Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: COc1ccc(S)cc1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cccc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
4-Methoxythiophenol (Aldrich, St. Louis, Mo., Cat. No. 109525; 0.91 mL, 7.4 mmol) was dissolved in DMF (10 mL) and chilled to 0° C. in an ice bath. NaH (0.227 g, 9.5 mmol) was added slowly and the mixture was allowed to stir under an inert atmosphere. After 1 hour, 2,6-dichloropyridine (1.000 g, 6.8 mmol) was added to the mixture and the ice bath was removed. The resulting mixture was allowed to stir under inert atmosphere overnight. The mixture was quenched with 1N NaOH and diluted with DCM. The aqueous layer was extracted with 4:1 DCM/MeOH three times, and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (1-30% DCM/hexanes) to give 2-chloro-6-(4-methoxyphenylthio) pyridine (0.950 g, 56% yield) as a yellow oil. MS (ESI pos. ion) m/z: 252 (MH+). Calculated exact mass for Cl2H10ClNOS: 251.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22].CCN(CC)CC>C(Cl)Cl>[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH:22][S:1]([C:4]1[C:16]2[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COC(CN)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CNS(=O)(=O)c1cccc2c(N(C)C)cccc12)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of dansyl chloride (270 mg, 1.00 mmol) in CH2Cl2 (10 mL) was added aminoacetaldehyde dimethyl acetal (130 μL, 1.2 mmol) and Et3N (170 μL, 1.2 mmol); the solution was allowed to stir for 1 h at 25° C. The reaction mixture was then evaporated to dryness under reduced pressure and the material left was purified by silica gel chromatography using a gradient of MeOH (0→1%) in CH2Cl2 as the eluent. Fractions containing the product were collected and evaporated to dryness under low pressure affording 11 (318 mg, 940 μmol) as a solid in a yield of 94%. 1H NMR (300 MHz, DMSO-d6): δ 8.45 (dt, J=8.5, 1.1 Hz, 1H), 8.29 (dt, J=8.8, 0.9 Hz, 1H), 8.16 (t, J=5.5 Hz, 1H), 8.10 (dd, J=7.3, 1.1 Hz, 1H), 7.61 (t, J=8.5 Hz, 1H), 7.58 (t, J=8.5 Hz, 1H), 7.25 (dd, J=7.6, 0.7 Hz, 1H), 4.11 (t, J=5.5 Hz, 1H), 3.06 (s, 6H), 2.89 (t, J=5.5 Hz, 2H), 2.81 (s, 6H). 13C NMR (75 MHz, DMSO-d6): δ 151.2, 136.2, 129.3, 128.9, 127.9, 127.7, 123.5, 119.1, 115.0, 102.4, 53.3, 44.9, 43.9. +ESI-HRMS: Calcd for C16H22N2O4S [M+H]+ 339.1373. found 339.1374.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:29][CH3:30])=[C:9]([C:27]#[N:28])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20]C(=O)C(C)(C)C)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:29][CH3:30])=[C:9]([C:27]#[N:28])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH2:20])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(OCCNC(=O)C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(OCCN)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Combine 4-cyano-3-{4-[2-(2,2-dimethyl-propionylamino)-ethoxy]-phenyl}-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (211 mg, 0.45 mmol) and CH2Cl2 (1 ml), add trifluoroacetic acid 99% (1 ml) and stir at room temperature for 2 days. Remove the solvents in vacuo to give 222 mg (quantitative yield) of title compound: Rf (hexane:ethyl acetate, 4:1)=0.1. Mass spectrum (EI+): m/z 363 (M++1 free base).
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([CH3:28])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=S)[NH:14][C:12]2=[O:13])[C@H:8]([O:20]C(=O)C)[C@@H:7]1[O:24]C(=O)C)(=O)C.[NH3:29]>>[CH3:28][C@:6]1([CH2:5][OH:4])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15]([NH2:29])=[N:14][C:12]2=[O:13])[C@H:8]([OH:20])[C@@H:7]1[OH:24]
Reactant: N
Reactant: CC(=O)OC[C@@]1(C)O[C@@H](n2cc(C)c(=S)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1cn([C@@H]2O[C@](C)(CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Temperature: 25 °C
Yield: 57 %

Procedure:
Compound 16 (0.160 g, 0.386 mmol) was treated with methanolic ammonia (previously saturated at −10° C.), (10 mL) at 100° C. in a stainless-steel bomb for 3 hours, then cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride (30 mL) and water (30 mL). The aqueous layer was washed with methylene chloride (2×30 mL), concentrated under reduced pressure. The crude material was purified by silica gel column chromatography [eluent: 20% methanol in methylene chloride] to afford 1-(4-C-methyl-β-D-ribofuranosyl)-5-methyl-cytosine (60 mg, 57%). This compound was dissolved in EtOH 100 (1.5 mL), treated with a 2N hydrochloric acid solution (0.3 mL), and the mixture was stirred before being concentrated under reduced pressure. The procedure was repeated twice and 17 was precipitated from absolute ethanol. Mp: 194–200 (dec.); UV (H2O): λmax=275.6 nm (ε=7300), λmin=255 nm (ε=4700); HPLC 100%, 1H-NMR (DMSO-d6): δ 9.34 and 9.10 (2s, 2H, NH2), 8.21 (s, 1H, H-6), 5.80 (d, 1H, H-1′, J1′-2′=6.0 Hz), 5.3–4.3 (m, 3H, OH-2′, OH-3′ and OH-5′), 4.21 (t, 1H, H-2′, J=5.7 Hz), 3.98 (d, 1H, H-3′, J=5.3 Hz), 3.5–3.3 (m, 2H, H-5′ and H-5″), 1.97 (s, 3H, CH3), 1.12 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9]O)=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]C(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][Br:30])=[CH:4][N:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)cnc1Cl
Yield: 72.5 %

Procedure:
2,3-Dichloro-5-(hydroxymethyl)pyridine (275 mg) was dissolved in dichloromethane (10 ml) and stirred in the presence of triphenylphosphine (444 mg) and tetrabromometliane (641 mg) overnight. The solution was concentrated in vacuo and the residue purified by column chromatography using isohexane: 2.5% ethyl acetate as eluent to yield the product as a white solid (270 mg, 73%). NMR: δ 4.75 (s, 2H), 8.25 (m, 1H), 8.5 (m, 1H); m/z 242 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.N1CC[CH2:15][C@H:11]1[C:12](O)=O.CC(C)=O>CCO>[CH3:15][C:11]1[CH:12]=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccc2cccnc2n1
Reaction time: 8 h
Yield: 887.8 %

Procedure:
To a suspension of 2-aminonicotinaldehyde (732 mg, 6 mmol) and L-proline (69 mg, 0.6 mmol) in EtOH (15 mL) was added acetone (1.74 g, 30 mmol). Then the mixture was heated at reflux and stirred for 8 h. The resulting mixture was concentrated under reduced pressure to give a residue, which was washed with water (10 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product 2-methyl-1,8-naphthyridine as a yellow solid (768 mg). MS (ESI): m/z 145 [M+H]+. See e.g., Bioorg. Med. Chem. Lett., 2005, 15, 2679-84.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[C@H:10]([C:12]([O:14]C)=[O:13])[CH3:11])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:18])([F:19])[F:20])[C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])=[CH:5][C:4]=1[C:21]([F:22])([F:24])[F:23])#[N:2]
Reactant: COC(=O)[C@H](C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 82.8 %

Procedure:
To a solution of methyl N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)alaninate (0.034 g, 0.11 mmol) in THF:methanol (1:1; 3 mL) was added 1N NaOH (1.1 ml, 1.1 mmol). The solution was heated at 60° C. for 30 min. Upon cooling, the solution was treated with 1N HCl (5 mL) and partitioned between ethyl acetate and saturated brine. The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give 0.031 g (100% yield) of the desired product as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.8 Hz, 1H), 7.13 (d, J=2.7 Hz, 1H), 6.98 (dd, J=8.8, 2.7 Hz, 1H), 4.55 (q, J=7.2 Hz, 1H), 4.17-4.01 (m, 2H), 1.69 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Br)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[C:26]=1[O:35][CH3:36].[F-].[Cs+].COCCOC>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.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:35][CH3:36])[C:27]=2[F:34])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(Br)cc(NC(C)=O)c1OCc1ccccc1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1OCc1ccccc1
Temperature: 100 °C

Procedure:
Methyl 4-acetamido-3-(benzyloxy)-6-bromopicolinate (prepared as in Kong, L. C. C. et al. U.S. Patent Application Publication 2005/0176767; 1.5 g, 4.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (1.2 g, 5.9 mmol), bis(triphenylphosphine)-palladium(II) dichloride (PdCl2(PPh3)2; 278 mg, 0.4 mmol), cesium fluoride (CsF; 1.2 g, 7.9 mmol), 1,2-dimethoxyethane (DME; 7 mL), and H2O (7 mL) were combined and heated in a Biotage microwave at 100° C. for 15 min. H2O was added to the reaction mixture, and the product was extracted with EtOAc. The combined organic extracts were washed with satd aq NaCl, dried with sodium sulfate (Na2SO4), filtered and concentrated. Flash chromatography (SiO2; 0-45% EtOAc/cyclohexane gradient) afforded methyl 4-acetamido-3-(benzyloxy)-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate as a yellow solid: mp 115-120° C.; 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=1.6 Hz, 1H), 7.66 (s, 1H), 7.59 (dd, J=8.5, 7.7 Hz, 1H), 7.45 (s, 5H), 7.24 (dd, J=8.6, 1.7 Hz, 1H), 5.13 (s, 2H), 4.03 (s, 3H), 3.99 (d, J=1.0 Hz, 3H), 1.88 (s, 3H); ESIMS m/z 459 ([M+H]+).
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[CH2:30](Br)[CH2:31][CH2:32][CH3:33]>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[O:19])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)C3(c4ccc(O)cc4)CC3)cc2)C1
Reactant: CCCCBr
Product: CCCCOc1ccc(C2(C(=O)Nc3ccc(N4CCC(NCC(C)=O)C4)cc3)CC2)cc1

Procedure:
1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl -amino)pyrrolidin-1yl]phenyl}amide was reacted with n-butyl bromide by method H. This resulted in the product with the molecular weight of 449.60 (C27H35N3O3); MS(ESI): 450 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH:22]([O:25][CH2:26][CH:27]1[CH2:29][O:28]1)([CH3:24])[CH3:23]>>[OH:28][CH:27]([CH2:26][O:25][CH:22]([CH3:24])[CH3:23])[CH2:29][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: CC(C)OCC1CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)OCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 169 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(isopropoxymethyl)oxirane and conditions outlined in procedure X. M.p.=97-99° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.95-7.9 (m, 1H), 7.94-7.7 (m, 2H), 7.65-7.5 (m, 1H), 4.42 (br. s, 1H), 3.72 (br. s, 1H), 3.6-3.45 (m, 1H), 3.35-3.2 (m, 2H), 3.07 (s, 2H), 2.8 (m, 2H), 2.5-2.2 (m, 4H), 2.05-1.7 (m, 4H), 1.07 (d, J=5.2 Hz, 6H); LCMS: 418 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:15]O>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2ccccn2)c1
Reactant: OO
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2cccc[n+]2[O-])c1

Procedure:
Starting from 2-(3-cyanophenyl)-pyridine, the title compound is prepared by oxidation with H2O2 in glacial acetic acid [J. Heterocycl. Chem. 11, 299 (1974)].
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:13])=[CH:7][CH:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NC1CC1)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(OCc2ccccc2)cc1

Procedure:
N-Cyclopropyl-4-hydroxybenzamide was stirred with benzyl bromide and potassium carbonate in DMF at room temperature to obtain 4-(benzyloxy)-N-cyclopropylbenzamide.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6]
Reactant: C1=COCCC1
Reactant: OCCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100.0 g of 1,4-butanediol and 20 ml of 3,4-dihydro-2H-pyrane in 80 ml of dichloromethane and 140 ml of tetrahydrofuran, 1.8 g of pyridinium p-toluenesulfonate was added. After stirring at room temperature for 18 hours, the solvent was evaporated under reduced pressure. The residue was extracted three times with diethyl ether after adding saturated brine. After the extract was washed with a small amount of water and dried over anhydrous magnesium sulfate, the solvent was evaporated to obtain 35.98 g of the desired crude product as a colorless oily substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=[O:20])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[F:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[F:36][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=3)=[O:20])=[CH:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3C)cc2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a suspension of 3-fluoro-4′-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester (35 mg) in THF (0.2 ml) and MeOH (0.2 ml) was added a 1M aqueous LiOH solution (0.145 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. Since the reaction was not finished, 1 M aqueous LiOH solution (0.435 ml) was added portionwise while stirring for another 24 h at room temperature. The reaction mixture was acidified using 1 M HCl. The organic solvents were removed under vacuum. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (29 mg) as a colorless solid, MS (ESI−): m/z=468.2 [M−H]−.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23]([C:25]3[C:29]4[N:30]=[CH:31][N:32]=[C:33]([NH:34][CH:35]5[CH2:37][CH2:36]5)[C:28]=4[S:27][CH:26]=3)=[O:24])[CH:16]=2)=[CH:9][C:8]=1[C:39]([F:42])([F:41])[F:40])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:49][C:50]1[N:51]=[CH:52][NH:53][CH:54]=1>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([NH:34][C:33]2[C:28]3[S:27][CH:26]=[C:25]([C:23]([NH:22][C:17]4[CH:16]=[C:15]([C:14](=[O:38])[NH:13][C:10]5[CH:11]=[CH:12][C:7]([CH2:6][N:53]6[CH:54]=[C:50]([CH3:49])[N:51]=[CH:52]6)=[C:8]([C:39]([F:42])([F:40])[F:41])[CH:9]=5)[CH:20]=[CH:19][C:18]=4[CH3:21])=[O:24])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:36][CH2:37]1
Reactant: Cc1ccc(C(=O)Nc2ccc(COS(C)(=O)=O)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn(Cc2ccc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(NC6CC6)ncnc45)c3)cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
4-(3-(4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzamido)-2-(trifluoromethyl)benzyl methanesulfonate (30 mg, 0.048 mmol) was dissolved in DMF (1 mL), K2CO3 (20 mg, 0.145 mmol) and 4-methyl-1H-imidazole (20 mg, 0.242 mmol) were added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography (MeOH/DCM=5/95) to obtain the title compound (23 mg, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.II.[CH:12]([C@@H:14]1[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][C@@H:15]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:13].[NH4+].[Cl-]>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C@H:12]([C@@H:14]2[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][C@@H:15]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:13])[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)Cc1cccc(Cl)c1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A portion of a mixture of 3-chlorobenzyl bromide (0.53 mL, 4.0 mmol) and Et2O (0.5 mL) was added to Mg turnings and I2 (catalytic amount) in Et2O (4 mL). Once the reaction was initiated, the rest of the 3-chlorobenzyl bromide was added. When the reaction subsided, the resulting green mixture was transferred into a −78° C. suspension of CeCl3 (1.05 g, 4.3 mmol) in THF (4 mL). A solution of the (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 1M in THF, 3 mL, 3 mmol) was added and the reaction mixture was allowed to warm to room temperature, then was treated with a saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure. The crude green oil was purified by flash chromatography (EtOAc) to give (±)-(4R*,5R*)-5-[(1R*)-2-(3-chlorophenyl)-1-hydroxyethyl]-1-methyl-4-phenylpyrrolidin-2-one (340 mg, 34%): mp 50-52° C.; TLC (EtOAc) Rf 0.25.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11].[O:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[CH3:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH2:19][CH2:20]1)[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CC(N2CCOCC2)CCN1
Product: Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 4-chloro-3-methylnitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 199–200° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]#N)[CH2:24][CH2:23]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].S(=O)(=O)(O)[OH:31]>C1(C)C=CC=CC=1>[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH:28]=[O:31])[CH2:24][CH2:23]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C#N)CC2)CC1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=O)CC2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
24 ml of a 1.2M solution of diisobutylaluminium hydride in toluene were added dropwise over a period of 30 minutes at 0° C. and under an inert gas atmosphere to a solution of 5.5 g of trans-4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexanecarbonitrile in 500 ml of toluene. The mixture was stirred at 0° C. for another hour and then at room temperature for 3 hours. The mixture was subsequently poured into 500 ml of 0.5N sulphuric acid and extracted three times with 200 ml of diethyl ether each time. The combined organic phases were washed first with saturated sodium hydrogen carbonate solution and then with water, dried over sodium sulphate and concentrated, thereby obtaining 5.6 g of trans-4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexanecarboxaldehyde.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[O:4][C:3]1=[O:10].I.NC(N)=[S:14].[OH-].[Na+]>O>[SH:14][CH:5]([CH3:9])[CH2:6][CH2:7][CH2:8][CH:2]([CH3:1])[C:3]([OH:4])=[O:10]
Reactant: CC1CCCC(C)C(=O)O1
Reactant: NC(N)=S
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(S)CCCC(C)C(=O)O
Temperature: 25 °C
Yield: 91 %

Procedure:
A 10 mL round bottom flask equipped with a stir bar was charged with 3,7-dimethyloxepan-2-one (61, 0.729 g, 5.13 mmol), hydroiodic acid (2.029 ml, 15.38 mmol) and thiourea (2.73 g, 35.91 mmol). The flask was equipped with a water cooled water condenser, placed under a nitrogen atmosphere and heated to reflux. The reaction proceeded at reflux overnight. A sodium hydroxide (3.69 g, 92 mmol) solution in water (5 mL) was then added to the reaction flask. The reaction was refluxed overnight. The reaction mixture was removed from heat, cooled to room temperature and the flask contents were transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate and the extract was set to the side. The aqueous layer was acidified with HCl to pH 2 and extracted with ethyl acetate (2×100 mL) and methylene chloride (1×100 mL). The organic extracts were combined, washed with 30 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 823 mg of crude 6-mercapto-2-methylheptanoic acid (62, 92% yield) as a light brown oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[C:14]([Br:15])=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[Br:15][C:14]1[C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2cccc(Br)c2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cccc(Br)c2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, the thermometer and reflux condenser. 2-Amino-7-bromobenzothiazole (0.1 mole) is added with stirring. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 7-bromobenzothiazol-2-yl isocyanate dimer.