Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([C:34]2[N:35]=[N:36][S:37][CH:38]=2)[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([C:34]2[N:35]=[N:36][S:37][CH:38]=2)[CH:27]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1-c1csnn1
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1csnn1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-(1,2,3-thiadiazol-4-yl)phenyl)methanamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.66 (6H, s, 2×CH3), 4.02 (4H, m, 2×CH2), 4.57 (2H, d, J=6.6 Hz, NCH2), 5.32 (2H, s, OCH2), 7.18 (1H, m, aromatic), 7.27–7.34 (4H, m, aromatics), 7.54 (2H, m, aromatics), 7.74 (1H, dd, J=6.2 Hz and J=8.6 Hz, aromatic), 8.71 (1H, s, CH), 8.80 (1H, broad t, NH). HRMS (ESI+) calculated for C26H25FN5O4S [M+H+]: 522.1611. Found: 522.1601.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][CH:2]=1.[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20](=[O:23])[CH2:21]Br)([O-:16])=[O:15]>CN(C=O)C>[N+:14]([C:17]1[CH:18]=[C:19]([C:20](=[O:23])[CH2:21][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2]2)[CH:24]=[CH:25][CH:26]=1)([O-:16])=[O:15]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: O=c1[nH]cnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1cnc2ccccc2c1=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4(3H)-quinazolinone (2.19 g, 15.0 mol) in anhydrous DMF (10 mL) was added NaH (60% dispersion in mineral oil, 0.719 g, 18.0 mmol) in two portions with caution. The mixture was stirred at rt for 30 min. 3-Nitrophenacyl bromide (4.39 g, 18.0 mmol) was added and the resulting suspension was stirred at rt for 16 h. Solvent was removed under reduced pressure. To the residue were added water (10 mL) and 4 N HCl (aq) to adjust the pH to ≈6. The solid material was collected by filtration, washed with water (20 mL) and dichloromethane (3×20 mL) to afford the title compound as a white powder. 1H-NMR (CD3OD, 400 MHz): δ=5.70 (d, J=10.0 Hz, 2H), 7.60 (d, J=7.2 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.86-7.91 (m, 2H), 8.25 (d, J=8.0 Hz, 1H), 8.30 (s, 1H), 8.51-8.58 (m, 2H), 8.90 (t, J=1.2 Hz, 1H). MS (ES+): m/z 310.06 [MH+]. HPLC: tR=2.90 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 76, 45.0 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (81%) of the title compound as a pale-yellow solid.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O>[CH3:6][NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH3:23])=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: CCOc1ccc(N2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(N2CCC(CNC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
[1-(4-Ethoxy-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (963 mg, 2.88 mmol, prepared in accordance with Example 106) is added to a molar solution of lithium aluminium hydride in tetrahydrofuran (10 mL, 10 mmol) and the resulting mixture is refluxed for 2 hours. After cooling with an ice bath, water (1 mL) is added carefully and the mixture is stirred overnight at room temperature. The reaction is then filtered and the filtrate is concentrated under reduced pressure. The residue obtained is dried under high vacuum to afford the desired product (701 mg; 2.83 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH:13]([C:14]([O:16]CC)=[O:15])[CH:8]1[CH2:7][CH2:6]2.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH:8]1[CH2:7][CH2:6]2
Reactant: CCOC(=O)C1C2CCc3cc(OC)ccc3C21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCC1C(C(=O)O)C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate (0.2 g, 0.8 mmol) was dissolved in 2 ml of methanol and the solution of sodium hydroxide (0.2 g, 50 mmol) in 2 ml of water was added to the reaction mixture and stirred at ambient temperature overnight. The extraction of basic reaction mixture into hexane showed that no starting material present. The reaction mixture was acidified with excess of 3M HCl solution (pH=1), and extracted into ethylacetate (3×15 ml). The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated by rotary evaporation to give 0.1 5 g of mixture of cis/trans acids as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][C:11]([CH3:18])=[CH:12][C:13](OCC)=[O:14].S(=O)(=O)(O)O.CCOCC>C1C=CC=CC=1>[CH3:10][C:11]1([CH3:18])[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=2[CH3:8])[O:9][C:13](=[O:14])[CH2:12]1
Reactant: Cc1cc(C)cc(O)c1
Reactant: CCOC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)c2c(c1)OC(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
3,5-Dimethylphenol (IIa) (3.2 g, 26.2 mmol), ethyl 3,3-dimethylacrylate (5 mL, 36 mmol, 1.4 eq.) and concentrated sulfuric acid (1.5 mL) were dissolved in anhydrous benzene (30 mL), and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and washed successively with water (2×40 mL), 5% aqueous NaHCO3 solution (2×20 mL), brine (2×20 mL) and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under vacuum to obtain a dark brown gummy material. To this gummy material was added anhydrous ether (5 mL) and boiled for 2 min on a steam bath. The title compound, IIIa, (3.34 g, 16.4 mmol, Y: 62.4%) was crystallized out from the mixture upon cooling in an ice bath; mp, 95.8-96.3° C.; 1H-NMR (300 MHz, acetone-d6) δ ppm: 1.41 (6H, s, 4,4-Me2), 2.24 (3H, s, 5-Me), 2.46 (3H, s, 7-Me), 2.61 (2H, s, 3-H2), 6.68 (1H, s, Ar-H), 6.76 (1H, s, Ar-H); MS (Isobutane-DCI) m/e: 205 (M+H)+ ; IR (KBr) ν max: 1770, 1250, 1190, 870 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=O.[CH3:7][C:8]([CH3:10])=[O:9]>[O-2].[Zn+2]>[CH3:1][C:2](=[CH:3][CH:4]=[CH:7][C:8](=[O:9])[CH3:10])[CH3:6]
Reactant: CC(C)=CC=O
Reactant: CC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)C=CC=C(C)C
Temperature: 180 °C
Yield: 93 %

Procedure:
A mixture of 50 parts of 3,3-dimethylacrolein, 100 parts of acetone and 12 parts of zinc oxide is heated for 3 hours at 180° C and a pressure of 45 atmosphere in a vibrated autoclave. The reactor is then cooled and the mixture is fractionally distilled. 52.5 parts of 2-methyl-2,4-heptadien-6-one is obtained in a yield of 93% of theory based on 3,3-dimethylacrolein at a conversion 76% of theory and with a boiling point of 92° C at 15 mm Hg.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:37]=[CH:36][C:19]3[N:20]([CH2:27][CH:28]4[CH2:33][CH2:32][C:31]([F:35])([F:34])[CH2:30][CH2:29]4)[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:22][C:18]=3[CH:17]=2)(=[O:15])=[O:14])[CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[C:23]([C:21]1[N:20]([CH2:27][CH:28]2[CH2:29][CH2:30][C:31]([F:34])([F:35])[CH2:32][CH2:33]2)[C:19]2[CH:36]=[CH:37][C:16]([S:13]([N:10]3[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]3)(=[O:15])=[O:14])=[CH:17][C:18]=2[N:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@H](N)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 112, step B, using tert-butyl[(3S)-1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)pyrrolidin-3-yl]carbamate (2.8 g, 5 mmol) (see the following step B for preparation), and 4N HCl in dioxane (50 mL). Yield: 2.0 g (82%). 1H NMR (400 MHz, METHANOL-D4) δ 1.45-1.56 (m, 3 H), 1.63 (s, 9 H), 1.65-1.80 (m, 4 H), 1.94-2.05 (m, 2 H), 3.10-3.18 (m, 1 H), 3.33-3.42 (m, 2 H), 3.46-3.54 (m, 1 H), 3.54-3.59 (m, 2 H), 3.70-3.80 (m, 1 H), 4.53 (d, J=7.23 Hz, 2 H), 7.96 (d, J=8.98 Hz, 1 H), 8.11 (d, J=8.98 Hz, 1 H), 8.16 (s, 1 H); MS (APPI) (M+H)+=455.3; Anal. Calc. for C22H32F2N4O2S+2.5HCl+1.2H2O: C, 46.57; H, 6.56; N, 9.88. Found: C, 46.73; H, 6.55; N, 9.40.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.O>N1C=CC=CC=1>[CH:18]1([C:21]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
A solution of 0.300 gm (1.30 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 40 mL pyridine was heated to 50° C. To this solution was added 0.13 mL (1.43 mMol) cyclopropanecarbonyl chloride and the reaction mixture was stirred for 1.5 hours. An additional 0.10 mL of cyclopropanecarbonyl chloride were added and the reaction mixture was stirred for an additional hour. The reaction mixture was treated with 1.0 mL of water and was then concentrated under reduced pressure. The residue was diluted with 3:1 chloroform:isopropanol and the solution washed sequentially with water, dilute aqueous sodium hydroxide, and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 1 mm), eluting with a gradient of dichloromethane (5-10% methanol) containing 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol/water to provide 0.22 gm (55.9%) of the title compound as a crystalline solid.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[OH:27][NH3+:28]>CO.C(O)C>[Cl:17][C:12]1[CH:11]=[C:10]([C@H:9]2[CH2:8][C@H:7]3[N:18]([CH3:19])[C@H:4]([CH2:5][CH2:6]3)[C@@H:3]2[CH:1]=[N:28][OH:27])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: [NH3+]O
Reactant: CN1[C@H]2CC[C@@H]1[C@H](C=O)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CN1[C@H]2CC[C@@H]1[C@H](C=NO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1R,2R,3S)-2-formyl-3-(3,4-dichlorophenyl)tropane (6.9 g, 23 mmol) in methanol (100 ml), sodium carbonate (4 g) and hydroxylammonium chloride (2.6 g, 37 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with water. A crude product was isolated by filtration and recrystallization first in a mixture of ethanol and water (1+1) and then in 99% ethanol yielded the title compound (mixture of syn/anti isomers--approximately 1+2) as white crystals, m.p. 230°-235° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D6) (1.20 g, 5.43 mmol) and cesium carbonate (1.77 g, 5.43 mmol) in DMF (10 ml) was sonicated for 15 minutes. Iodomethane (0.372 ml, 5.97 mmol) was added and the mixture was stirred at room temperature. After 1 hr more iodomethane (0.05 ml) was added and stirring was continued for a further 30 minutes. The solvent was evaporated, ethyl acetate and 2N HCl were added and the product was extracted into ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by trituration with ethyl acetate and/or chromatography on silica gel (elution with ethyl acetate) gave the title compound (D41). (1.042 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[C:9]=2[N:10]=1>CCS>[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:9]=2[N:10]=1
Reactant: COc1cccc2sc(N)nc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: Nc1nc2c(O)cccc2s1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A solution of AlCl3 (5 mmole) in EtSH (10 mL) was cooled to 0° C. and treated with 2-amino-4-methoxybenzothiazole (1 mmole). The mixture was stirred at 0-5° C. for 2 h. Evaporation and extraction gave 2-amino-4-hydroxybenzothiazole as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[C:18](=[O:19])[N:17]4[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:16]4=[N:15][CH:14]=3)=[N:9]2)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Br.[CH:42]([C:45]1[N:46]=[C:47]([NH2:50])[S:48][CH:49]=1)([CH3:44])[CH3:43].Cl>CN(C)C=O>[CH:42]([C:45]1[N:46]=[C:47]([NH:50][C:24]([C:22]2[CH:21]=[CH:20][N:17]3[C:18](=[O:19])[C:13]([C:10]4[N:11]=[N:12][N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=5)[N:9]=4)=[CH:14][N:15]=[C:16]3[CH:23]=2)=[O:25])[S:48][CH:49]=1)([CH3:44])[CH3:43]
Reactant: CC(C)c1csc(N)n1
Reactant: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)O)ccn4c3=O)n2)cc1
Agent: Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)Nc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
3-[2-(4-Methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4-oxo-4H-pyrido[1,2-a]-pyrimidine-8-carboxylic acid (250 mg, 0.66 mmol) was dissolved in dimethylformamide (6 ml), added with N,N-carbonylbis-1H-imidazole (abbreviated as “CDI” hereinafter, 160 mg, 0.991 mmol) and heated to 90° C. with stirring. After 1 hour and 30 minutes, the reaction solution was further added with CDI (170 mg), further stirred for 1 hour, and then further added with CDI (170 mg). The reaction solution was stirred further 2 hours, then returned to room temperature, added with 4-isopropyl-1,3-thiazol-2-amine hydrobromide (1.32 mmol) and stirred at room temperature for 2 hours and 30 minutes. The reaction solution was added with 2 N hydrochloric acid (7 ml), and the deposited crystals were collected by filtration and washed with water. The resulting yellow crystals were dissolved in chloroform and washed with saturated brine, and the collected organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound as yellow crystals without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.[CH3:9][N:10]=[C:11]=[O:12]>ClCCl>[CH3:9][NH:10][C:11]([S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)=[O:12]
Reactant: S=c1ncc(Cl)c[nH]1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Sc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (3 mmol) and methylisocyanate (4 mmol) in dichloromethane (15 ml) was stirred at room temperature for 2 h, the solvent was then distilled off and the residue was crystallised from CHCl3 : Pet. ether; yield 85%, m.p. 115° C. 1H NMR (CDCl3) δ3.03 (Me), 8.62 (H-4, H-6).
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2([CH2:18][CH3:19])[CH2:17][O:16][CH2:15]2)=[CH:4][CH:3]=[C:2]1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.C([Li])CCC.C(O[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1)(C)C>C1COCC1>[CH2:18]([C:14]1([CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]2[S:1][C:2]([C:20]3[S:21][C:22]([B:34]4[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]4)=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[CH2:17][O:16][CH2:15]1)[CH3:19]
Reactant: CCC1(COCCCCCCc2ccc(-c3cccs3)s2)COC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)s3)s2)COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a stirred solution of 3-(6-[2,2′]bithiophenyl-5-yl-hexyloxymethyl)-3-ethyl-oxetane (6.0 g, 16.46 mmol) in anhydrous THF (100 ml) was added n-butyllithium (2.5 M in hexanes, 7.0 ml, 17.50 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.26 g, 17.5 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. NH4Cl, and the reaction mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water, brine, and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1 to 4:1), to give 2-{5′-[6-(3-ethyl-oxetan-3-ylmethoxy)hexyl]-[2,2′]bithiophenyl-5-yl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as a blue oil (4.53 g, 56%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.49 (d, J=3.6 Hz, 1H, Ar—H), 7.14 (d, J=3.6 Hz, 1H, Ar—H), 7.03 (d, J=3.6 Hz, 1H, Ar—H), 6.66 (d, J=3.6 Hz, 1H, Ar—H), 4.43 (d, J=5.8 Hz, 2H, OCH2), 4.34 (d, J=5.8 Hz, 2H, OCH2), 3.48 (s, 2H, OCH2), 3.42 (t, J=6.6 Hz, 2H, OCH2), 2.76 (t, J=7.5 Hz, 2H, ArCH2), 1.32-1.75 (m, 22H, CH2 and CH3), 0.86 (t, J=7.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 144.8 (quat.), 143.7 (quat.), 137.0 (CH), 133.7 (quat.), 124.0 (CH), 123.1 (CH), 123.0 (CH), 83.1 (quat.), 77.5 (OCH2), 72.4 (OCH2), 70.4 (OCH2), 42.4 (quat.), 31.5 (CH2), 30.5 (CH2), 29.1 (CH2), 28.4 (CH2), 27.8 (CH2) 25.8 (CH2), 24.9 (CH3), 8.3 (CH3); MS (m/e): 490 (M+, 16%) □305 (79), 223 (25), 205 (100).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH3:13])=[C:6]([S:14][CH3:15])[S:5][C:4]=1[C:16]#[N:17])[CH3:2].S(=O)(=O)(O)[OH:19]>>[CH2:1]([C:3]1[C:7]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH3:13])=[C:6]([S:14][CH3:15])[S:5][C:4]=1[C:16]([NH2:17])=[O:19])[CH3:2]
Reactant: CCc1c(C#N)sc(SC)c1-c1oncc1C
Reactant: O=S(=O)(O)O
Product: CCc1c(C(N)=O)sc(SC)c1-c1oncc1C
Temperature: 60 °C
Yield: 42 %

Procedure:
To 3-ethyl-4-(4-methylisoxazol-5-yl)-5-(methylthio)thiophene-2-carbonitrile (0.87 g, 3.3 mmol) was added conc. sulfuric acid (11 ml) and the mixture was heated at 60° C. for 1.5 hours. The reaction solution was allowed to cool down to room temperature, ice was added and then the mixture was extracted with ethyl acetate. The organic layer was washed (with water, saturated aqueous sodium hydrogen-carbonate and saturated aqueous sodium chloride, in turn), dried (over anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing solvent: chloroform/ ethyl acetate=1:0-3:1) and recrystallized from diethyl ether to afford 3-ethyl-4-(4-methylisoxazol-5-yl)-5-(methylthio)thiophene-2-carboxamide (0.39 g, 42%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:15][O-:16].[Na+]>>[CH3:15][O:16][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: [Na+]
Product: COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reaction time: 15 h

Procedure:
A mixture of 5-chloro-2-nitrobenzotrifluoride (5 g, 22.2 mmol) and 0.5M NaOMe (in MeOH) is stirred for 15 h at reflux. After removal of the solvent, the residue is diluted with H2O (40 mL) and extracted with CH2Cl2 (3×150 mL). The organic phase is washed with H2O (30 mL), and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound: ES-MS: 221.0 [M]−; single peak at tR=4.72 min (System 2).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH2:17]>N1C=CC=CC=1>[CH3:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][NH:17][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: CC(CN)c1ccccc1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Product: CC(CNC(=O)c1cnc2ccccc2n1)c1ccccc1
Yield: 69.5 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 0.84 mmol), β-methylphenethylamine (103 mg, 0.76 mmol), and pyridine (2 mL) yielding 154 mg (69%) of (131):