Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(C(Cl)=O)=O.[NH2:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:21](=[O:34])[N:22]2[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1>C(#N)C.CN(C=O)C.C(Cl)Cl>[NH2:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:21](=[O:34])[N:22]2[C:27]1[CH:28]=[C:29]([NH:33][C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
To a suspension of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride salt (94 mg, 0.57 mmol) in dry acetonitrile (5 mL) was added 1 drop of DMF before introducing (COCl)2 (0.5 mL, 5.3 mmol). Resulting mixture was stirred at room temperature for 1 hour. Concentrated and dissolved in dry DCM (2 mL) before introducing a solution of 6-amino-9-(3-aminophenyl)-7-(4-chlorophenyl)-7H-purin-8(9H)-one (13) (100 mg, 0.28 mmol) in DCM (2 mL). Resulting solution was stirred at room temperature for 2 hours before quenched the reaction with MeOH (2 mL). Solvent was removed and the residue was pre-purified by column chromatography (silica gel, 0 to 10% methanol in methylene chloride (0.3% Et3N)) followed by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3.H2O)) to give (E)-N-(3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (14) (25 mg, 19.1%) as a white solid. LC-MS (ESI): m/z (M/M+2) 464/466. 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 9.82 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.56-7.45 (m, 3H), 7.35 (d, J=8.8 Hz, 1H), 6.82-6.65 (m, 1H), 6.46 (d, J=15.3 Hz, 1H), 5.98 (s, 2H), 4.01-3.87 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH:15]([CH3:26])[CH2:14]2)[CH:3]=1.[CH2:27]([NH2:30])[CH2:28][NH2:29]>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH:15]([CH3:26])[CH2:14]1)[CH:3]=[C:2]2[NH:29][CH2:28][CH2:27][NH2:30]
Reactant: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(Cl)c2c1
Reactant: NCCN
Product: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(NCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 30 by using 4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and ethane 1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J=7.83 Hz, 1 H), 7.85 (brs, 1 H), 7.70-7.60 (m, 2 H), 7.52-7.40 (m, 2 H), 7.30 (dd, J=8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.13 (brs, 2 H), 3.67-3.57 (m, 1 H), 3.56-3.48 (m, 2 H), 3.31-3.30 (m, 3 H), 3.15-3.04 (m, 2 H), 2.42 (s, 3 H), 1.51 (brs, 2 H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:28][NH2:29]>>[CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:14](=[O:16])[NH:29][CH3:28])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Agent: Cl
Product: CNC(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and methanamine hydrochloride as starting materials and isolated (114 mg, 96%) as a racemate; MS (ESI, m/z): 388.6 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:9]2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:9]2
Reactant: CCOC(=O)c1ccc2cccc([N+](=O)[O-])c2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2cccc(N)c2c1
Yield: 73.2 %

Procedure:
According to the procedure of W. Adcock, et al. Aust. J. Chem. 18, 1351 (1965), a suspension of ethyl 8-nitro-2-naphthoate (8.2 g, 0.033 mol) in ethanol (240 mL) was hydrogenated at 50 psi over 10% Pd/C (820 mg) for 4 hours. The mixture was filtered through Solka floc® and concentrated. Recrystallization of the residue from EtOH/H2O gave a yellow solid (5.2 g, 72%), m.p. 97°-98° C.
Reaction SMILES: C(O)(C)(C)C.[C:6]1([C:14]([CH2:16][C:17]2[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[CH:19][CH:18]=2)=[O:15])[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].CO[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[O:36]>CCCCCC>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:14]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[CH:12][CH:13]=2)=[O:15])=[CH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:24][CH:23]=1
Reactant: COC=CC(=O)OC
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To 430 ml of tert-butanol were added 128 g of deoxyanisoine, 67.3 g of potassium tert-butoxide and 116 g of methyl 3-methoxyacrylate, and the mixture was stirred at 70° C. for 3 hours. To the resulting mixture was added n-hexane, and the mixture was allowed to stand at room temperature. A formed precipitate was filtered and dissolved by adding 1,000 ml of ethyl acetate and 300 ml of 3N-sulfuric acid. An organic layer was separated, washed with 3N-sulfuric acid and saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give 153 g (yield 90%) of methyl 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenoate as an oil.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[CH3:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[N:36]=[CH:37][N:38]=[C:39]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:40]=2)[CH:20]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C3CCOCC3)[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2nc(C3CCOCC3)[nH]c12

Procedure:
33 mg (0.13 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 40 mg (0.12 mmol) 7-methyl-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 μL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 60° C. The reaction mixture was poured onto ice water and the precipitate formed was suction filtered. The precipitate was dissolved and then purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C.Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:10][CH:11]=1
Reactant: Cc1ncccc1Oc1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ncccc1Oc1ccc(N)cn1
Temperature: 50 °C
Yield: 85.6 %

Procedure:
2-(2-Methylpyridin-3-yloxy)-5-nitropyridine (D8, 81.1 g, 0.35 mole) in ethanol (2L) was treated with tin (II) chloride (232 g, 1.23 mole) in conc. hydrochloric acid (500 ml) and heated to 50° C. for 1 hour. After cooling to ambient temperature, the mixture was basified with 40% aqueous sodium hydroxide solution, extracted into ethyl acetate, dried (Na2SO4) and evaporated in vacuo to afford the title compound (60.3 g, 86%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(C)CCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-{hydroxy-[4-(3-methyl-butoxy)-phenyl]-methyl}-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 25 mg of the title compound. 1H NMR (DMSO) δ 0.93 (s, 3H), 0.95 (s, 3H), 1.64-1.82 (m, 3H), 4.13 (t, 2H, J=6.41 Hz), 7.12 (d, 2H, J=8.67 Hz), 7.75-7.91 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 380 (M−1). CHN Calc C, 56.62; H, 5.28; N, 3.67. Found C, 56.54; H, 5.04; N, 3.73.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1>>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:31])=[CH:25][CH:24]=1
Reactant: Cc1ccc(N=C=S)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(C)cc4)CC3)nc21

Procedure:
Pipemidic acid (89 mg, 0.293 mmol) and p-tolyl isothiocyanate (40 mg, 0.268 mmol) were used. Purification on silica yielded compound 27 in Table 1, below (82 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.67 (s, 1H), 7.40 (s, 1H), 7.17 (d, J=7.60 Hz, 2H), 7.09 (d, J=7.44 Hz, 2H), 4.33 (q, J=6.40 Hz, 2H), 4.23-3.91 (m, 8H), 2.34 (s, 3H), 1.49 (t, J=7.03 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].[OH-].[Na+].[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>ClCCl>[CH2:1]([N:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[C:33](=[O:34])[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN(C(=O)Cc1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (100 mg) in dichloromethane (3 ml) were sequentially added an aqueous solution of 1N sodium hydroxide (1 ml) and phenylacetyl chloride (0.06 ml) on an ice bath, and the solution was stirred overnight while warming to room temperature. To the reaction solution was added water, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo to provide the title compound (140 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([OH:26])[CH2:24][OH:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:37]=[C:38]=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:26][C:38](=[O:39])[NH:37][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][O:25][C:38](=[O:39])[NH:37][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCN=C=O
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-dihydroxypropylthio) propanoate (13) was stirred in anhydrous benzene (0.1 M) under nitrogen at room temperature. Decyl isocyanate (2.02 eq) and DMAP (dimethylaminopyridine, 2.02 eq) were added and the resulting mixture heated to 40° C. and stirred overnight. The reaction mixture was concentrated to remove benzene then reconstituted in DCM and purified on a COMBIFLASH® system (ISCO) using a gradient of 0-50% EtOAc/Hex to give the title product as a colorless oil.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:7]1([C:5]2[CH2:4][CH:3]=[CH:2][CH:1]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1C=CCC1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Product: C1=CCC(c2ccccc2)=C1
Yield: 120.1 %

Procedure:
100 ml (1.2 mol) of 2-cyclopenten-1-one in 400 ml of diethyl ether are added dropwise to 2.3 mol of phenyllithium in 1000 ml of diethyl ether at −5° C. After hydrolysis and extraction of the aqueous phase with the diethyl ether, the combined organic phases are dried over sodium sulfate. After the solvent has been stripped off, 205 g of crude product are obtained. The product is heated to 180° C. for three hours in a vigorous argon stream in a
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.C1(C)C=CC=CC=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(N(CC)CC)C>[C:16]([NH:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: CCc1nnc(N)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC(=O)Nc1nnc(CC)s1
Yield: 80.4 %

Procedure:
2-Amino-5-ethyl-1,3,4-thiadiazole (0.5 g) was added to a mixture of toluene (5 ml) and triethylamine (0.4 g). With stirring, butyryl chloride (0.5 g) was added to the suspension at room temperature. After stirring for 2 hours, aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with water several times. The precipitated crystals and the organic layer were combined and the solvent was concentrated to 5 ml. The precipitated crystals were filtrated and dried. The title compound (0.62 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([C:19]([O:21]C)=[O:20])[O:10][C@@H:9]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([C:19]([OH:21])=[O:20])[O:10][C@@H:9]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1O[C@H](c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc([C@H]2O[C@H](C(=O)O)[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 93.7 %

Procedure:
33 mg (0.08 mmol) of (2R,4S,5S)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine, in suspension in 15 cm3 of methanol, are put, under an argon atmosphere, into a 50 cm3 round-bottomed flask equipped with a magnetic stirrer system. 5 cm3 of water and 33 mg (0.24 mmol) of potassium carbonate are then added. The mixture is allowed to react for 96 hours at a temperature in the region of 25° C. The reaction mixture becomes homogeneous. The methanol is removed under reduced pressure. The basic aqueous phase is diluted in 10 cm3 of water and then extracted with 3 times 15 cm3 of ether. The aqueous phase is cooled to 0° C. and is then acidified, with vigorous stirring in the presence of 20 cm3 of dichloromethane, with a 4M aqueous hydrochloric acid solution to a pH of less than 1. The acidic aqueous phase is extracted 8 times with 20 cm3 dichloromethane. The combined organic phases are washed with 3 times 5 cm3 of water and then once with 5 cm3 of a saturated aqueous sodium chloride solution. The organic phases are dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, there are obtained, with a yield of 94%, 30.0 mg (0.075 mmol) of (2R,4S,5S)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[C:26](=[N:38]\[NH:39]C(OCC)=O)/[CH2:27][C:28]2[C:29]([C:34]([F:37])([F:36])[F:35])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:45](Cl)(Cl)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:26]2[N:38]=[N:39][S:45][C:27]=2[C:28]2[C:29]([C:34]([F:37])([F:36])[F:35])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N/N=C(/Cc1cccnc1C(F)(F)F)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(-c2nnsc2-c2cccnc2C(F)(F)F)cc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
A mixture of (Z)-ethyl 2-(1-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)ethylidene)hydrazinecarboxylate (0.388 g, 0.64 mmol), in thionyl chloride (2 mL) was refluxed until no more starting material was detected. Excess of solvent was removed and the residue was purified by chromatography over silica gel using a mixture of dichloromethane/ethanol as eluent. Homogeneous fractions were pooled and evaporated to afford 4-(3,4-bis(benzyloxy)-5-nitrophenyl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,2,3-thiadiazole, 0.184 g (51%).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]([N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])/[C:11](=[N:20]/[C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:23]=2[F:32])/[S:10]1)([CH3:8])([CH3:7])[CH3:6].[CH3:34][Mg]Br>C1COCC1>[C:5]([N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])([CH3:34])[CH3:18])/[C:11](=[N:20]/[C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[C:23]=2[F:32])/[S:10]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(=O)CCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cccc(C(F)(F)F)c1F
Reactant: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To the suspension of cerium(III) chloride (86 mg, 0.35 mmol) in THF (3 mL) was added the product from Example 77 (100 mg, 0.23 mmol) in THF (0.5 mL). The mixture was stirred at rt for 1 hr. The above mixture was cooled to −40° C. and methylmagnesium bromide (41.6 mg, 0.348 mmol) was added dropwise. The reaction was stirred for 40 min at −40° C., quenched with saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 57 mg (55%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.23 (s, 6H) 1.57-1.61 (m, 2H) 1.68 (s, 9H) 1.74 (s, 1H) 1.81-1.89 (m, 2H) 2.88 (t, J=7.63 Hz, 2H) 7.30 (t, J=7.93 Hz, 1H) 7.69 (t, J=6.41 Hz, 1H) 8.01-8.04 (m, 1H) 8.39 (td, J=7.93, 1.53 Hz, 1H); MS (DCI/NH4+) m/z 447 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:26][C:27](=O)[CH3:28].CSC.B.[ClH:37].C(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:37].[CH2:27]([NH:26][CH:7]1[CH:6]([CH2:5][C:4]2[CH:30]=[CH:31][CH:32]=[C:2]([F:1])[CH:3]=2)[C:15]2[CH:14]=[C:13]([CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]1)[CH3:28]
Reactant: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(NC(C)=O)CC2
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: CSC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(F)c1)C(NCC)CC2
Temperature: 50 °C
Reaction time: 5 h

Procedure:
N-(1-(3-Fluorobenzyl)-7-(3-(propylsulfonamido)propyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (cf. example 214, 19.5 mg, 0.042 mmol) was dissolved in tetrahydrofuran (1 mL) and borane dimethylsulfide (106 μL, 0.212 mmol) was added. The reaction mixture was stirred for 5 hours at 50° C. After cooling to room temperature aqueous hydrochloric acid was added. The mixture was made alkaline by the addition of sodium bicarbonate and extracted several times with dichloromethane. The combined organic extracts were dried (MgSO4), concentrated in vacuo and the crude product purified by flash-chromatography (silica gel, dichloromethane, methanol). An excess of 1 M hydrochloric acid in ether was added to the purified product and the ether distilled off. Yield: 7 mg (0.016 mmol, 37%).
Reaction SMILES: Cl.[CH3:2][N:3]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][CH3:23])[C:4](=[O:15])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].[CH2:29](Br)[CH:30]1[O:34][CH2:33][CH2:32][CH2:31]1>ClCCl.CN(C)C=O>[CH3:2][N:3]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]([CH3:23])[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][O:34]1)[C:4](=[O:15])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CN[C@@H]1CCCC[C@H]1N(C)C(=O)Cc1cccc2sccc12
Reactant: BrCC1CCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CC1CCCO1)[C@@H]1CCCC[C@H]1N(C)C(=O)Cc1cccc2sccc12
Reaction time: 20 h
Yield: 31.6 %

Procedure:
A solution of trans-(±)-N-methyl-N-[2-(methylamino)cyclohexyl]benzo[b]thiophene-4-acetamide monohydrochloride (120 mg, 0.34 mmol) in dichloromethane (10 ml) was treated with saturated aqueous sodium bicarbonate to liberate the parent amine. The oil was dissolved in dimethyl formamide and treated with tetrahydrofurfuryl bromide (68 mg, 0.41 mmol) and sodium bicarbonate (43 mg, 0.5 mmol). The resulting mixture was stirred in an oil bath at 95°-110° C. for 20 hours then concentrated in vacuo, poured into saturated aqueous sodium bicarbonate (15 ml) and extracted with dichloromethane (2×15 ml). Silica gel chromatography (70:30:1 ethyl acetate-hexanetriethylamine) furnished trans-(±)-N-methyl-N-(2-(methyl[(tetrahydro-2-furanyl)methyl]amino)cyclohexyl)-benzo[b]thiophene-4-acetamide as a colourless oil (43 mg, 32%); m/e: 400 (M+), 329, 286, 195, 147; t.l.c. analysis of this product (50:50:1 ethyl acetate-hexane-triethylamine, multiple development) indicated that it consisted of two components.