Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2NC1C=CC(C(NC2CCN(CC3C=CC=CC=3)CC2)=O)=CC=1.FC(F)(F)C1C=C(C[N:48]2CCC(N)CC2)C=CC=1.FC(F)(F)C1C=C(C=CC=1)CCl.O1C2(CCNCC2)OCC1.O>>[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:8]=[C:9]([C:13]([NH2:48])=[O:15])[CH:10]=1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Reactant: NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Agent: C1CC2(CCN1)OCCO2
Agent: FC(F)(F)c1cccc(CCl)c1
Solvent: O
Product: NC(=O)c1cnc2ccccc2c1

Procedure:
8-Methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-3-quinolinecarboxamide was prepared as a hygroscopic solid (0.46 hydrate) by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinamine as described for Example 17, Step 5. 1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinamine can be prepared from 3-(triflouromethyl)benzyl chloride and 1,4-dioxa-8-azaspiro[4.5]-decane as described in U.S. Pat. Nos. 3,875,165 and 4,816,464: mp 132°-138° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.48 (s, 1 H), 8.76 (s, 1 H), 8.39 (d, J=7.6 Hz, 1 H), 7.97 (d, J=7.8 Hz, 1 H), 7.68 (d, J=8.7 Hz, 2 H), 7.10-7.65 (m, 12 H), 6.87 (d, J=8.7 Hz, 2 H), 3.94 (s, 3 H), 3.62-3.80 (m, 1 H), 3.35-3.60 (m, 5 H), 2.6-2.9 (m, 4 H), 1.95 (m, 4 H), 1.3-1.8 (m, 8 H); Karl Fischer, 0.46 moles of H2O.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH2:38][F:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:37][CH2:38][F:39])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: FCCBr
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OCCF)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-2-fluoro-ethane
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]3[N:15]([CH3:24])[C:16](=[O:23])[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]3=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl[C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27].C(N(C(C)C)CC)(C)C>C1COCC1.CO>[CH3:22][C:19]([CH3:21])([CH3:20])[CH2:18][N:17]1[C:12]2[C:13](=[N:14][C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][C:26](=[O:27])[O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:10][CH:11]=2)[N:15]([CH3:24])[C:16]1=[O:23]
Reactant: CC(C)COC(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(CN)c3)nc21
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)NCc1cccc(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a microwave vial, 5-[3-(aminomethyl)phenyl]-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (23-1) (15 mg, 0.05 mmol) was added under nitrogen and dissolved in THF (0.25 ml). Isobutyl chloroformate (4.4 mg, 0.055 mmol) was added followed by diisopropyl ethyl amine 9 mg, 0.07 mmol). The reaction was allowed to stir for 2 hours at room temperature. The reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-methylpropyl {3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]benzyl}carbamate (23-2). HRMS (M+H)+: observed=425.2549, calculated=425.2547.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=O)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:33][NH:34][CH3:35]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:34]([CH3:35])[CH3:33])=[O:24])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1
Agent: Cl
Product: CN(C)C(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1

Procedure:
1-Cyclohexyl-6-[(5-(methoxycarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is reacted according to general operating instructions 7 with dimethylamine hydrochloride. 1-Cyclo-hexyl-6-[(5-((N,N-dimethylamino)carbonyl)pentyl)oxy]-2-phenyl-benzimidazole is obtained as a solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2cncc(/C=C/Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cncc(CCCc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 49.3 %

Procedure:
Part B. To a solution of 4-methyl-2-[6-((E)-3-phenyl-propenyl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (39 mg, 0.09 mmol, 1.0 equiv) in ethyl acetate was added Pd/C (15 mg, 10%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 60 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by prep HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 4-methyl-2-[6-(3-phenyl-propyl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (19 mg, 60%). 1H NMR (400 MHz, CD2Cl2) δ 9.14 (s, 1H), 9.12 (s, 1H), 7.14-7.36 (m, 10H), 6.23 (bs, 1H), 4.59 (d, J=8.0 Hz, 2H), 2.86 (t, J=8.0 Hz, 2H), 2.72 (s, 3H), 2.69-2.72 (m, 2H), 2.07-2.15 (m, 21-1); HRMS (M+H)+=429.17.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]1[CH2:11][CH:10]1[C:12](=[O:14])[CH3:13].[BH4-].[Na+].Cl>C(O)C>[CH3:15][C:2]1([CH3:1])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]1[CH2:11][CH:10]1[CH:12]([OH:14])[CH3:13]
Reactant: CC(=O)C1CC1CC1CC=C(C)C1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1=CCC(CC2CC2C(C)O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
1.5 g (7.3 mmol) of 1-[2-(2,2,3-trimethylcyclopent-3-enylmethyl)cyclopropyl]-ethanone dissolved in 5 ml of ethanol was added to a suspension of 0.50 g (13 mmol) of sodium borohydride in 30 ml of the same solvent under nitrogen at 5° C. The reaction mixture was stirred at room temperature for further 2 hours. After addition of 50 ml of 1N aqueous hydrochloric acid it was extracted with 200 ml of MTBE, the organic layer washed with 2×100 ml of brine, dried (MgSO4) evaporated in vacuo and bulb-to-bulb distilled to give 1.3 g of 1-[2-(2,2,3-trimethylcyclopent-3-enylmethyl)cyclopropyl]ethanol (87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:21][C:20]3[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Reactant: OCc1c(F)cccc1F
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cccc3F)cc2)C1

Procedure:
In an analogous manner to that described in Example 28b), the alkylation of the (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 28a)] with 2,6-difluorobenzylalcohol yields the (R)-1-[4-(2,6-difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=362 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[NH2:44][C:45]1[S:46][C:47]([CH3:50])=[N:48][N:49]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:44][C:45]2[S:46][C:47]([CH3:50])=[N:48][N:49]=2)=[O:42])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1nnc(N)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C)s4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-methyl-1,3,4-thiadiazole (47 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 49 mg of the title compound.
Reaction SMILES: C=O.[C:3](=O)([O-])O.[Na+].[Br-].[C:9]1([CH2:15][C:16]([NH:18][C@@H:19]2[C:54](=[O:55])[N:21]3[C:22]([C:46]([O:48][CH2:49][C:50]([Cl:53])([Cl:52])[Cl:51])=[O:47])=[C:23]([CH2:26][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:24][S:25][C@H:20]23)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:9]1([CH2:15][C:16]([NH:18][C@@H:19]2[C:54](=[O:55])[N:21]3[C:22]([C:46]([O:48][CH2:49][C:50]([Cl:51])([Cl:53])[Cl:52])=[O:47])=[C:23]([CH:26]=[CH2:3])[CH2:24][S:25][C@H:20]23)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])O
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: C=O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.42 h
Yield: 9 %

Procedure:
40%-Formaldehyde solution (3 ml.) and 4%-sodium hydrogen carbonate solution (6 ml.) were added to a solution of [7β-Phenylacetamido-4-(2,2,2-trichloroethoxycarbonyl)ceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (403 mg., 0.5 mmole) in methylene chloride (10 ml.), and the two phase mixture was stirred vigorously for 25 minutes. The organic phase was washed with 2N-hydrochloric acid and water (10 ml of each), dried (MgSO4), and evaporated to an orange oil which was crystallised from ethanol (ca. 2 ml.) to give the title ester (22 mg., 9%), λmax. (EtOH) 297 nm (ε 14,100).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:22])[O:5][C:6]1[C:7]([N+:19]([O-])=O)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.O>C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][CH:4]([CH3:22])[O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCC(C)Oc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1N
Temperature: 100 °C
Yield: 64 %

Procedure:
3-(2-Methoxy-1-methyl-ethoxy)-2-nitro-5-phenoxy-pyridine (0.4 mmol) is dissolved in acetic acid (1.5 ml). After addition of water (1.5 ml), zinc powder (6 eq.) is added and the reaction suspension is heated to 100° C. for 90 minutes. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are extracted with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-ylamine is obtained as yellow powder in a yield of 64%. HPLC (method C): 1.51 min, LC-MS (method A): 0.923 min, 275.15 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccccc1)C(C)(C)C
Temperature: 5 °C
Yield: 91 %

Procedure:
Diisopropylamine (5.6 ml) was dissolved in tetrahydrofuran (56 ml), butyllithium (1.6M hexane solution, 25 ml) was added dropwise thereto at 5° C. with stirring under a nitrogen atmosphere, and the resulting mixture was stirred for 15 minutes. The reaction mixture was cooled to -70° C., and 3,3-dimethylbutyric acid ethyl ester (6.7 ml) was added dropwise thereto, followed by stirring of the resulting mixture for 10 minutes. Then, benzoyl chloride (2.3 ml) was added dropwise to the reaction mixture and the resulting mixture was stirred at the same temperature for 10 minutes. After the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to obtain the title compound (4.5 g, 91%) as a colorless oil.
Reaction SMILES: C([O:9][CH2:10][C:11]1[C:12]2[N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]3)[S:18][C:13]=2[N:14]=[C:15]([CH3:17])[N:16]=1)(=O)C1C=CC=CC=1.O(C)[Na].Cl.CCOC(C)=O>CO>[CH3:27][C:24]1([CH3:28])[CH2:23][CH2:22][CH:21]([C:19]2[S:18][C:13]3[N:14]=[C:15]([CH3:17])[N:16]=[C:11]([CH2:10][OH:9])[C:12]=3[N:20]=2)[CH2:26][CH2:25]1
Reactant: Cc1nc(COC(=O)c2ccccc2)c2nc(C3CCC(C)(C)CC3)sc2n1
Agent: CO[Na]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(CO)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a mixture of [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methyl benzoate (13.8 g) and MeOH (250 mL) was added a 28% NaOCH3 solution (670 μL) in MeOH, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized by the addition of 4 M HCl/EtOAc (870 μL), and concentrated under reduced pressure. To the residue was added water, followed by extraction with EtOAc. To the organic layer were added MgSO4 and basic silica gel, followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methanol (7.9 g).
Reaction SMILES: CNC(NC)=O.[P:7]([O:16]CCCl)([O:12]CCCl)[O:8]CCCl.C(C(CCCC)C=O)C.ClCCOP1(=O)[CH:37]([CH:38]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40])[N:36]([CH3:45])[C:35](=[O:46])[N:34]1[CH3:47]>C1CCCCC1.O>[CH3:45][N:36]([CH:37]([P:7](=[O:8])([OH:12])[OH:16])[CH:38]([CH2:39][CH3:40])[CH2:41][CH2:42][CH2:43][CH3:44])[C:35]([NH:34][CH3:47])=[O:46]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: CCCCC(CC)C1N(C)C(=O)N(C)P1(=O)OCCCl
Agent: CCCCC(C=O)CC
Agent: CNC(=O)NC
Solvent: O
Solvent: C1CCCCC1
Product: CCCCC(CC)C(N(C)C(=O)NC)P(=O)(O)O

Procedure:
A mixture of 88.1g (1.0 mole of 1,3-dimethylurea, 269.5g (1.0 mole) of tris(2-chloroethyl) phosphite, and 135g (1.05 moles) of 2-ethylhexaldehyde is warmed at 105°-110° for 2 hr, giving a clear colorless solution containing 2-(2-chloroethoxy)-1,4-dimethyl-3-(3-heptyl)-1,4,2-diazaphospholidin-5-one-2-oxide, as an intermediate ester product, 31P nmr-30.8. Four-fifths of the reaction mixture is dissolved in 200ml of cyclohexane containing 34.5g of H2O, and the mixture is warmed at 82° for 0.5 hr. Filtration after cooling, and extraction of the solid with hot acetonitrile gives 54.7g of white solid (100.8g more separates from the filtrate while standing); mp 184-186° dec; 31P nmr (CD3SOCD3) -23.5 ppm(m); 1H nmr δ 9.8 (broad, 2, OH), 4,4 (d of d, 1, J = 10 and 20Hz, PCH), 2.7 (s, 3, NCH3), 2.5 (s, 3, NCH3), 0.5 - 2.0 (broad, 15, hexyl); acidity 1.985 equiv/mole, pK1 = 1.76, pK2 = 5.29.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([CH:18]=[CH2:19])[CH:12]=1>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N+:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH3:10])=[CH:12][C:13]=1[CH:18]=[CH2:19]
Reactant: C=Cc1cc(C)cc(C)n1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C=Cc1cc(C)cc(C)[n+]1C

Procedure:
Trimethyloxonium tetrafluoroborate (0.50 g; 3.76×10-3 mol) is added in one portion to a solution of 4,6-dimethyl-2-vinylpyridine (0.61 g; 4.13×10-3 mol) in 4.0 ml of methylene chloride under an inert atmosphere. The suspension is left to react for 2 h at 25° C. The suspension is filtered and the product is dried under vacuum. Yield=0.162 g (18%), white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[F:10][C:11]1[C:12]([NH2:19])=[C:13]([NH2:18])[CH:14]=[C:15]([F:17])[CH:16]=1>>[NH2:19][C:12]1[C:11]([F:10])=[CH:16][C:15]([F:17])=[CH:14][C:13]=1[NH:18][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1cc(F)cc(F)c1N
Product: Cc1cscc1NC(=S)Nc1cc(F)cc(F)c1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3,5-difluoro-1,2-diaminobenzene. Crystalline solid, 1st melting point: 178-182° C., another crystallization with 2nd m.p.: 299-301° C.
Reaction SMILES: C(N(CC)[C:4]1[CH:9]=[CH:8]C=CC=1)C.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]CC(C)=C)[C:14]=1[CH3:24].[C:25](OCC)(=O)C>>[Cl:12][C:13]1[C:14]([CH3:24])=[C:15]([OH:19])[C:16]([CH2:25][C:9]([CH3:8])=[CH2:4])=[CH:17][CH:18]=1
Reactant: CCN(CC)c1ccccc1
Reactant: CCOC(C)=O
Reactant: C=C(C)COc1cccc(Cl)c1C
Product: C=C(C)Cc1ccc(Cl)c(C)c1O
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of N,N-diethylaniline (12.1 mL) containing 1-chloro-2-methyl-3-[(2-methylprop-2-en-1-yl)oxy]benzene (3.00 mg, 15.3 mmol) synthesized in Reference Example 153 was reacted under microwave irradiation at 220° C. for 20 minutes. After cooled to room temperature, the reaction solution was diluted with ethyl acetate, and washed serially with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated saline. It was dried using anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. After that, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10:1) to give 2.89 g of the title compound as a yellow solid (yield: 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])(=[O:22])=[O:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O-])=O.[H][H]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])(=[O:22])=[O:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: [H][H]
Reactant: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc(N)c2)c1

Procedure:
The nitrobenzylindole (Example 3) (2.7 g) was dissolved in methanol (125 ml) and ethyl acetate (125 ml), and 10% palladium on charcoal (0.5 g) added. The reaction mixture was hydrogenated in a Parr bottle at 50 p.s.i. with shaking until hydrogen uptake was complete (approximately 1 hour). The catalyst was filtered off through Celite and the solvent removed in vacuo to give N-[1-(3-aminobenzyl)indol-5-ylcarbonyl]-2-methylbenzene sulphonamide as a foam. This crude product was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([NH:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[N:7]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(C(F)(F)F)cc2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile and 4-trifluoromethylbenzylamine in DME. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)OCC)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NC1C=CC=CC=1>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Nc1ccc(C(C)(C)C)cc1
Solvent: Nc1ccccc1
Solvent: CCO
Product: CC(C)(C)c1ccc(N)cc1
Temperature: 180 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A mixture of 110 parts of ethyl N-(4-tert.-butyl-phenyl)-carbamate, 370 parts of aniline and 700 parts of ethanol is heated to 180° C. in an autoclave and kept at this temperature for 6 hours. The mixture is then subjected to fractional distillation under reduced pressure. 60 parts (80% of theory) of 4-tert.-butylaniline, of boiling point 93°-94° C./4 mbar, are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=[O:21].[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:27]2[CH:28]=[CH:29][C:24]([CH:30]=[O:21])=[CH:25][CH:26]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCO)nc1
Reactant: Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCc1ccc(CCOc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g of 5-ethyl-2-pyridine ethanol, 10.2 ml triethylamine and 75 ml toluene are added to the round bottom assembly at ambient temperature. Thereafter 6.16 ml methane sulfonyl chloride are added via dropping funnel in 1 hour. The reaction mixture is stirred at ambient temperature for 1 hour and then washed with water. To the toluene layer are added 22.6 ml PEG200, 13.6 g potassium carbonate and 12 g 4-hydroxy benzaldehyde and the reaction mixture stirred for 4 hours at 80° C. The reaction mixture is cooled to ambient temperature and washed with 1 N alkali followed by water. Toluene is distilled off to obtain 4[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil to which are added methanol, pyrrolidine followed by 2,4-thiazolidinedione. The reaction mixture is stirred at 50° C. for 6 hours and then cooled to 10° C. Stirring is continued at 10° C. for 2 hours and the mixture filtered to obtain 5-[4[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methenyl-2,4-thiazolidinedione. The wet cake is washed with Methanol.