Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH2:21])=[O:13])=[CH:6]2.C(N(CC)CC)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34](Cl)(=[O:36])=[O:35].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][S:34]([C:30]1[S:29][CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])=[O:13])=[CH:6]2
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: N[C@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1cccs1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1.25 h
Yield: 74.4 %

Procedure:
(±)-cis-N-[(5-Chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (200 mg) was dissolved in N,N-dimethylformamide (1 ml), and triethylamine (0.28 ml) and 2-thiophenesulfonyl chloride (111 mg) were added to stir the mixture for 75 minutes. Water was added to the reaction mixture, and deposit was collected by filtration and recrystallized from methanol to obtain the title compound (198 mg) as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=O)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:31])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)C>[CH2:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][C:11]([CH3:31])=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1oc2c(C)c(C)c(NC(=O)c3ccccc3)c(C)c2c1-c1ccc(C(C)C)cc1
Solvent: CCO
Product: Cc1oc2c(C)c(C)c(NCc3ccccc3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 55 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 55%. Melting point: 94-95° C. (Ethanol)
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1.CN1C(=O)N(C)CCC1>[CH3:22][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: -60 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (2.107 g, 7.23 mmol) in dry THF (22 mL) and DMPU (1.4 mL, 1160 mmol) cooled at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (1.271 g, 7.59 mmol, 7.60 mL of 1M solution in THF). After addition, the reaction mixture was stirred at −60° C. for 1 h. Then iodomethane (0.520 mL, 8.32 mmol) in DMPU (0.344 mL, 2.86 mmol was added dropwise. After addition, the reaction was stirred at −60° C. for 1.5 h, then slowly warmed up to −20° C. over approximately 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction solution was extracted with EtOAc (2×). The combined organics were washed with saturated aqueous NH4Cl and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex. The desired fractions were concentrated to give product, benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (1.66 gm, 5.44 mmol, 75.2% yield) as a light brown oil. Anal. Calcd. for C17H23NO4 m/z 305.3, found: 306.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.27 (m, 5 H), 5.20-5.09 (m, 2 H), 4.24-4.04 (m, 2 H), 3.99 (d, J=13.19 Hz, 1 H), 3.59 (br. s., 1 H), 3.27 (d, J=7.15 Hz, 1 H), 3.13 (d, J=12.64 Hz, 1 H), 2.16-1.95 (m, 1 H), 1.74-1.52 (m, 2 H), 1.51-1.39 (m, 1 H), 1.25-1.07 (m, 6 H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=1[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:32]([NH2:42])[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>>[O:38]1[C:39]2[CH:40]=[CH:41][C:33]([CH2:32][NH:42][C:19]([C:17]3[S:18][C:14]([CH3:13])=[C:15]([NH:22][C:23](=[O:31])[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:16]=3)=[O:21])=[CH:34][C:35]=2[O:36][CH2:37]1
Reactant: Cc1sc(C(=O)O)cc1NC(=O)Cc1ccccc1
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)NCc2ccc3c(c2)OCO3)cc1NC(=O)Cc1ccccc1
Yield: 95.7 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.26 g, 1.7 mmol), 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid from Example 10, Step 1 (0.3 g, 1.1 mmol), and piperonyl amine (0.17 g, 1.1 mmol) to afford 0.43 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide. A sample of the product was chromatographed on silica gel, eluting with ethyl acetate. Evaporation of the effluent under reduced pressure gave product with a mp 138-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.C[OH:18]>>[Cl:1][C:2]1[C:3]([S:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Cl)c1SCc1ccccc1
Reactant: CO
Product: O=S(Cc1ccccc1)c1c(Cl)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4.7 g of the starting sulfide (Sec Example 24 above) dissolved in 25 ml of methanol were added a pinch of Na2WO4 followed by 1.5 g of 50% aqueous hydrogren peroxide. The mixture was stirred at room temperature for four hours, filtered, and the solid was washed with NaHSO3 solution, followed by water. The dried solid 2.2 g, melting point of 119-122° C., gave an NMR which indicated mostly the desired sulfoxide but some contamination by the sulfone and sulfide. A second crop of 1.1 g, melting point 118-123° C., was also obtained. Attempts to recrystallize from toluene and from ethyl acetate gave material still contaminated by sulfone, so the mixture was finally separated by preparative HPLC and then recrystallized from ethyl acetate, having a melting point of 124-126° C. The elemental analysis for C,N&N, the infrared spectrum, and the NMR spectrum were all consistent with the proposed structure.
Reaction SMILES: O.C(C(CCCC)C([O-])=O)C.[K+:12].[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C@@H:25]1[CH2:38][CH2:37][C:28]2([O:32][C@H:31]([CH2:33][OH:34])[C@@H:30]([CH2:35][OH:36])[O:29]2)[CH:27]=[C:26]1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:24])=[O:23]>C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N-:21][S:22]([C@@H:25]1[CH2:38][CH2:37][C:28]2([O:29][C@H:30]([CH2:35][OH:36])[C@@H:31]([CH2:33][OH:34])[O:32]2)[CH:27]=[C:26]1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:24])=[O:23].[K+:12]
Reactant: CCOC(=O)C1=CC2(CC[C@H]1S(=O)(=O)Nc1ccc(F)cc1Br)O[C@H](CO)[C@@H](CO)O2
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CC2(CC[C@H]1S(=O)(=O)[N-]c1ccc(F)cc1Br)O[C@H](CO)[C@@H](CO)O2
Temperature: 25 °C
Yield: 65.4 %

Procedure:
422 mg (2.31 mmol) of potassium 2-ethylhexanoate hydrate was dissolved in 23 mL of ethyl acetate, and 1.215 g (2.31 mmol) of ethyl(2R,3R,8R)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]deca-6-ene-7-carboxylate [a compound described as a low polarity compound (first peak) of Example 166 in WO 2007/032362] was added thereto under stirring at room temperature. The resulting reaction solution was concentrated under reduced pressure, and to the residue, diethyl ether was added. A precipitated solid was obtained by filtration and washed with diethyl ether, whereby 954 mg of a crude product was obtained as an amorphous solid. Then, the crude product was dissolved in 6 mL of ethyl acetate, and the resulting solution was heated under stirring at 70° C. for 5 minutes. After the resulting mixture was cooled, a precipitated solid was obtained by filtration and washed with ethyl acetate and diethyl ether, whereby 850 mg of the title compound was obtained as a white crystal (yield: 65%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:21]([CH2:31][CH3:32])[CH:20]=1)=O.BrC(Br)=O>>[CH2:31]([C:21]1[CH:20]=[C:19]([CH2:17][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][CH2:11][C:5]=23)=[O:10])[CH:24]=[C:23]([CH3:25])[C:22]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:32]
Reactant: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Reactant: CCc1cc(C=O)cc(C)c1CCC(=O)O
Agent: O=C(Br)Br
Product: CCc1cc(CCC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc(C)c1CCC(=O)O

Procedure:
3-{2-Ethyl-4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-6-methyl-phenyl}-propionic acid is prepared from 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (Example R) and 3-(4-formyl-2-ethyl-6-methyl-phenyl)-propionic acid (Aldehyde 6) in analogy to Intermediate 2; LC-MS: tR=1.16 min, [M+1]=441.36; 1H NMR (CDCl3): δ 6.95 (s, 1H), 6.93 (s, 1H), 3.12-2.94 (m, 8H), 2.74 (q, J=7.6 Hz, 2H), 2.66 (q, J=7.6 Hz, 2H), 2.56-2.48 (m, 2H), 2.36 (s, 3H), 2.32 (s, 2H), 1.56 (t, J=7.0 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H), 1.24 (t, J=7.6 Hz, 3H).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N+:14]([C:6]1[CH:5]=[CH:4][C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:8][C:7]=1[N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: COc1ccc([N+](=O)[O-])c(-n2cccn2)c1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1-n1cccn1
Yield: 8.5 %

Procedure:
Under N2 a solution of 1-(5-Methoxy-2-nitro-phenyl)-1H-pyrazole (3.00 g, 13.7 mmol), of Example 611a, in Morpholine (100 mL, 1000 mmol; Acros) was warmed to 120° C. for 100 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between 10% Na2CO3 and EtOAc. The aqueous phase was washed with a second portion of EtOAc, then the organics were combined, dried over Na2SO4, filtered and concentrated to yield 1.46 g of crude product 4-(4-Nitro-3-pyrazol-1-yl-phenyl)-morpholine (26% by LC). An initial purification by normal phase chromatography eluting with a gradient of 100% CH2Cl2 to 10:1 CH2Cl2:MeOH met with limited success. The purest fractions were concentrated and rerun on another normal phase column eluting with a gradient of 10% EtOAc/Hexane to 65% EtOAc/Hexane. The purest fractions were combined and concentrated under reduced pressure to give 0.48 g of purer material. This material was crystallized from Et2O and the resulting solid was filtered and rinsed with a small amount of Et2O to yield 318 mg (9%) of 4-(4-Nitro-3-pyrazol-1-yl-phenyl)-morpholine, which was carried on without further purification.
Reaction SMILES: C(O[CH:4]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=4)[S:25][C:18]=23)=[C:12]([F:32])[CH:11]=1)[C:5]([F:8])([F:7])[F:6])C.[C:33]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].[H-].[Na+].Cl>O1CCCC1.CCOC(C)=O.O>[F:8][C:5]([F:6])([F:7])[CH:4]([CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:33]([O:41][CH2:42][CH3:43])=[O:40])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=4)[S:25][C:18]=23)=[C:12]([F:32])[CH:11]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Yield: 83.2 %

Procedure:
To a solution of 318 (470 mg, 1.01 mmol) and diethyl malonate (0.17 mL, 1.11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was added sodium hydride (60% in oil, 89 mg, 2.22 mmol). The mixture was heated to reflux for 2 h, cooled, diluted with EtOAc and water and acidified to pH 3 using a 1N HCl solution. The organic layer was separated and the aqueous layer extracted twice with EtOAc. The extracts were combined, dried over sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 0:100 to 20:80) to afford 319 (490 mg, 0.84 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (d, J=5.2 Hz, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.24 (t, J=9.2 Hz, 1H), 6.98 (dd, J=13.6, 2.8 Hz, 1H), 6.72 (dd, J=9.2, 2.8 Hz, 1H), 6.62 (d, J=10.0 Hz, 1H), 6.46 (d, J=5.2 Hz, 1H), 5.05-4.95 (m, 1H), 4.23-4.07 (m, 4H), 3.91 (d, J=9.2 Hz, 1H), 3.72 (s, 3H), 1.18 (t, J=7.0 Hz, 3H), 1.11 (t, J=7.0 Hz, 3H). LRMS (M+1) 581.0 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[C:37]([NH:38]C(=O)OCC3C=CC=CC=3)=[CH:36][C:35]3[C:30](=[CH:31][C:32]([C:49]4[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH:54]=4)=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:38][C:37]1[C:28]([C:26]([NH:25][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:19]=2[N:11]2[CH2:12][C@H:13]([C:15]([F:18])([F:16])[F:17])[CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]2)=[O:27])=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([CH:49]1[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]1)[CH:31]=2
Reactant: CN1CC=C(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2ccc3cc(N)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Yield: 79.7 %

Procedure:
A mixture of benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl]carbamate (0.010 g, 0.013 mmol) in 1.5 mL of MeOH was hydrogenated in the presence of 10% Pd on carbon (3.5 mg) under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl [(3S,5R)-1-[3-({[3-amino-7-(1-methylpiperidin-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.0065 g, 79%). LCMS calc. for C32H41F3N7O3 [M+H]+: m/z=628.3. found: 628.3.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5].[C:16]([N:20]=[C:21]=[S:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(O)C>[C:16]([NH:20][C:21]([NH:2][C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5])=[S:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=S)N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The process is performed as in Example 2, starting with 5.65 g of (2S)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride, 3.7 cm3 of tert-butyl isothiocyanate and 3.41 cm3 of triethylamine in 60 cm3 of ethanol, After stirring for 3 days at a temperature in the region of 20° C. and then heating for 30 minutes at a temperature in the region of 60° C., 3.7 cm3 of tert-butyl isothiocyanate are added to the reaction medium and heating is then continued for a further 3 hours at the same temperature. After an identical work-up, 6.45 g of N-(tert-butyl)-N′-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea are obtained in the form of a yellow foam. (Rf=0.61 in a 40/5/0.5 by volume mixture of dichloromethane/methanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=O.C(O)(=O)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]2[CH2:37][O:38][CH2:39][C:40]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:41])(=[O:30])=[O:29])=[C:23]([CH3:48])[CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[NH:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][C:6]=1[CH2:7][N:45]1[CH2:46][CH2:47][N:42]([C:40](=[O:41])[CH2:39][O:38][CH2:37][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][N:31]2[S:28]([C:24]2[C:23]([CH3:48])=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=2[CH3:27])(=[O:29])=[O:30])[CH2:43][CH2:44]1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(Cc3nc(-c4ccccc4)[nH]c3Cl)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
4-Chloro-2-phenyl-1H-imidazole-5-carbaldehyde (1.5 eq.) and acetic acid (cat.) were added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone (1 eq.) in dichloromethane (25 ml/mmol). The reaction mixture was stirred for 30 min. at 25° C., then sodium triacetoxyborohydride (4 eq.) was added and stirring was carried out for a further 16 h at 25° C. The mixture was diluted with dichloromethane and washed with saturated bicarbonate solution and saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography using 3% methanol in ethyl acetate. Yield: 50%; MS, m/z 630.2 (MH+)
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([CH2:13][NH:14][C:15]([CH:17]2[CH2:22][CH2:21][N:20]3[C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=[C:19]3[CH2:18]2)=O)=[N:9][CH:10]=[CH:11][N:12]=1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Cl:6][C:7]1[C:8]2[N:9]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]4[C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=[C:19]4[CH2:18]3)=[N:14][CH:13]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=C(NCc1nccnc1Cl)C1CCn2c(nnc2C(F)(F)F)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: FC(F)(F)c1nnc2n1CCC(c1ncc3c(Cl)nccn13)C2
Temperature: 70 °C
Yield: 44.7 %

Procedure:
POCl3 (1.7 g, 11.09 mmol) was added dropwise to a solution of N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (800 mg, 2.218 mmol) in CH3CN (4.4 mL) at 0° C., then DMF (0.11 mL) was added dropwise for 5 minutes at 0° C. The reaction was heated at 70° C. for overnight The reaction was poured into ice-water, then neutralized with aq. Na2CO3 to adjust to pH=8. The resulting mixture was extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/THF=100/20) to afford 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (0.34 g, yield 44%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH2:18]([O:20][CH:21]([O:29][CH2:30][CH3:31])[C:22]1[S:26][CH:25]=[C:24]([CH:27]=O)[CH:23]=1)[CH3:19]>C1COCC1>[CH2:18]([O:20][CH:21]([O:29][CH2:30][CH3:31])[C:22]1[S:26][CH:25]=[C:24](/[CH:27]=[CH:3]/[C:1]#[N:2])[CH:23]=1)[CH3:19]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(OCC)c1cc(C=O)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(/C=C/C#N)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (100 mg, 0.0008 mol) in THF (2 mL, 0.02 mol) cooled at 0° C. and 1.0 M potassium tert-butoxide in THF (0.8 mL) was added dropwise. The bath was removed and the reaction was warmed to room temperature for 30 minutes. The reaction was cooled to 0° C. and a solution of 5-(diethoxymethyl)thiophene-3-carbaldehyde (170 mg, 0.00079 mol) in THF (2 mL, 0.02 mol) was added drop wise. The reaction was stirred overnight at room temperature. The reaction was partitioned between water and ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (ethyl acetate:hexane, 1:5) to give (2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile as an oil (160 mg, 84.9%). 1H NMR (300 MHz, CDCl3): δ 7.4-7.0 (m, 3H), 5.65 (m 1H), 4.2 (m, 1H), 3.65 (m, 4H), 1.25 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[O-].[Na+].[C:7]([O:13]C)(=O)[C:8]([O:10][CH3:11])=[O:9].P(=O)(O)(O)O>CO>[CH3:1][N:2]([CH3:3])[C:7](=[O:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: CNC
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 1,000 mL reactor are added at 0° C., 360 g (4 mol) of dimethylamine (DMA) solution at 50% by weight in methanol and 43.2 g (0.2 mol) of sodium methylate at 25% by weight in methanol. To this mixture are added at 0-5° C. and within 1 hour, 472 g (4 mol) of dimethyl oxalate. The mixture is maintained with stirring and at 0° C. for 2 hours. The reaction medium is concentrated in vacuo (Pmax=200 mbars) for removing residual DMA and methanol and an 85% orthophosphoric acid solution (23 g 0.2 mol) is then added. The salts formed are filtered and then the filtrate is distilled in vacuo (Tbp=68-70° C., P<1 mbar) in order to recover the desired product (461 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=O.[C:15]([NH2:18])(=[S:17])[CH3:16]>C(O)C>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([C:3]2[N:18]=[C:15]([CH3:16])[S:17][CH:2]=2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: CC(N)=S
Solvent: CCO
Product: COc1ccc(-c2csc(C)n2)cc1OC
Yield: 99.6 %

Procedure:
Ex-69A: A solution of 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone (0.62 g, 2.39 mmol) and thioacetamide (0.18 g, 2.39 mmol) in ethanol (30 mL) was refluxed for 2 hours and the solvent was removed under reduced pressure. The product, 4-(3,4-dimethoxy-phenyl)-2-methyl-thiazole (0.56 g, 100%) was obtained as a white solid and used without further purification. To a suspension of 4-(3,4-dimethoxy-phenyl)-2-methyl-thiazole obtained above (0.70 g, 2.97 mmol) in dichloromethane (60 mL) at 0° C. was added dichloromethyl methyl ether (0.40 mL, 4.46 mmol) followed by addition of titanium tetrachloride (1.0 M solution in dichloromethane, 8.9 mL, 8.9 mmol) dropwise. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. The aqueous solution was extracted with dichloromethane. The solution of dichloromethane was washed with hydrochloric acid (0.5M), saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The product, 2,4-dimethoxy-5-(2-methyl-thiazol-4-yl)-benzaldehyde, was obtained as a white solid. 1H NMR (CDCl3) δ 10.33 (s, 1H), 8.67 (s, 1H), 7.56 (s, 1H), 6.52 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 2.75 (s, 3H).