Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: COCC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 72.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid (143 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (75 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 24 h. At this time, the reaction was diluted with methylene chloride (5 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (133 mg, 72%) as a white solid: mp 170-172° C.; EI-HRMS m/e calcd for C21H24N2O2S (M+) 368.1558, found 368.1556.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][CH:7]1[CH2:12][CH:11]2[CH2:13][CH:8]1[C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=12.[C:20](Cl)(=[O:22])[CH3:21].O>C(Cl)Cl>[C:20]([CH:12]1[CH:11]2[CH2:13][CH:8]([C:9]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=32)[CH:7]1[O:6][CH3:5])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1C1CC2CC1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1C1CC2C(C(C)=O)C1OC

Procedure:
23.5 g of aluminum chloride are added in small portions to a mixture of 30 g of 1,4-dimethoxybenzonorbornene and 13.8 g of acetyl chloride in 300 cm3 of methylene chloride. At this stage, a check is made that all the starting material has been converted. The reaction mixture is poured into 300 cm3 of water. The organic phase is washed with sodium bicarbonate, then with water, and dried over magnesium sulphate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:37][CH3:38])[CH:29]=1>C(O)(=O)C.C1COCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:3]=[C:4]([NH:22][CH3:23])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:32][C:31]=2[O:37][CH3:38])[CH:29]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Yield: 26.9 %

Procedure:
2-Chloro-N-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (220 mg, 0.640 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (215 mg, 0.960 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (92 mg, 0.172 mmol, 26.8% yield). LC-MS (M+H)+=531.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.93 (1H, s), 7.66 (1H, br s), 7.50 (1H, s), 7.10-7.23 (4H, m), 7.02 (2H, d, J=15.3 Hz), 6.83 (1H, d, J=8.2 Hz), 4.70-4.83 (1H, m), 4.13-4.28 (1H, m), 3.12 (3H, d, J=4.9 Hz), 2.74 (1H, br. s.), 2.65 (2H, d, J=8.2 Hz), 1.97-2.08 (1H, m), 1.25 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[NH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1)=[O:16]>C1COCC1>[O:26]=[C:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:17]([C:15]([C:14]3[CH:13]=[C:12]([NH:11][C:8]([C:3]4[CH:4]=[N:5][N:6]([CH3:7])[C:2]=4[Cl:1])=[O:9])[CH:29]=[CH:28][CH:27]=3)=[O:16])=[CH:18][CH:19]=2)[NH:23]1
Reactant: Cn1ncc(C(=O)Cl)c1Cl
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1Cl
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A dry flask was charged with 5-Chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.200 g, 1.1 mmol) was dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.178 g, 0.706 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for overnight. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was filtered. The solid residue was washed with 0° C. THF (10 mL) to afford the 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.199 g, 0.504 mmol, 71%).
Reaction SMILES: CC(C)=[O:3].[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[C:10]([F:16])[C:9]=1[F:17])[CH3:6]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3].O>[CH2:5]([O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:3])=[O:13])=[C:10]([F:16])[C:9]=1[F:17])[CH3:6]
Reactant: CCOc1ccc(CO)c(F)c1F
Reactant: CC(C)=O
Agent: [Cr+3]
Agent: [O-2]
Solvent: O
Product: CCOc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetone solution (140 mL) containing 4-ethoxy-2,3-difluorobenzyl alcohol (2.1 g) was dropped into a 1.5 M sulfuring acid solution (70 mL) containing chromium (III) oxide (4.23 g), at 0° C. over one hour. The reaction mixture was stirred at room temperature for 24 hours, and added with water to thereby terminate the reaction. The organic layer was extracted three times with ethyl acetate, the organic layers were combined, and the combined organic layer was extracted twice with a 1 M aqueous sodium hydroxide solution. The organic layer was then neutralized with a 2 M hydrochloric acid, extracted three times with ethyl acetate, the organic layers were combined, and the combined organic layer was washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was vaporized off under reduced pressure, to thereby obtain 4-ethoxy-2,3-difluorobenzoic acid (7) (yield=1.8 g, yield ratio=80%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:14])[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].CCCCCC>O1CCCC1>[CH2:3]([O:5][C:6]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:13])[CH3:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C(OCC)O[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
To a dispersion of 3.1 g of NaH in 20 mL of tetrahydrofuran (THF) at room temperature was added 20 mL of diethylmethylmalonate, at an addition rate of 0.5 mL/minute. The mixture was kept below 30° by the use of a water/ice bath. After complete addition of the diethylmethylmalonate, the mixture was stirred for 30 minutes, then cooled to 0° and 13.5 mL of chlorotrimethylsilane was added. After 40 minutes, 10 mL of hexane was added and the mixture was stirred overnight, filtered under argon, and distilled A forerun (40°-58°, 0.32 mm) was discarded, the product distilling at 62°-64°, 0.40 mm. NMR. (CD3CN, TMS) indicates that the product is a 75/25 mixture of E/Z isomers of ECPS; major isomer: 0.303 (s, 9H, SiMe3); 1.255 (t, J=b 7 Hz, 6H, OCH2CH3); 1.754 (s, 3H, vinyl CH3); 3.988-4.250 (m, all OCH2 for both isomers. Minor isomer: 0.308 (s, 9H, SiMe3); 1.264 (t, J=7H, 6H, OCH2CH3); 1.727 (s, 3H, vinyl CH3 1.754); 3.988-4.250 (m, all OCH2 for both isomers). Anal. calc. for C11H22SiO4 : C 53.67; H 8.94. Found C 53.33; H 8.76.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:3].[Br:16]Br>>[CH:10]1([C:7]2[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH2:1][Br:16])=[CH:9][CH:8]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrBr
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Product: O=C(CBr)c1ccc(C2CCCCC2)cc1

Procedure:
p-cyclohexylphenyl methyl ketone is reacted with bromine in a non-polar solvent to produce the corresponding p-cyclohexylphenacyl bromide. Reaction of this reactive alpha-bromo ketone with commercially available thioacetamide in an protic solvent such as methanol with heat affords the corresponding 2-methyl-4-(4-cyclohexylphenylthiazole. N-Alkylation of this thiazole with [methoxy(polyethylene)n-1]ethyl chloride (where n is from 19 to 24) in aprotic solvents such as dimethylformamide and heat readily forms the corresponding methochioride product, which is also named either N-[methoxy(polyethylene)n-1]ethyl-2-methyl-4-(4-cyclohexylphenypthiazolium chloride or 3-[methoxy(polyethylene)n-1]ethyl-2-methyl-4-(4-cyclohexylphenyl)thiazolium chloride. Reaction of this thiazolium chloride with (N,N-dimethyl)amino benzaldehyde in a protic solvent such as methanol with a basic catalyst such as piperidine and heat then produces the desired 4-(4-cyclohexylphenyl)-2-(N,N-diethylaminostyryl)-3-[methoxy(polyethylene)n-1]ethylthiazolinm chloride, which can also be named 4-(4-cyclohexylphenyl)-2-[2-(4-dimethylaminophenyl)vinyl]-3-[methoxy(polyethylene)n-1]ethylthiazol-3-ium chloride. In all of the above reactions n is from 19 to 24.
Reaction SMILES: [C-]#N.[K+].CC(C)(O)[C:6]#[N:7].[Cl:10][C:11]1[CH:12]=[C:13](/[C:18](/[C:41]([F:44])([F:43])[F:42])=[CH:19]\[C:20]([C:22]2[CH:39]=[CH:38][C:25]([C:26]([NH:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:27])=[C:24]([CH3:40])[CH:23]=2)=[O:21])[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>C1(C)C=CC=CC=1>[C:6]([C@@:18]([C:13]1[CH:12]=[C:11]([Cl:10])[CH:16]=[C:15]([Cl:17])[CH:14]=1)([C:41]([F:44])([F:42])[F:43])[CH2:19][C:20]([C:22]1[CH:39]=[CH:38][C:25]([C:26]([NH:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:27])=[C:24]([CH3:40])[CH:23]=1)=[O:21])#[N:7]
Reactant: CC(C)(O)C#N
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Reaction time: 96 h
Yield: 31.7 %

Procedure:
Potassium cyanide (0.0082 g, 0.125 mmol) and acetone cyanohydrin (0.031 ml, 0.336 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (0.0600 g, 0.111 mmol) in toluene (3.0 ml). To this vigorously stirred suspension was added antracen-9-yl-methyl quininium chloride (0.0153 g, 0.028 mmol). The reaction mixture was stirred at 90 C for 4 days. After this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (0.020 g, 32%) as a light yellow solid. Chiral HPLC analysis (Chiralpack AS-RH, acetonitrile:water:methanol=45:5:50, 1 ml/min, retention time 8.70 minutes (major enantiomer), 11.30 minutes (minor enantiomer) indicated that the reaction proceeded with 94% enantioselectivity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])=[C:6]([CH3:11])[CH:5]=1)=[O:12]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A (2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol, the reaction was heated at 100° C. overnight. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography with a solvent gradient of 25% to 50% dichloromethane in hexane provided 2.0 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][CH:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(O)Cc1ccc(N)cc1
Reactant: CC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Product: CC(=O)c1cnc(Nc2ccc(CC(C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al. J. Med. Chem., 1990, 33, 2231-2239.) and 1-(4-aminophenyl)-2-propanol (step 1 of Example 6).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].[C:10]1([CH2:16][C@H:17]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:18]2[O:23][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:20]=3[N:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.C([Li])CCC.CCCCCC>[O:24]=[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:31])([F:32])[F:30])[C:20]=1[NH:19][C:18]([C@@H:17]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:23])[CH2:2][C:1](=[O:3])[NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 103 %

Procedure:
Using the procedure of Step B of Example 7, a solution of 9.09 g of 2-acetylaminothiazole in 280 ml of tetrahydrofuran, 91 ml of n-butyllithium in solution in hexane and 13.9 g of product of Step A in 100 ml of tetrahydrofuran were reacted to obtain 19 g of 1,1-dimethylethyl N-[(S) 1-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-(trifluoromethyl)-phenyl]-amino-carbonyl]-2-(phenyl)-ethyl]-carbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)CCC>>[N:36]1[CH:37]=[CH:38][N:39]=[CH:40][C:35]=1[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([N:19]4[C:20](=[O:29])[C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:27]4=[O:28])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(c1ccc2c(c1)ncn2-c1cccc(Br)c1)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: CC(c1ccc2c(c1)ncn2-c1cccc(-c2cnccn2)c1)N1C(=O)c2ccccc2C1=O

Procedure:
This was prepared analogously from 2-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-isoindole-1,3-dione and 2-tributylstannylpyrazine.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>ClCCl>[CH3:24][S:25]([O:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:27])=[O:26]
Reactant: CCCCCCCCCCCCCCCCCCOCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
In dichloromethane (50 ml) is dissolved 3-(octadecyloxy)propanol (8.0 g). To the solution are added, under ice-cooling, methanesulfonyl chloride (4.18 g) and triethylamine (5.1 ml). The mixture is stirred at room temperature for one hour. The reaction mixture is washed with water and an aqueous solution of sodium hydrogencarbonate, successively, and then dried. The solvent is distilled off under reduced pressure to give the above-titled compound (9.7 g).
Reaction SMILES: [O:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][PH:12]([OH:14])=[O:13].O>C1(C)C(C)=CC=CC=1>[P:12]([O:10][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9])([OH:14])([OH:13])=[O:11]
Reactant: CC(O)Oc1ccccc1
Reactant: O=[PH](O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(Oc1ccccc1)OP(=O)(O)O

Procedure:
1 mol of phenoxyethanol is esterified azeotropically in the presence of 1.1 mol of H3PO3 in xylene on a water separator. The reaction product which precipitates on cooling is filtered off, washed with petroleum ether and dried to give a white powder. The amount of the phosphoric diester (2-phenoxyethanol hydrogensulphate, 0-50%) which may be formed in this reaction in addition to phenoxyethanol phosphate (phenoxyethanol dihydrogenphosphate) does not interfere in the polycondensation which subsequently takes place; it is also incorporated into the polycondensate.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1.C(NC(N)=[S:26])(=O)C.C(OCC)(=O)C>C(O)C>[SH:26][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)NC(N)=S
Reactant: CC(=O)Nc1nc(CCc2ccc(CCBr)cc2)cs1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(CCS)cc2)cs1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a suspension of N-(4-{2-[4-(2-bromoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (353.3 mg, 1.000 mmol) in ethanol (4 ml) was added 1-acetyl-2-thiourea (177.4 mg, 1.501 mmol), and the mixture was heated under reflux for 7 hr. 1-Acetyl-2-thiourea (176.6 mg, 1.495 mmol) was added, and the mixture was heated under reflux for 17 hr. The mixture was cooled to room temperature, ethyl acetate (10 ml) was added, and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and purified twice by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. DM-2035 21 g, ethyl acetate:hexane=2:3→1:1) to give N-(4-{2-[4-(2-sulfanylethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (210.4 mg, 0.687 mmol, 68.7%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.5 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (8.9 g, 59.7 mmol) and triethylamine (11 mL, 78.9 mmol) in 90 mL of DCM at 0° C., was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.89 g, 24.4 mmol). The mixture was stirred at room temperature for 3 days, concentrated under vacuum and purified by flash chromatography (eluent: 0 to 50% EtOAc in hexane with 0.1% triethylamine) to afford 3.09 g (40%) of 17a.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:23]>ClCCl>[O:23]1[CH2:3][CH:2]1[CH2:1][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])=[CH:9][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1ccc(N2C(=O)C=CC2=O)cc1
Solvent: ClCCl
Product: O=C1C=CC(=O)N1c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(4-Allyloxyphenyl)maleimide (175 g, 76.4 mole) and 3-chloroperoxybenzoic acid (262 g, 70-75%, Across) were dissolved in 2.0 l of dichloromethane. After stirring for 72 h at room temperature, the reaction mixture was concentrated under reduced pressure to a slurry. Ether (2.0 l) was added to the slurry and stirred for 0.5 h at room temperature. The product was filtered off, washed with ether, and dried in an oven.
Reaction SMILES: [CH3:1][C:2]([S-:5])([CH3:4])[CH3:3].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1>CN(C=O)C.C(OCC)(=O)C>[C:2]([S:5][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[N:9]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[S-]
Reactant: Clc1cccc(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)Sc1cccc(Cl)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
A suspension of sodium 2-methylpropane-2-thiolate (188 mg, 1.68 mmol) in DMF was treated with 2,6-dichloropyridine (4865 μl, 1.46 mmol) at ambient temperature in a vial. The vial was capped and heated to 80° C. with rapid stirring of the colorless solution. After 12 hours, the reaction was cooled to ambient temperature and diluted with ethyl acetate. The ethyl acetate solution was washed with brine solution, dried with sodium sulfate, filtered, concentrated and purified on silica gel. Elution with 2% to 10% ethyl acetate/hexanes provided the title compound (271 mg, 1.34 mmol, 92.0% yield) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:30]1([C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)Cl)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:19]([O:18][C:16]([C:13]([O:12]/[N:11]=[C:7](/[C:5]1[N:6]=[C:2]([NH:1][C:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[S:3][CH:4]=1)\[C:8]([OH:10])=[O:9])([CH3:14])[CH3:15])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 22.5 °C
Reaction time: 6 h

Procedure:
To a suspension of (Z)-2-(2-aminothiazol-4-yl)-2-(2-tert-butoxycarbonylprop-2-oxyimino) acetic acid (monoblocked acid) (100 g) prepared as in Example 1 in methylene chloride (1.74 lt) is added triethylamine (33.76 g) slowly at 5-10° to obtain a clear solution. Add triphenylchloromethane (118.5 g) at 5-10° and then mass temperature is raised to 36-38°. The resulting reaction mixture is stirred for 6 hours. It is then cooled to 20-25° and washed with DM water. The organic layer is concentrated and toluene is added to the residue. The resulting slurry is cooled to 20-25° C., the product is filtered, washed with toluene and dried under reduced pressure at 40-45° C. Yield 171 g (98.5% of theory), water <0.2% w/w, assay 96-97% w/w, methylene chloride 2-2.5% w/w and toluene 1-2% w/w.