Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](S(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[NH2:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)S(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 15.5 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (4) (3 g, 16 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an inert atmosphere at 60° C. BSA (4.37 ml, 17 mmole) was added and the mixture was stirred for 10 minutes. 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (5.09 g, 16 mmole) and TMSTf (3.29 ml, 17 mmole) were added to the clear solution and the mixture was allowed to stir at 60° C. for 1 hr. The mixture was concentrated under reduced pressure and separated on a silica column to yield 1.14 g (15%) of 2-amino-5,6-dichloro-1-(2,3,5,tri-O-acetyl-β-D-ribofuranosyl) benzimidazole (43). 13C NMR (CDCl3): d 170.04ppm, 169.56, 169.11, 154.57, 141.64, 132.53, 125.90, 1123.45, 117.72, 109.49, 85.78, 80.99, 70.95, 69.83, 62.91, 20.74, 20.54, 20.20. 1H NMR (CDCl3): d 0.96 ppm (s, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 3.75 (m, 2H), 4.08 (dd, 1H), 5.00 (dd, 1H), 5.13 (t, 1H), 5.42 (s, 2H), 5.61 (d, 1H), 7.27 (s, 1H), 7.42 (s, 1H). MS (FAB): m/e 758, 718, 676, 460, 426, 259, 217, 139.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([N:40]3[CH2:45][CH2:44][C:43]([F:47])([F:46])[CH2:42][CH2:41]3)=[O:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:16][CH2:15]2)[C:10]1=[O:31].O.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([N:40]3[CH2:45][CH2:44][C:43]([F:47])([F:46])[CH2:42][CH2:41]3)=[O:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)N5CCC(F)(F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(c1ccc(-c2ccc(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
To a solution of (R)-3-[3-chloro-4′-(4,4-difluoro-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one (0.15 g) in THF (3 mL), add water (3 mL) and TFA 1 mL). Stir the mixture at room temperature for 5 hours. Partition the reaction with ethyl acetate and sodium bicarbonate (sat. solution), separate the organic layer, extract the aqueous with ethyl acetate again, combine the organic solutions, dry over sodium sulfate, filter and concentrate. Purify the residue on silica gel column with ethyl acetate for 30 minutes and then switch to 8% methanol in dichloromethane to afford 0.06 grams (52%) of the desired product as white solid. MS (m/z): 532 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH:11]=O)[C:7]([F:10])([F:9])[F:8])[CH3:2].[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([C@H:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.FC(F)(F)C1C=C([C@@H]2CO2)C=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH2:11][N:24]1[CH2:25][CH2:26][O:27][C@H:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=2)[CH2:23]1)[C:7]([F:10])([F:9])[F:8])[CH3:2]
Reactant: CCOC(=O)CC(C=O)C(F)(F)F
Reactant: FC(F)(F)c1cccc([C@@H]2CNCCO2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: FC(F)(F)c1cccc([C@@H]2CO2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CC(CN1CCO[C@H](c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A mixture of the unpurified racemic 4,4,4-trifluoro-3-formyl-butyric acid ethyl ester from above (step b), 0.498 g (2.15 mmol) of (R)-2-(3-trifluoromethyl-phenyl)-morpholine [prepared from (R)-2-(3-trifluoromethyl-phenyl)oxirane in a similar manner to that described in Example 4 (steps b-e)], 0.162 g (2.7 mmol) of acetic acid and 8 mL of dichloromethane was stirred at room temperature. After 30 min, 0.913 g (4.3 mmol) of sodium triacetoxyborohydride was added. The mixture was stirred overnight at room temperature and then diluted with ethyl acetate and washed successively with 0.5 M sodium carbonate solution, water and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexanes-ethyl acetate (90:10) to give 0.592 g (66%) of 4,4,4-trifluoro-3-[(R)-2-(3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-butyric acid ethyl ester as an oil. Used as is in the next step
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].Br[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21]>>[CH2:1]([C:3]1[N:4]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCC(Br)CC
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(CC)CC

Procedure:
Synthesized as described in Example 145B from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-bromopentane: MS (ESI): m/z 309 (M+1).
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]2[CH:8]=[C:9]([CH2:12][C:13]#[N:14])[CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1.Br[CH2:16][CH2:17]Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[S:3]1[C:7]2[CH:8]=[C:9]([C:12]3([C:13]#[N:14])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: ClCCBr
Reactant: N#CCc1ccc2ncsc2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc3ncsc3c2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
50% aqueous sodium hydroxide (1.51 mL) was added to a mixture of 1,3-benzothiazol-6-ylacetonitrile (586 mg, 3.36 mmol), 1-bromo-2-chloroethane (335 mg, 4.04 mmol), benzyltriethylammonium chloride (76.6 mg, 3.36 mmol) at 50° C. The reaction mixture was stirred at 50° C. for 3 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column with ethyl acetate in hexane from 0-30% to afford the desired product (157 mg, 24%). Analytical LCMS: (M+H)+=201.2.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:24]([C:23]3[CH:25]=[CH:26][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with 4-isopropylaniline as a mixture of cis and trans diastereomers. Light brown solid. MS (m/e): 288.1 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:38][C:34]1[CH:33]=[C:32]([C:22]2([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.4 %

Procedure:
N,N'-Carbonyldiimidazole (0.59 g) is added to a solution, cooled to +4° C., of (2-dimethylaminophenyl)acetic acid (0.65 g) in dry dichloromethane (20 cc). The mixture is stirred for 90 minutes at 25° C. and a solution of 7,7-bis(3-fluorophenyl)perhydro-4-isoindolone hydrochloride (1.3 g) and triethylamine (1.02 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 16 hours at 25° C. and washed with water (2×250 cc) and with saturated sodium chloride solution (250 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2.3 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55:45) and collecting 15-cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is solidified with isopropyl ether to give (3aRS,7aRS)-7,7-bis(3-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (0.6 g), the hydrochloride of which is prepared by dissolution in ethyl acetate (1 cc) and the addition of a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone hydrochloride (0.48 g) is obtained in the form of a white solid.
Reaction SMILES: FC(F)(F)C1C=CC(C([Cl:9])=O)=CC=1.C(N(CC)CC)C.CN(C(C1C=CC=CC=1)C1CCCCC1O)C.[OH-].[K+].[CH3:40][N:41]([CH:43]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[O:50][C:51](=[O:62])[C:52]1[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][CH:53]=1)[CH3:42]>C(Cl)Cl>[ClH:9].[CH3:42][N:41]([CH:43]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[O:50][C:51](=[O:62])[C:52]1[CH:53]=[CH:54][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:56][CH:57]=1)[CH3:40]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(c1ccccc1)C1CCCCC1O
Agent: CN(C)C(c1ccccc1)C1CCCCC1OC(=O)c1ccc(C(F)(F)F)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Reaction time: 15 h

Procedure:
1.34 g (6.43 mmole) of 4-(trifluoromethyl)benzoyl chloride were dissolved in 4 ml methylene chloride, and 870 mg (8.57 mmole) triethylamine were added at −10° C. (methanol/ice cooling bath). 1.0 g (4.29 mmole) 2-(dimethylaminophenylmethyl)cyclohexanol, dissolved in 2 ml methylene chloride, was then added dropwise, and the mixture was subsequently stirred for 15 hours. For working up, 2 ml potassium hydroxide solution (0.5 N) were added and the organic phase was separated, dried over sodium sulfate, filtered and concentrated on a rotary evaporator (500 to 10 mbar). 1.7 g of crude base were obtained. 877 mg of the hydrochloride of [2-(dimethylaminophenyl-methyl) cyclohexyl]4-trifluoromethylbenzoate (34% of theoretical) with a melting point above 230° C. were obtained from the crude base in accordance with Example 1 (4th stage) using chloro-trimethylsilane/water in 2-butanone.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:32][C@H:33]([C:39]([OH:41])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37].Cl>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:32][C@H:33]([C:39]([OH:41])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
Boc-Phe-Gly-Leu-Gln-NA was prepared by coupling Boc-Phe-Gly-Leu-OH (1.42 g, 3.25 mmol) to H-Gln-NA HCl (1.00 g, 3.25 mmol) by a mixed anhydride coupling procedure. A total of 10 mL DMF was used to dissolve H-Gln-NA HCl. During workup of the organic phase resulting from the mixed anhydride coupling procedure, some product crystallized and was separated, washed with water, and dried to yield 0.91 g of Boc-Phe-Gly-Leu-Gln-NA, mp 238°-239°. The remaining organic phase was washed with a saturated salt solution, and a second crop of crystalline product (0.62 g) was obtained, mp 238°-239°. A sample of the first crop was analyzed.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N=C=N.C([NH+](CC)CC)C.C(=O)([O-])[O-].[N-]=C=O>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:25][CH:22]4[CH2:24][CH2:23]4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1CC1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Agent: CC[NH+](CC)CC
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of 8.7 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 5.1 mg of cyclopropylamine, 4.1 mg of 1-hydroxybenzotriazole, 1 ml of DMF, and 28 μl of diisopropylethylamine was added 50 mg of polystyrene N-cyclohexylcarbodiimide-N′-propyloxymethyl (PS-Carbodiimide manufactured by Biotage), followed by stirring at room temperature for 16 hours. Subsequently, 1 ml of DMF, 50 mg of macroporious triethylammonium methylpolystyrene carbonate (MP-Carbonate manufactured by Biotage) and 50 mg of polystyrene methyl isocyanate (PS-Isocyanate manufactured by Biotage), followed by stirring at room temperature for 3 hours. The resin of the reaction mixture was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (high performance liquid chromatography) to obtain 8.7 mg of 8-(cyclohexylmethoxy)-N-cyclopropyl-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: C([Si](CCCC)(CCCC)O[C:7]1([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:11][C:10](=[O:13])[CH:9]=[CH:8]1)CCC.C(O)(=O)C.O>C(O)C.[Zn]>[F:15][C:14]([F:16])([F:17])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: CCCC[Si](CCCC)(CCCC)OC1(C(F)(F)F)C=CC(=O)C=C1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 24.7 %

Procedure:
A solution of 3.9 g (20 mmol) of 4-tri-n-butylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one in 10 mL of absolute ethanol was treated successively with 1.3 g (20 mmol) of zinc dust and 10 mL of a solution of 80% acetic acid - 20% water. The mixture was heated to reflux for one hour, allowed to cool to room temperature, and poured into 100 mL of water. The resulting aqueous mixture was extracted with three 50 mL portions of diethyl ether. Combination, drying (MgSO4), and concentration of the ether layers afforded a residue which purified by short path distillation at 5.0 torr. At 60°-65° C., 0.80 g (47% yield) of 4-trifluoromethylphenol was collected.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1CC(CC[Si](OC)(OC)OC)[CH2:5][CH2:6]2.COC([SiH3])(OC)OC.C1([Si](OC)(OC)OC)C=CC=CC=1.[C:38](O)(=O)[C:39]([OH:41])=[O:40]>CO.O>[C:39]([O:41][CH:6]([CH3:5])[CH2:7][O:1][CH3:2])(=[O:40])[CH3:38]
Reactant: CO[Si](CCC1CCC2OC2C1)(OC)OC
Reactant: O=C(O)C(=O)O
Agent: COC([SiH3])(OC)OC
Agent: CO[Si](OC)(OC)c1ccccc1
Solvent: O
Solvent: CO
Product: COCC(C)OC(C)=O
Temperature: 40 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
In a 1000 ml glass flask, to a mixture of 150 g of methanol, 22 g of 2-(3,4-epoxycyclohexyl) ethyl trimethoxy silane, 77 g of trimethoxymethyl silane, 14 g of phenyl trimethoxy silane, and 1.5 g of oxalic acid was added dropwise a mixed solution of 40 g of deionized water and 20 g of methanol at a liquid temperature of 40 degrees C. After that, this solution was stirred for 12 hours at 40 degrees C. After the reaction finished, the solvent was removed under a reduced pressure. Thus-obtained residue was dissolved in 1000 ml of ethyl acetate, and washed with deionized water for washing. After the water layer was separated, the organic layer was washed twice with deionized water. To this organic layer was added 600 g of propylene glycol monomethyl ether acetate (PGMEA), and the contents were heated up to a liquid temperature of 40 degrees C. under a reduced pressure to remove ethyl acetate and to give a PGMEA solution of a polymer.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:17][C:18]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1)=[O:19])(=[O:15])[CH3:14]
Reactant: COc1cccc2sc(N)nc12
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)COC(C)=O)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-4-methoxybenzothiazole (4.5 g) is dissolved in pyridine (80 ml) and thereto is added dropwise acetoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water and then with diethyl ether, dried and recrystallized from ethanol to give the title compound (4.3 g) having the following physical properties.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1.Cl[C:42]1[N:47]=[C:46]([O:48][CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)[CH:45]=[C:44]([CH3:54])[N:43]=1.ClC1C=C(C)N=C(OC2CCCC2)N=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:49]1([O:48][C:46]2[CH:45]=[C:44]([CH3:54])[N:43]=[C:42]([NH:40][C:30]3[CH:31]=[CH:32][C:33]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:28]([O:27][CH3:26])[CH:29]=3)[N:47]=2)[CH2:50][CH2:51][CH2:52][CH2:53]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(OC2CCCC2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(Cl)nc(OC2CCCC2)n1
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(C)cc(OC3CCCC3)n2)ccc1-n1cnc(C)c1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
Palladium acetate (7.1 mg, 0.03 mmol) and 2-(dicyclohexylphosphino)biphenyl (23.1 mg, 0.64 mmol) were dissolved in dioxane (3.6 mL) and stirred for 10 minutes at. Sodium tert.-butylate (59 mg, 0.6 mmol), 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (81 mg, 0.4 mmol) and 1:1 mixture of 2-chloro-4-cyclopentyloxy-6-methyl-pyrimidine and 4-chloro-2-cyclopentyloxy-6-methyl-pyrimidine (94 mg, 0.44 mmol) were added and the reaction was heated to 200° C. for 30 minutes in a microwave oven. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using methylenechloride/methanol (19:1 v/v) as eluent to yield the title compound as a white solid (56 mg, 37%). MS ISP (m/e): 380.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.70 (s, 1H), 7.62 (s, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 7.05 (s, 1H), 6.87 (s, 1H), 6.06 (s, 1H), 5.30 (m, 1H), 3.85 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 1.75-2.00 (m, 6H), 1.60-1.68 (m, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].CN(C)C=O.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([Cl:20])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Yield: 103.4 %

Procedure:
3-(2,2-Dichloroethenyl)-2,2-dimethylcyclopropane carboxylic acid (32.0 grams) was stirred in 400 ml of methylene chloride under nitrogen. To this was added N,N-dimethylformamide (12 ml) and thionyl chloride (22.6 grams). The resulting solution was heated at reflux temperature for about 1.5 hours. The solvent was then removed in vacuo leaving about 36 grams of the desired 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane carboxoyl chloride, which was confirmed by IR and NMR spectroscopy.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[CH:5][CH:4]([C:8](OC)=[O:9])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:1][N:2]1[CH2:7][CH:6]=[CH:5][CH:4]([CH2:8][OH:9])[CH2:3]1
Reactant: COC(=O)C1C=CCN(C)C1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CN1CC=CC(CO)C1
Yield: 21.1 %

Procedure:
A solution of methyl 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylate (88 g, 0.56 mol) dis-solved in dry diethyl ether (250 ml) was slowly added to a slurry of lithium aluminium hydride (23 g, 0.6 mol) in diethyl ether (500 ml). The mixture was refluxed for 30 min. Water (100 ml) and potassium carbonate (100 g, 0.72 mol) were added carefully and the mixture was filtered and evaporated to dryness in vacuo. The residue was distilled in vacuum giving one pure fraction of (1-methyl-1,2,3,6-tetrahydro-3-pyridyl)methanol (Yield:15 g). (bp 38-40° C./0.2 bar).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([NH2:13])[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O>[N:14]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:12])=[C:4]([NH2:13])[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cc1c(N)nc(Br)c2ccccc12
Reactant: C1COCCN1
Solvent: O
Product: Cc1c(N)nc(N2CCOCC2)c2ccccc12
Yield: 83 %

Procedure:
A mixture of 12 g (0.051 mole) of 1-bromo-3-amino-4-methylisoquinoline and 120 ml of morpholine is refluxed for 6 hours, then diluted with water. 8.5 g (83%) of 1-morpholinyl-3-amino-4-methylisoquinoline are obtained.