Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CN1CCOCC1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C1CCNCC1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCCC1
Yield: 75 %

Procedure:
4.0 g (17.3 mmol) N-BOC-L-hydroxy-proline in 150 ml CH2Cl2 were treated with 1.71 ml (17.3 mmol) piperidine, 1.9 ml (17.2 mmol) NMM and 6.16 g (20.7 mmol) TPTU at RT over night. The mixture was washed with 1M KHSO4, water, 5% aq. NaHCO3 solution, water and brine, dried over Na2SO4 and was concentrated. Column chromatography yielded 3.87 g (75%) (2S,4R)-4-Hydroxy-2-(piperidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as white solid, MS: 298 (M).
Reaction SMILES: [CH:1]([C:3]1[C:4]2[CH2:28][CH2:27][CH2:26][CH2:25][C:5]=2[S:6][C:7]=1[NH:8][C:9](=[O:24])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]1)=[O:2].[BH4-].[Na+].C(O)(=O)C>CCO.C(OCC)C>[OH:2][CH2:1][C:3]1[C:4]2[CH2:28][CH2:27][CH2:26][CH2:25][C:5]=2[S:6][C:7]=1[NH:8][C:9](=[O:24])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]1
Reactant: O=Cc1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1CO)CCCC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97.5 %

Procedure:
N-(3-Formyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(3-trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetamide (1.30 g, 3.16 mmol) was added portionwise, with stirring, to a solution of sodium borohydride (359 mg, 9.49 mmol) in EtOH (300 mL). The resulting mixture was stirred at RT for 40 min. Acetic acid was added dropwise until the effervescence ceased. The resulting mixture was concentrated in vacuo to afford an off-white solid. The solid was dissolved in diethyl ether (200 mL) and washed with water (100 mL). The organics were dried over sodium sulfate and concentrated in vacuo to yield the title compound as a yellow solid (1.27 g, 3.08 mmol, 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[CH3:29][Mg]Cl.C1COCC1>C(OCC)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:26]([OH:28])([CH3:29])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: C[Mg]Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanone (0.732 g, 1.88 mmol) in diethyl ether (15.7 mL) and toluene (14.7 mL) at 0° C. under argon was added methylmagnesium chloride, 3.0 M solution in THF (1.38 mL, 4.14 mmol). After stirring at 0° C. for 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for another 1 hour. The reaction mixture was quenched with saturated NH4Cl solution and diluted with CH2Cl2; the aqueous layer was back-extracted with CH2Cl2. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 10% to 30% EtOAc/Hexanes afforded 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-ol as a colorless foam. MS (ESI) m/z: Calculated: 404.1; Observed: 405.1 (M++1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7].O.[NH2:20][NH2:21].O>CCO>[NH:20]([C:3](=[O:2])[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])[NH2:21]
Reactant: COC(=O)CNC(=O)c1cccc2ccccc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CNC(=O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 81.6 %

Procedure:
The above compound 2a (3.3 g, 13.1 mmol) was heated at 60° C. with hydrazine hydrate (3.5 mL, 65 mmol) in EtOH (30 mL) for 2 hours. After cooling at room temperature, water (10 mL) was added. The resulting white precipitate was filtered and dried under vacuum to give hydrazide derivative 3a (2.6 g, 79%). 1H NMR (acetone-d6) δ 3.91 (d, J=5.9 Hz, 2H, CH2), 7.55-7.58 (m, 3H, Ar), 7.68 (dd, J=1.1 and 7.0 Hz, 1H, Ar), 7.98 (d, J=8.0 Hz, 1H, Ar), 8.02 (d, J=8.3 Hz, 2H, Ar), 8.35 (m, 1H, NH), 8.74 (t, J=6.3 Hz, 1H, NH), 9.31 (bs, 1H, NH); 13C NMR (acetone-d6) δ 41.08 (CH2), 124.88, 124.92, 125.13, 125.72, 126.12, 126.56, 128.07, 129.67, 129.80, 129.83, 133.08, 134.46, 168.34 (CO), 168.91 (CO).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5](NC)=[O:6].N([NH-])=O.[BH4-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C1COCC1>[Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][N:11]=1
Reactant: CNC(=O)c1ccnc(Cl)c1Cl
Agent: [BH4-]
Agent: [NH-]N=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1Cl
Reaction time: 16 h

Procedure:
2,3-Dichloro-N-methyl-isonicotinamide (0.353 g, 1.72 mmol) was stirred in 6 mL DCM (not quite homogeneous). tBuONO (0.412 mL, 3.44 mmol) was added followed by the addition of two drops of TFA. After 3 h an additional 0.600 ML tBuONO (5.00 mmol) and three drops TFA were added. The resulting solution was stirred an additional 16 h. An additional 0.400 mL tBuONO (3.34 mmol) and 2 drops TFA were added. After an additional 4.5 h an 0.600 mL tBuONO (5.00 mmol) and 3 drops TFA were added. The reaction was stirred 3 days and was quenched with half-sat NaHCO3 (aq). The mixture was extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered, and concentrated. The slightly impure N-nitrosoamide (0.425 g, 1.82 mmol) was stirred in 5 mL THF. NaBH4 (0.137 g, 3.63 mmol) was added and after 2 h the reaction was slowly quenched with 1M HCl until the bubbling stopped. The solution pH was adjusted to pH 9 with Na2CO3 (s). The mixture was extracted 3× with EtOAc. The organic phases were dried over Na2SO4, filtered, and concentrated to afford the titled compound in good purity. 1H NMR (CDCl3) δ8.32 (d, 1H, J=4.8 Hz), 7.51 (d, 1H, J=5.0 Hz), 4.82 (s, 2H), 2.34 (bs, 1H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23](Cl)[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+:2]=[N-:3].[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C(N(CC)C(C)C)(C)C>C(O)CCC>[N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:30][CH2:29][C:28]4[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:27]=4[O:26][CH3:25])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 80 °C

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 2,4-dimethoxybenzylamine (1.2 mL, 7.8 mmol) in 1-butanol (18.6 mL) was treated with N,N-diisopropylethylamine (1.4 mL, 7.8 mmol) and heated at 80° C. for 22 h; HPLC/LC MS indicated ˜90% conversion to the desired product. The volatiles were removed and the yellow-brown paste was taken up in CH2Cl2 (90 mL) and washed with water (2×30 mL) and brine (1×45 mL). The separated organic layer was dried (Na2SO4) and concentrated in vacuo to afford an orange oil. Purification by column chromatography (2×22 cm silica; 0-50% EtOAc/Hex) afforded the title compound (2.23 g, 72%) as a pale yellow glass/foam: MS (ESI+) for C24H29N7O4 m/z 480.5 (M+H)+; MS (ESI−) for C24H29N7O4 m/z 524.3 (M+HCO2)−; HPLC purity >95% (ret. time, 3.551 min).
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)=[CH:11]/1)=[O:5].[CH3:31][C:32]([OH:37])([CH3:36])[CH2:33][CH2:34][OH:35].CC([O-])(C)C.[Na+]>C1COCC1.O>[OH:37][C:32]([CH3:36])([CH3:31])[CH2:33][CH2:34][O:35][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]2([CH3:15])[CH2:13][CH2:14]2)=[CH:11]/1)=[O:5]
Reactant: Cn1c(C2(C)CC2)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1C[C@H]1CCCO1
Reactant: CC(C)(O)CCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2(C)CC2)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)n1C[C@H]1CCCO1
Yield: 54.4 %

Procedure:
A mixture of Example 68D (600 mg, 1.41 mmol), 3-methylbutane-1,3-diol (294 mg, 2.82 mmol) and sodium 2-methylpropan-2-olate (271 mg, 2.82 mmol) in THF (30 mL) was heated at 40° C. for 12 hours. The reaction mixture mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 391 mg (54%) of the title compound. 1H NMR (500 MHz, chloroform-d) δ ppm 0.76-0.83 (m, 2H) 0.89-0.98 (m, 2H) 1.31 (s, 6H) 1.34 (s, 3H) 1.69-1.82 (m, 2H) 1.81-1.90 (m, 1H) 1.96-2.11 (m, 3H) 3.66-3.80 (m, 2H) 3.83 (s, 3H) 4.15-4.32 (m, 4H) 4.52 (dd, J=14.49, 2.59 Hz, 1H) 5.62 (s, 1H) 6.98 (d, J=8.54 Hz, 1H) 7.03 (s, 1H) 7.53 (dd, J=8.54, 2.14 Hz, 1H) 8.30 (d, J=2.14 Hz, 1H); MS (DCI/NH3) m/z 510 (M+H)+.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[S:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[OH:37][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([OH:25])[CH2:23][NH:22][CH:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH:4]4[S:3][C:2](=[NH:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)=[CH:31][C:30]=1[NH:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: N=C1NC(=O)C(Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(CC4SC(=N)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-one (which was obtained in Example 45) and N-[5–2-amino-1hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp>90° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–2.00 (m, 2 H), 2.50–2.80 (m, 6 H), 2.93 (s, 3 H), 3.25 (dd, J=14.2, 3.9 Hz, 1 H), 3.45–3.60 (m, 2 H), 4.40–4.55 (m, 2 H), 6.81 (d, J=8.3 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 6.96 (dd, J=8.3, 2.0 Hz, 1 H), 7.04 (d, J=8.6 Hz, 2 H), 7.16 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 267.7 ((M+2H)2+100%), 534.3 (MH+, 45%), 1067.0 (2MH+, 2%); HRMS Calcd. for C24H32N5O5S2 (MH+): 534.1845. Found: 534.1850.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH3:18][NH2:19]>C(O)C.CCOCC>[N+:1]([CH:4]=[C:5]([NH:19][CH3:18])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Solvent: CCOCC
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene with methylamine according to the process of Example 8(ii) yielded the title compound, m.p. 103°-104°, (from ethanol ether).
Reaction SMILES: [CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C(OCC)C.C1COCC1>[CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1cccc(Oc2ccc(C3CCCCC3)cc2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1cccc(Oc2ccc(C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
At 0° C., a solution of 600 mg (2.16 mmol) of 3-(4-cyclohexylphenoxy)benzonitrile from Ex. I in 6 ml of anhydrous diethyl ether is added dropwise to 4.32 ml (4.32 mmol) of a 1-molar solution of LiAlH4 in THF. Over a period of 4 h, the reaction mixture is warmed to room temperature, and 10 ml of a sat. solution of NH4Cl are then added carefully, the mixture is diluted with ether and the organic phase is removed. The organic phase is washed successively with water and a sat. solution of NaCl, dried over MgSO4 and, after filtration, freed from the solvent. This gives 573 mg (1.81 mmol, purity 88.82%, 84% yield) of 3-(4-cyclohexylphenoxy)benzylamine.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH2:22]([O:21][CH2:20][CH2:19][N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Yield: 76.3 %

Procedure:
9-(2-Benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (25) (35 g, 9.3 mmol) was dissolved in ethanol (9 mL) and then NaOH (1.56 g) in water (15 mL) was added. The reaction was heated at reflux for 2 h. The reaction was concentrated in vacuo and the residue diluted with water and washed with dichloromethane (2×150 mL). The aqueous layer was added drop wise to 2 N HCl (150 mL) and then extracted into dichloromethane (3×150 mL). The organics were dried and concentrated in vacuo to afford 2.48 g (92%) of 9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (26) as a yellow solid which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 20.4, 21.8, 26.4, 38.3, 42.9, 68.7, 73.3, 105.7, 108.8, 118.7, 119.3, 102.9, 127.4, 127.6, 128.3, 136.2, 137.1, 137.8, 108.9.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[S:9][CH:10]=1.C(O)(=O)C.O>O1CCCC1>[CH:2]([C:6]1[CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[S:9][CH:10]=1)=[O:1]
Reactant: COC(=O)/C=C/c1cc(C2OCCO2)cs1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(C=O)cs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of methyl (2E)-3-[4-(1,3-dioxolan-2-yl)thiophen-2-yl]acrylate (3.050 g, 12.69 mmol) in tetrahydrofuran (10 ml) were added acetic acid (30 ml) and water (10 ml), and the mixture was stirred at 50° C. for 2 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure, and water (30 ml) was added to the residue. The mixture was extracted 3 times with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated to about 50 ml under reduced pressure, and hexane (200 ml) was added. The mixture was concentrated again to about 50 ml under reduced pressure, and the precipitate was collected by filtration, washed 3 times with hexane, and dried under reduced pressure to give methyl (2E)-3-(4-formylthiophen-2-yl)acrylate (2.213 g, 11.28 mmol, 88.9%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13](C#N)=[CH:12]1.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N:18]=2)[CH:13]=[CH:12]1
Reactant: Cc1ccc2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Agent: O=S(=O)(O)O
Product: Cc1ccc2ccn(-c3ccc(C(C)C)cc3Br)c2n1

Procedure:
Material from Example 72 was treated with 65% sulfuric acid as described in Example 65 to give the desired product as a viscous oil. TLC on silica gel with 70:30 hexane-ethyl acetate showed Rf =0.57. Mass spec. (m+H)+=329.0641; calcd., 329.0653 (79Br).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][SH:25])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25][C:4]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1
Reactant: COc1ccc(CS)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.6 g, 0.088 mol) was added to a cold solution of 2-chloro-5-nitrobenzoic acid (16.1 g, 0.08 mol) in dimethylformamide (200 mL) and the mixture was stirred for 5 min. The cold mixture was treated dropwise with a solution of 4-methoxy-α-toluenethiol (13.2 g, 0.08 mol) in dimethylformamide (80 mL) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the residue was diluted with water and acidified with dilute hydrochloric acid to pH 1. The resulting precipitate was filtered, washed with water and azeotroped to dryness from a mixture of methylene chloridetoluene. The residue was suspended in ethyl ether, filtered and washed with ethyl ether to give the title compound as a yellow solid (16 g, 63%), which was used without further purification. Mp 200-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([N:13]([CH2:17]C3C=C4C(=CC=3)N=CC=C4)[SH:14](=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)N2CC(O)C2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:74]1[C:83]2[C:78](=[C:79](CNS(=O)=O)[CH:80]=[CH:81][CH:82]=2)[CH:77]=[CH:76][CH:75]=1.N(C(OCC)=O)=NC(OCC)=O.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:10][CH:11]([N:13]([CH2:17][C:79]3[CH:80]=[CH:81][CH:82]=[C:83]4[C:78]=3[CH:77]=[CH:76][CH:75]=[N:74]4)[SH:14](=[O:15])=[O:16])[CH2:12]2)=[CH:33][CH:32]=1
Reactant: O=[SH](=O)N(Cc1ccc2ncccc2c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: O=[SH](=O)NCc1cccc2ncccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[SH](=O)N(Cc1cccc2ncccc12)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
N-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-quinol-6-ylmethylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.70 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol and 0.597 g of triphenylphosphine are added, under argon, to a solution of 0.50 g of N-(quinol-5-yl)methylsulfonamide in 70 cm3 of anhydrous tetrahydrofuran and then 0.40 cm3 of diethyl azodicarboxylate and 0.45 g of 1,2-bis(diphenylphosphine)ethane are poured in. After stirring for 20 hours at 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 70 cm3 of ethyl acetate, the resulting solution is washed with 30 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness at 50° C. under reduced pressure (2.7 kPa). The violet oil obtained is purified by chromatography on a silica gel column (particle size 0.063-0.200 mm, height 35 cm, diameter 3.9 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (40/60 then 30/70 and 20/80 by volume) and collecting 50-cm3 fractions. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 15 cm3 of methanol, the resulting white suspension is filtered, the solid drained and then dried at 50° C. under reduced pressure (2.7 kPa). 0.35 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-quinol-5-ylmethylsulfonamide is obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.60 (t, J=7 Hz: 1H); 2.84 (t, J=7 Hz: 1H); 2.99 (s: 3H); 3.36 (split t, J=7 and 2.5 Hz: 1H); 3.56 (split t, J=7 and 2.5 Hz: 1H); 4.01 (s: 1H); 4.85 (mt: 1H); from 7.10 to 7.25 (mt: 8H); 7.40 (dd, J=7.5 and 1 Hz: 1H); 7.54 (dd, J=8.5 and 4 Hz: 1H); 7.74 (dd, J=8 and 7.5 Hz: 1H); 8.20 (broad d, J=8 Hz: 1H); 8.54 (broad d, J=9 Hz: 1H); 8.99 (dd, J=4 and 1.5 Hz: 1H)].
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[CH:40][CH:39]=1>CCOC(C)=O.CCCCCC>[CH2:28]([C:26]1[N:25]([CH3:30])[N:24]=[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:37][C:38]4[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[CH:42][CH:43]=4)[C:4](=[O:31])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])[CH:27]=1)[CH3:29]
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCC(=O)O)cc3)c2)nn1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
A small screw cap test tube was charged with 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 345, 60 mg, 0.1441 mmol) and THF (2.0 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (24.2 mg, 0.146 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The solid that precipitated was collected by filtration and washed with 0° C. iPrOH (˜10 mL) affording the title compound in 41% yield (0.033 g, 0.059 mmol).