Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:9])[CH2:3][NH:4][C@H:5]([CH3:8])[CH2:6][OH:7].C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>ClCCl>[OH:7][CH2:6][C@H:5]([N:4]([CH2:3][C@H:2]([OH:1])[CH3:9])[C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:8]
Reactant: C[C@H](CO)NC[C@@H](C)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CO)N(C[C@@H](C)O)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a mixture of (R)-2-((R)-2-hydroxypropylamino)propan-1-ol (11 g, 83 mmol) in 200 mL dichloromethane stirred at 0° C. was added a sat. solution of sodium bicarbonate (8.3 g, 99 mmol), then added dropwise benzyl chloroformate (15 g, 91 mmol). The mixture was stirred from 0° C. warming to RT over 4 h. The mixture was extracted with dichloromethane (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by column eluting with 20-70% ethyl acetate in hexane to give the benzyl (R)-1-hydroxypropan-2-yl((R)-2-hydroxypropyl)carbamate as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]([NH2:19])=O)[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>N1C=CC=CC=1>[C:17]([CH:10]1[C:9]2[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)#[N:19]
Reactant: NC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: N#CC1CCCc2ccc(-c3ccccc3)nc21
Yield: 16.2 %

Procedure:
2-Phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (8 g.) was dissolved in pyridine (20 ml.), treated with P2S5 (5.2 g.) and the mixture heated at reflux temperature for 30 minutes. The solvent was removed in vacuo and the residual oil dissolved in dilute HCl, washed with ether (2× 50 ml.) and the washings discarded. The aqueous solution was made basic, extracted into chloroform (3× 50 ml.) and the combined extracts dried and evaporated to dryness. The residual oil was chromatographed on silica gel by elution with chloroform giving 8-cyano- 2-pheny-5,6,7,8-tetrahydroquinoline (1.2 g.) as colourless needles from ether mpt. 100° C. Found: C, 82.0; H, 6.2; N, 11.7% C16H14N2 requires: C, 82.0; H, 6.0; N, 11.9%. Further elution with chloroform gave the title compound (1.1 g.) as colourless needles from ether mpt. 154° C. Found: C, 71.8; H, 6.1; N, 10.2%, C16H16N2S requires: C, 71.6; H, 6.0; N, 10.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](S(C3C=CC=CC=3)(=O)=O)[CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3ccc(Cl)cc3)n2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c[nH]c(-c3ccc(Cl)cc3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11fa) (2.0 mmol) in THF (20.0 mL) was added 1.0 M tetrabutyl ammonium fluoride (4.0 mmol) and stirred overnight. The reaction mixture was diluted by 50 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 3:1) or recrystallized from water and methanol to give a white solid. Yield: 80-95%. Yield: 36.9%; mp 193-195° C. 1H NMR (500 MHz, CDCl3) δ 10.75 (br, 1H), 7.96 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.23 (s, 2H), 3.97 (s, 3H), 3.94 (s, 6H), 2.43 (s, 3H). MS (ESI): calculated for C19H17ClN2O4, 372.1. found 395.1 [M+Na]+, 370.9 [M−H]−. HPLC Gradient: Solvent A (water) and Solvent B (methanol): 0-15 min 40-100% B (linear gradient), 15-25 min 100% B: tR 16.36 min, purity >99%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:20]([NH:29][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[C:19]([C:36]([OH:38])=O)=[N:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[N:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[Cl:10])[N:18]=[C:19]3[C:20]=2[NH:29][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:36]3=[O:38])=[CH:23][CH:24]=1
Reactant: O=C(O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1NCC1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2NCC2CCCN12
Reaction time: 5 h
Yield: 30.1 %

Procedure:
Diisopropylethylamine (250 microliters, 2 mmol) was added to a mixture of 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-[(pyrrolidin-2-ylmethyl)-amino]-1H-pyrazole-3-carboxylic acid (I-5b, 160 mg, 0.37 mmol) and HATU (380 mg, 1 mmol) in DMF (50 ml) at room temperature. The reaction mixture was stirred for 5 hours, quenched with saturated aqueous NaCl, and extracted twice with EtOAc. The combined organic extracts were washed with 0.5 M citric acid, 1 M K2CO3, and saturated aqueous NaCl, dried, and concentrated in vacuo. The residue was slurried in CH2Cl2 and the solvent decanted, a process repeated once more with EtOAc. The combined organic solutions were concentrated under vacuum and the residue was purified on a chromatogram using 4 mm plates and a solvent gradient of 10:1 EtOAc/MeOH to 5:1 EtOAc/MeOH to give 4A-1 as a white solid (46 mg): +ES MS (M+1) 413.4; 1H NMR (CD3OD) δ 7.58 (bs, 1H), 7.52–7.44 (m, 3H), 7.34 (d, 2H, J=7.6 Hz), 7.22 (d, 2H, J=7.6 Hz), 3.93–3.82 (m, 2H), 3.64–3.50 (m, 2H), 3.10–2.99 (m,1 H), 2.38–2.29 (m,1 H), 2.04–1.96 (m, 1H), 1.95–1.74 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[C:15]([S:25][CH3:26])[C:14]=1[C:27]#[N:28])=[O:4]>CO.ClCCl>[OH:4][CH2:3][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[C:15]([S:25][CH3:26])[C:14]=1[C:27]#[N:28]
Reactant: COc1ccc(-c2nc(-c3cccnc3)cc(SC)c2C#N)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2nc(-c3cccnc3)cc(SC)c2C#N)c(CO)c1
Reaction time: 0.33 h
Yield: 64.2 %

Procedure:
Sodium borohydride (2.2 mg, 0.058 mmol) was added to a solution of 6-(2-formyl-4-methoxyphenyl)-4-(methylthio)-2,3′-bipyridine-5-carbonitrile (4.3 mg, 0.012 mmol) in methanol (0.45 mL) and dichloromethane (0.450 mL) at room temperature. After 20 min at ambient temperature, the mixture was quenched with TEA (10 μL) and concentrated. Silica gel chromatography, eluting with 0-10% methanol in dichloromethane, gave 6-(2-(hydroxymethyl)-4-methoxyphenyl)-4-(methylthio)-2,3′-bipyridine-5-carbonitrile as white solid (2.8 mg, 65% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (1H, δ, J=2.01 Hz), 8.72-8.77 (1H, m), 822-8.28 (1H, m), 7.60-7.65 (1H, m), 7.43-7.49 (2H, m), 7.11 (1H, δ, J=2.76 Hz), 6.97-7.02 (1H, m), 4.44 (2H, s), 3.90 (3H, s), 2.72 (3H, s); MS (ES+) 111/Z: 364 (M+H); LC retention time: 3.061 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:24][CH2:25][C:26](=[O:30])[NH:27][C:28]=3[N:29]=2)[CH2:11][CH2:10]1.C(OCC)(=O)C>C1COCC1.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:24][CH2:25][C:26](=[O:30])[NH:27][C:28]=3[N:29]=2)[CH2:11][CH2:10]1
Reactant: O=C1COc2ccc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1COc2ccc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Yield: 83 %

Procedure:
6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.774 g, 1.73 mmol) was hydrogenated using Ra—Ni (0.25 g) in THF for 16 hours. The reaction was filtered and concentrated to give an oil. Ethyl acetate was added and the product crashed out. The precipitate was filtered and dried to give the title compound as a white solid (0.645 g, 83%). MS: APCI: M+1: 449.1 (Exact Mass: 448.14).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[F:12].[CH3:13]CN(CC)CC.CN(C=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:11]=[CH:13][NH:8]2)=[CH:4][C:3]=1[F:12]
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc2cc[nH]c2cc1Br
Temperature: 130 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 2 L dry round bottom flask was charged with 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (24.5 g, 0.1 mol, 97%), DMF-DIPA (39 g, 0.22 mol), Et3N (16 mL, 0.11 mol) and dry DMF (100 mL). The mixture was stirred at 130° C. for 2 h. After removal of the volatiles the residue was dissolved in a mixture of toluene (650 mL) and acetic acid (390 mL) followed by addition of iron powder (55 g) and silica gel (50 g). The dark red mixture was heated to 100° C. with vigorous stirring. The dark color disappeared after refluxing for 20 min indicating completion of reaction. The mixture was then cooled to 25° C., diluted with EtOAc and filtered. The cake was washed thoroughly with EtOAc. The combined filtrates were washed with sat. aq. Na2S2O5, sat. aq. NaHCO3, and brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with 5/1 hexanes/CH2Cl2 to provide 6-bromo-5-fluoro-1H-indole as a white crystalline solid (16.2 g, 76%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])C=C.F[C:13]1[CH:18]=CC=C[C:14]=1O.C(Br)C=C>CCOCC>[CH2:18]([C:10]1[C:5]([OH:4])=[C:6]([F:11])[CH:7]=[CH:8][CH:9]=1)[CH:13]=[CH2:14]
Reactant: Oc1ccccc1F
Reactant: C=CCOc1ccccc1F
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCc1cccc(F)c1O
Yield: 80 %

Procedure:
Other workers have prepared o-fluorophenyl allyl ether in a 90.5-93% yield from o-fluorophenol and allyl bromide. Thereafter using a thermal Claisen rearrangement of the ether gave 6-allyl-2-fluorophenol in an 80% yield. However, attempts to oxidize this last named compound to 3-fluorosalicylaldehyde using dichromate solutions gave no reproducible results, i.e., a 55% yield from the first experiment but less than 5% in subsequent runs.
Reaction SMILES: [C:1]([C:3]1([O:15][Si](C)(C)C)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH2:6][CH2:5][CH2:4]1)#[N:2].[F-].[Na+].O>O1CCCC1>[NH2:2][CH2:1][C:3]1([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH2:6][CH2:5][CH2:4]1
Reactant: COc1cccc2c1C(C#N)(O[Si](C)(C)C)CCC2
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1C(O)(CN)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a mixture of lithiumaluminumhydride (0.99 g) in tetrahydrofuran (18 ml) was added dropwise a solution of 1-cyano-8-methoxy-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.59 g) in tetrahydrofuran (18 ml) under ice-cooling and a nitrogen atmosphere. After stirring at room temperature for 3 hours, sodium fluoride (1.09 g) and water (1.41 ml) were added to the reaction mixture under ice-cooling. After stirring for additional 30 minutes, insoluble materials were filtered off and washed with 5% ethanol in ethyl acetate. The filtrate was evaporated in vacuo to afford 1-aminomethyl-1-hydroxy-8-methoxy-1,2,3,4-tetrahydronaphthalene (2.60 g), which was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[CH:6][N:5]([CH3:9])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)nc[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cnc(Br)cc1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution 6-bromopyrimidin-4(3H)-one (696 mg, 2.0 mmol) in DMF (3.0 mL) was added K2CO3 (828 mg, 6.0 mmol), CH3I (568 mg, 4.0 mmol), the reaction mixture was stirred at 50° C. for 30 minutes. The mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), washed with sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified with silica gel column (Petroleum ether:ethyl acetate=1:1) to obtain product: LC/MS m/z=189.01 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[S:13][C:12]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)=[N:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C:3]1([C:9]2[S:13][C:12]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)=[N:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: NO
Reactant: COC1(c2cnc(Sc3ccc(C(C)=O)cc3)s2)CCOCC1
Agent: Cl
Product: COC1(c2cnc(Sc3ccc(/C(C)=N/O)cc3)s2)CCOCC1
Yield: 80 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[5-(4-methoxytetrahydropyran-4-yl)thiazol-2-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-(4-methoxytetrahydropyran-4-yl)thiazol-2-ylthio]acetophenone oxime in 80% yield, m.p. 114°-116° C.;
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([NH:34][C:35]([N:13]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[CH:17][CH:16]=3)[CH2:9][C@@H:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: Clc1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of 3-(S)-benzyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine were dissolved in dichloromethane, 2 equiv. phenylisocyanate was be added. The reaction was shaken at room temperature overnight. The reaction was concentrated in vacuo and the crude purified by column chromatography to afford 50 mg of the title compound as the free base. Treatment with 1 equiv. 2 M HCl in dioxane afforded 44 mg of its hydrochloride salt. Yield: 62%, ES MS (+) m/z 496.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:40](O)[CH2:41][CH2:42][OH:43].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]12[O:43][CH2:42][CH2:41][CH2:40][O:27]1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C12OCCCO2
Yield: 61.7 %

Procedure:
To a rapidly and efficiently stirred suspension of 5-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione (16.13 g, 41.7 mmol) in benzene (785 mL) was added p-toluenesulfonic acid mono-hydrate (1.58 g, 8.34 mmol, 0.2 mole % ) and 1,3 propanediol (12.2 mL, 167 mmol, 4 eq) and the mixture was heated to reflux under a Dean Stark Trap for 5 hr. Additional p-toluenesulfonic acid (1.50 g, 0.2 mole % ) was added and the mixture was heated for another 1.5 hr. After cooling in an ice bath, the black reaction mixture was washed with sat. aq. NaHCO3 (3×350 mL), water (2×500 mL), brine (3×500 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified on silica gel eluting with CH2Cl2 followed by 50/50 Pet ether/EtOAc to give the title compound as an orange solid (11.44 g, 61.7% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (ES−) m/z 443 [M−H]. MS: (ES+) m/z 445 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCC=Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 83.4 %

Procedure:
3-(4-Fluorophenyl)acrylic acid (5.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 3.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained white powder was dissolved in tetrahydrofuran (110 ml), 1M diisobutylaluminum hydride/toluene solution (55 ml) was added dropwise at −78° C., and the mixture was stirred at it was at −78° C. for 1 Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature. Aluminum salt was collected by filtration through celite, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with water and hexane to give the object product (3.82 g) as a white powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]([C:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:50]=[CH:49][CH:48]=2)=[O:46])[CH2:41][C@@H:40]1[CH2:57][CH2:58]O)=[O:38])([CH3:35])([CH3:34])[CH3:33].[S:60]1C=C[CH:62]=[C:61]1CC(O)=O>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]([C:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:50]=[CH:49][CH:48]=2)=[O:46])[CH2:41][C@@H:40]1[CH2:57][CH2:58][C:61](=[S:60])[CH3:62])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Reactant: O=C(O)Cc1cccs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)CC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triphenylphosphine (0.65 g, 2.5 mmol), in tetrahydrofuran (7 mL) was cooled to 0° C. and diethylazodicarboxylate (0.41 mL, 2.5 mmol) added. The reaction was stirred for 30 min, and 1-tert-butoxycarbonyl-2(S)-(2-hydroxyethyl)-4-naphthoylpiperazine (0.50 g, 1.3 mmol) and thiolacetic acid (0.18 mL, 2.5 mmol) were added in tetrahydrofuran (8 mL). After stirring at 20° C. for 16 h, the solvent was removed in vacuo and the residue chromatographed on silica with 30% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [C:1]1(C)[CH:6]=C[C:4](S(OCCCC#C)(=O)=O)=[CH:3][CH:2]=1.[F:17][C:18]([F:30])([F:29])[CH2:19][CH2:20][S:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:30][C:18]([F:17])([F:29])[CH2:19][CH2:20][S:21]([CH:24]([CH2:4][CH2:3][CH2:2][C:1]#[CH:6])[C:25]([O:27][CH3:28])=[O:26])(=[O:22])=[O:23]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of 2.0 g of 4-pentynyl p-toluenesulfonate and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide, 1.2 g of potassium carbonate was added at room temperature. The mixture was stirred at 60° C. for 4 hours and at 90° C. for 1 hour, and then allowed to stand near room temperature. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.90 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-6-heptynoate (hereinafter referred to as the present compound (11)).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([SH:16])[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([S:16][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:25][CH:26]=2)[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: Cc1c(S)[nH]c(=O)n(Cc2ccccc2)c1=O
Product: Cc1c(SCc2ccc(-c3ccccc3)cc2)[nH]c(=O)n(Cc2ccccc2)c1=O

Procedure:
The product of Example 2, Step (C) was treated with 4-phenylbenzyl bromide as in Example 2, Step (D) to give 3-benzyl-6-(biphenyl-4-ylmethylsulfanyl)-5-methyl-1H-pyrimidine-2,4-dione. MS (APCI), m/z ([M+H]+) 415.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5](=[N:8][OH:9])[CH2:6]Br)[CH3:2].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:10])[C:5](=[N:8][OH:9])[CH2:6][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([Br:11])[CH:13]=2)[NH:17][CH:16]=1)[CH3:2]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C(CBr)=NO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(Cc1c[nH]c2ccc(Br)cc12)=NO
Reaction time: 20 h
Yield: 99.3 %

Procedure:
A solution of 3-bromo-2-hydroxyimino-propionic acid ethyl ester (3.21 g, 15.3 mmol) in CH2Cl2 (20 mL) was slowly added dropwise to a stirring mixture of 5-bromoindole (3.0 g, 15.3 mmol) and Na2CO3 (8.92 g, 84.2 mmol) in CH2Cl2 (30 mL) at room temperature. The mixture was stirred for 20 hours, filtered through CELITE® and concentrated to give 4.94 g of the title compound as a crude material. LCMS m/z (ESI) [M+H]+ calcd for C1-3H14BrN2O3 (Br79) 325.2, found 325.2.
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[C:10]([CH3:28])=[CH:11][C:12]([C:26]#[N:27])=[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[NH:22]C(=O)[O-])[CH:14]=1>C(O)C>[NH2:22][C@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]1[NH:15][C:13]1[CH:14]=[C:9]([Cl:8])[C:10]([CH3:28])=[CH:11][C:12]=1[C:26]#[N:27]
Reactant: Cc1cc(C#N)c(N[C@H]2CCCC[C@@H]2NC(=O)[O-])cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C#N)c(N[C@H]2CCCC[C@@H]2N)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4 M Hydrogen chloride/ethyl acetate (20 ml) was added to an ethanol solution of {(1S,2S)-2-[(5-chloro-2-cyano-4-methylphenyl)amino]cyclohexyl}carbamate, followed by stirring at room temperature for 12 hours. By concentrating the reaction liquid under a reduced pressure, 2-{[(1S,2S)-2-aminocyclohexyl]amino}-4-chloro-5-methylbenzonitrile was obtained.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[O:22][C:23]([C:26](Cl)=[O:27])=[CH:24][CH:25]=2)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[O:22][C:23]([C:26](=[O:27])[NH:4][CH2:3][CH2:1][OH:2])=[CH:24][CH:25]=2)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
0.23 g (3.7 mmol) of ethanolamine were initially charged in 20 ml of THF and a solution of 0.5 g (1.5 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise. After 0.75 h, the mixture was poured into ice-water and the precipitate was filtered off with suction and recrystallized from ethyl acetate. This gave 0.33 g (62%) of the title compound. m.p.: 119-127° C.