purine-2,6-dione was used in place of 1,3-dibutyl-3,7-dihydro-purine-2,6-dione and 3-chloropropanesulfonyl chloride was used in place of methanesulfonyl chloride. Yield: 71%: mp: 76-78° C.; 1H NMR (300 MHz, CDCl3): δ 0.92-0.99 (m, 6H), 1.33-1.42 (m, 4H), 1.57-1.65 (m, 2H), 1.67-1.74 (m, 2H), 2.32-2.41 (m, 2H) 2.74 (s, 3H), 3.69 (t, J=6.2 Hz, 2H), 3.99 (t, J=7.6 Hz, 2H), 4.08 (t, J=7.5 Hz, 2H), 4.23 (t, J=7.5 Hz, 2H); IR (KBr, cm−1): 2959m, 2874m, 1705s, 1620w, 1537m, 1522s, 1485m, 1183s, 1121s, 938m, 751m, 570m; MS (ES) m/z (relative intensity): 419 (M++H, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])=[N:33][CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cn(C3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 90 °C
Yield: 20.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 243f (300 mg, 0.74 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (567 mg, 1.48 mmol), Pd(dppf)Cl2 (60.5 mg, 0.074 mmol), K3PO4 (314 mg, 1.48 mmol), sodium acetate (201 mg, 1.48 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 1:1 dichloromethane/methanol containing 0.5% triethylamine to afford 243g as yellow solid (100 mg, 20%). MS-ESI: [M+H]+ 667.4.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[CH2:3]1.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C@@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:15])[F:16])[CH2:5][CH2:6][N:7]1[S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:18](=[O:20])[CH3:19])=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CN(c2ccccc2C(F)(F)F)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ccccc3C(F)(F)F)C[C@H]2C)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a stirred solution of (R)-3-methyl-1-(2-trifluoromethyl-phenyl)-piperazine (500 mg, 2.05 mmol) and 4-acetylbenzenesulfonyl chloride (448.23 mg, 2.05 mmol) in anhydrous dichloromethane (6 mL) was added diisopropylethylamine (0.71 mL, 4.1 mmol). The mixture was stirred at room temperature for over night. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to yield (R)-1-{4-[2-methyl-4-(2-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-phenyl}-ethanone in 74.0% yield (646.7 mg) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.20 (d, J=6.57 Hz, 3H) 2.67 (s, 3H) 2.75-2.83 (m, 2H) 2.98 (d, J=10.11 Hz, 1H) 3.06 (d, J=10.11 Hz, 1H) 3.33-3.43 (m, 1H) 3.76 (d, J=10.61 Hz, 1H) 4.26 (d, J=6.82 Hz, 1H) 7.23-7.30 (m, 2H) 7.52 (t, J=7.71 Hz, 1H) 7.62 (d, J=8.08 Hz, 1H) 7.89-7.99 (m, 2H) 8.07-8.14 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[CH3:24][C:25](=[O:30])[CH2:26][C:27](=[O:29])[CH3:28].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:26]([C:25](=[O:30])[CH3:24])[C:27](=[O:29])[CH3:28])=[CH:18][CH:17]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(C)=O
Yield: 59.1 %

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (3.07 g, 10 mmol) synthesized according to the method described in WO95/18125 in toluene (40 ml) were added 2,4-pentanedione (1.2 g, 12 mmol), acetic acid (300 mg) and piperidine (425 mg). While removing water through Dean-Stark trap, the mixture was refluxed under heating. Five hours later, toluene was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1) and the fraction containing the objective substance was concentrated under reduced pressure to give the title compound (2.3 g, yield 60%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1
Solvent: CCCO
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 46.7 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.1 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-(4-fluorophenyl)-1,8-naphthyridine (1.7 g). The product obtained by precipitation in water (2 g) is dissolved in boiling propanol (200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Fluorophenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (1.4 g), m.p. 210° C., is obtained.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[S:19][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][C:22]=2[CH3:23])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[S:19][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][C:22]=2[CH3:23])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:14])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(-c2ccccc2)sc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)sc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A solution of 4-[cyclohexyl(3-methyl-5-phenylthiophen-2-yl)methoxy]benzoic acid (122 mg), ethyl 3-(methylamino)propanoate (47 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg), hydroxybenzotriazole monohydrate (55 mg) and triethylamine (50 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.6 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (105 mg, 71%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.CCCCCC.C([Li])CCC.[C:21](#[N:23])[CH3:22].[CH3:24][O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][C:31]([CH3:37])([CH3:36])[C:32]2=O)=[CH:28][CH:27]=1>C1COCC1.O>[CH3:24][O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][C:31]([CH3:37])([CH3:36])/[C:32]/2=[CH:22]/[C:21]#[N:23])=[CH:28][CH:27]=1
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)C2
Reactant: CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc2c(c1)/C(=C\C#N)C(C)(C)C2
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (4.13 ml, 19.6 mmol) in THF (80 ml) was added dropwise, under argon atmosphere at −78° C., a 1.56M solution of n-butyllithium hexane solution (12.5 ml, 19.6 mmol). The mixture was stirred for 10 minutes, to which was added acetonitrile (0.94 ml, 17.9 mmol), and the mixture was stirred for further 15 minutes. To the mixture was added a solution of 6-methoxy-2,2-dimethyl-1-indanone (3.00 g, 16.3 mmol) in THF (10 ml), which was stirred for 15 minutes. To the reaction mixture was added water so that the temperature was gradually reverted to room temperature. The reaction mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was dissolved in toluene (100 ml). To the solution was added 10-camphor sulfonic acid (0.5 g), and the mixture was heated for 1.5 hours under reflux. The reaction mixture was cooled, to which was added water. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (hexane/ethyl acetate, 97:3→9:1) to give 1.03 g (yield 30%) of (Z)-(6-methoxy-2,2-dimethylindan-1-ylidene)acetonitrile as an oily product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[K+]>C(O)(=O)C>[C:17]([O:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:20][C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(-c2ccc(COC(C)=O)cc2)cc1
Yield: 68 %

Procedure:
0.1 moles 4,4'bis(chloromethyl)biphenyl (prepared by method A above), 0.25 moles potassium acetate and 100 mls glacial acetic acid were reflux for 17 hours with stirring. The reaction mixture was filtered and the filtrate evaporated to dryness at 80° C. under water pump vacuum. The residue was recrystallised from methanol to yield 0.068 moles product=68 percent of theory.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC(=O)O)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CCO)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.4 %

Procedure:
A solution of 2-(5-methylthiophen-2-yl)acetic acid (200 mg, 1.280 mmol) in dry THF (10 mL) was carefully added over 2 min to solution of 1M LAH (2.56 mL, 2.56 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 6 h. The reaction was quenched with 0.2 mL of water (stir for 10 min), 0.2 mL of 15% NaOH/water (stir for 10 min), and then 0.4 mL of water. After stirring for 18 h, the mixture was filtered through celite. The filtrate was concentrated in vacuum. The residue was dried under high vacuum for 16 h to afford 2-(5-methylthiophen-2-yl)ethanol (150 mg, 1.055 mmol, 82% yield) as clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.67 (d, J=3.3 Hz, 1H), 6.64-6.57 (m, 1H), 3.85 (t, J=6.2 Hz, 2H), 3.02 (t, J=6.2 Hz, 2H), 2.47 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC(OC)(C)C>[CH:12]1([NH:18][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCC1
Reactant: Nc1nc2cccc(Cl)n2n1
Solvent: COC(C)(C)C
Product: Nc1nc2cccc(NC3CCCCC3)n2n1
Yield: 59 %

Procedure:
A suspension of 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 10.0 g; 59.32 mmol; 1.0 eq.) in cyclohexylamine (60 mL) was heated to reflux for 52 h. Reaction mixture was taken up in MTBE and filtered. The resulting cake was washed with MTBE and filtrate was concentrated to dryness. Residue was purified by flash chromatography (Hept/EtOAc, 1:1) to give the title compound as a beige powder (8.08 g, 59%). HPLC, Rt: 2.46 min. (purity 98.9%). LC/MS, M+(ESI): 231.9.
Reaction SMILES: [NH2:1][C:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.ClCCl>[Si:15]([O:6][CH2:5][C:2]1([NH2:1])[CH2:4][CH2:3]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: NC1(CO)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1(N)CC1
Reaction time: 20 h
Yield: 87.1 %

Procedure:
To a stirring solution of (1-aminocyclopropyl)methanol (9.69 mmol), 4-(dimethylamino)pyridine (0.484 mmol), and triethylamine (21.32 mmol) in anhydrous dichloromethane (25 mL) was added chloro(1,1-dimethylethyl)dimethylsilane (10.66 mmol). After stirring 20 h, the reaction was quenched with saturated aq ammonium chloride and extracted with dichloromethane. The extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to afford the crude title compound (1.70 g, 78% yield) as a colorless liquid. MS(ES)+ m/e 202.2 [M+H]+.