Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@H:7]([N:10]([CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](O)=[O:38].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[OH:9][CH2:8][C@@H:7]([N:10]([CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:37]([C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][CH:34]=2)=[O:38])=[CH:30][CH:29]=1
Reactant: Cn1cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)[C@H](CO)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cccc1C(=O)Nc1ccc(C[C@@H](CO)N(C[C@H](O)COc2ccccc2)C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of tert-butyl N-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (200 mg) in N,N-dimethylformamide (2.0 ml) was added successively 1-methyl-1H-pyrrole-2-caroxylic acid (72.1 mg) and 1-hydroxybenzotriazole hydrate (77.9 mg). To the mixture was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (110 mg) at room temperature and the mixture was stirred overnight. The mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml×2), a saturated aqueous sodium hydrogencarbonate solution (20 ml×1) and brine (20 ml×1) successively. The organic solution was dried over magnesium sulfate, filtered, and evaporated to give a yellow solid. The crude product was purified by a recycling preparative high pressure liquid chromatography equipped with a gel permeation chromatography column (eluent: chloroform) to give tert-butyl N-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (163 mg) as a white foam.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:19][S:20](O)(=[O:22])=[O:21].C(Cl)(Cl)Cl.[Cl-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:13]1[CH:14]=[CH:15][C:16]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 24.6 grams (0.1 mole) of n-dodecylbenzene in 150 ml of carbon tetrachloride was added with stirring 34.8 grams (0.3 mole) of chlorosulfonic acid over a 1-hour period. The reaction was exothermic with the temperature rising to 27° C. Stirring was continued for 4 hours after which the reaction mixture was carefully poured onto 1 liter of cracked ice with vigorous stirring. Chloroform (200 ml) was added and the aqueous layer was saturated with sodium chloride. The chloroform layer was separated, washed two times with 500 ml of saturated aqueous sodium chloride solution, dried over Molecular Sieves 4A and filtered. The solvent was removed in vacuo, and the resulting residue was recrystallized from 100 ml of hexane. The dried product weighed 22.6 grams and melted at 33°-35° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])([O-:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N+:22]([O-:24])=[O:23])(=[O:32])=[O:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminopiperidine-1-carboxylic acid tert-butyl ester (400 mg, 200 mmol) in anhydrous dichloromethane (14 mL) under argon was added triethylamine (340 μL, 2.4 mmol) and the solution cooled in an ice bath. 2-Nitrophenylsulfonyl chloride (443 mg, 2.0 mmol) was added and the reaction allowed to stir at rt for 16 h. The crude solution was washed with water (2×30 mL) before removing the solvent in vacuo. The crude material was purified by chromatography using ethyl acetate/petroleum ether (30–60%) as the eluent to give the title compound as an off-white powder. δH (d6 DMSO): 8.43 (2H, m), 8.17 (1H, s), 8.09 (2H, m), 3.80–3.69 (2H, m), 3.31–3.23 (1H, m), 2.86–2.69 (2H, m), 1.63–1.51 (2H, m), 1.39 (9H, s), 1.29–1.17 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:31][O:15][C:14](=[O:16])[CH:13]([N:12]1[C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 1 g (2.47 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 10 ml N,N-dimethylformamide, 129 mg (2.964 mmol) sodium hydride (55% dispersion in mineral oil) and 368 mg (2.594 mmol) methyl iodide were added. The reaction was stirred at room temperature for 2 h and then poured on 100 ml ethyl acetate and 100 ml 1M aqueous hydrochloric acid. The phases were separated and the organic layer washed two times with 100 ml water and 100 ml brine. The combined water layers were extracted with 100 ml ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Colorless solid (92%). MS (Turbo Spray): m/z=419.1 [M+H].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl.CO>[C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2=[O:28])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2=O

Procedure:
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine (10 g) in dichloromethane (125 cc) there was rapidly added a solution of 85% m-chloroperoxybenzoic acid (6.61 g) in methanol (125 ml). At first the solids dissolved, then after a few minutes a new solid separated out of solution. After 1 and 1/2 hours the mixture was filtered and the solid washed with dichloromethane. The title compound was thus obtained pure (8.76 g), m.p. 179°-181° C.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=2)[N:8]([C:22](=[O:43])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=2)[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:44][NH2:45].Cl.[CH2:47](O)C>C(OCC)(=O)C>[CH3:44][N:45]([CH3:47])[CH2:3][CH2:2][C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=2)[N:8]([C:22](=[O:43])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: C=CC(=O)N1CCN(C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c2ccc(CCC(=O)OCC)cc21
Reactant: CN
Reactant: CCO
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc2c(c1)N(C(=O)CCN(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 20 °C

Procedure:
A stirred mixture of ethyl 3-(4-acryloyl-1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinoxalin-6-yl)-propanoate (283 mg, Reference Example 22) and methylamine (115 μl) in ethanol (5 ml) was heated at reflux for 8 hours, then treated with a further aliquot of methylamine (50 μl) and then heated at reflux for a further 2 hours. The reaction mixture was cooled to 20° C., then diluted with ethyl acetate, then treated with hydrochloric acid (50 ml, 0.1M) and separated. The ethyl acetate phase was washed with saturated aqueous sodium bicarbonate (10 ml), then washed three times with water (10 ml), then dried over magnesium sulfate and then evaporated under reduced pressure. The aqueous phase from above was extracted three times with dichloromethane (50 ml). The dichloromethane extracts were combined with the above ethyl acetate residue, dried over magnesium sulfate and then evaporated under reduced pressure. The crude residue (331 mg) was subjected to flash chromatography on silica (30 g, 0.040-0.063 mm particle size) eluting with a mixture of dichloromethane and methanol (99:1 to 96:4, v/v) to give the title compound as a white foam (275 mg). 1H NMR 400 MHz, (CD3)2SO, at a temperature of 383° K.]: δ1.20 (t, J=7 Hz, 3H); 2.19 (s, 6H); 2.28 (s, 3H); from 2.55 to 2.70 (m, 6H); from 2.75 to 3.00 (m, 2H); from 3.80 to 3.90 (m, 2H); 3.83 (s, 2H); 3.86 (s, 3H); 3.90 (m, 2H); 4.11(q, J=7 Hz, 2H); 6.67 (broad d, J=8 Hz, 1H); 6.81 (broad s, 1H); 6.99 (broad t, J=7.5 Hz, 1H); from 7.05 to 7.25 (m, 3H); 7.42 (broad s, 1H); 7.56 (d, J=8.5 Hz, 1H); 7.69 (broad d, J=8 Hz, 1H); 7.98 (d, J=8.5 Hz, 1H); 8.17 (broad s, 1H); 8.25 (broad s, 1H). MS (CI): 630 (MH+).
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.C(I)I.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22](=[CH2:26])[CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22]1([CH2:1][CH2:26]1)[CH2:21][CH2:20]2
Reactant: CC[Zn]CC
Reactant: C=C1CCc2cc(Br)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: Brc1ccc2c(c1)CCC21CC1
Yield: 94.9 %

Procedure:
The title compound was synthesized in analogy to example S87 using diethyl zinc (3.25 ml, 1M solution in hexane, 3.25 mmol), trifluoroacetic acid (251 μl, 3.25 mmol), CH2I2 (262 μl, 3.25 mmol) and 5-bromo-1-methyleneindan (340 mg, 1.63 mmol). The isolated residue was purified by flash column chromatography (100% pentane) to give 5′-bromo-2′,3′dihydro-spiro[cyclopropane1,1′-[1H]indene](345 mg, 95%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.40-7.29 (m, 3H), 3.02 (apt t, J=7.5 Hz, 2H), 2.11 (apt t, J=7.5 Hz, 2H), 0.96-0.84 (m, 4H).
Reaction SMILES: C(=O)([O-])O.[K+].[OH:6][C:7]1[C:8]([O:21][CH3:22])=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]3[CH2:17][CH2:18][CH2:19][C:12]=3[C:11]=2[CH:20]=1.Cl[CH2:24][CH2:25][CH2:26][OH:27]>C(O)(C)C>[OH:27][CH2:26][CH2:25][CH2:24][O:6][C:7]1[C:8]([O:21][CH3:22])=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]3[CH2:17][CH2:18][CH2:19][C:12]=3[C:11]=2[CH:20]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1O)CCC3
Reactant: OCCCCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCO)CCC3
Yield: 58 %

Procedure:
Method J (but using potassium hydrogencarbonate); Starting materials: 2,3-dihydro-8-hydroxy-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 109) and 3-chloro-1-propanol; yield 58%; fusion point 213°-215° C. (from isopropanol).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([O:44][C:45]2[CH:53]=[CH:52][C:48](C(O)=O)=[CH:47][CH:46]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>Cl.O1CCOCC1.O1CCOCC1.O>[C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][CH2:21][C@H:9]([NH:8][C:6](=[O:7])[C:48]1[CH:47]=[CH:46][C:45]([O:44][CH:41]2[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:43][CH2:42]2)=[CH:53][CH:52]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])#[N:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cccc(C#N)c1)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)N[C@@H](COc3cccc(C#N)c3)CC(=O)OCc3ccccc3)cc2)CC1
Reaction time: 16 h

Procedure:
1.46 g (3.56 mmol) of benzyl (3R)-3-(t-butoxycarbonyl)amino-4-(3-cyanophenoxy)butyrate was dissolved in 10 ml of 4 N dioxane hydrochloride and 5 ml of dioxane, and the solution was stirred for 15 hours. The solvent was evaporated, and the residue was dissolved in 20 ml of dichloromethane. 1.14 g (3.56 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 2.48 ml (17.8 mmol) of triethylamine, 748 mg (3.92 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 529 mg (3.92 mmol) of 1-hydroxybenzotriazole were added to the solution, and they were stirred for 16 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water, 1 N sodium hydroxide and saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was treated by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:37]([N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:39])[CH3:38]>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH:37]([CH3:39])[CH3:38])[CH3:50])=[O:49])[CH2:48][CH2:47]3)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)N(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-isopropyl-N-methyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide (example 16c) in an analogous manner as described in example 25. LR-MS: 728.4 [(M+H)+]
Reaction SMILES: [N-]=[C:2]=[O:3].[N-]=[C:5]=[O:6].[C:7]1(C)[C:8]([CH3:13])=CC=C[CH:12]=1.C1C=C(CN=C=[O:24])C=C(CN=C=O)C=1>>[CH2:12]([C:7]([CH2:2][OH:3])([CH2:5][OH:6])[CH2:8][CH3:13])[OH:24]
Reactant: O=C=NCc1cccc(CN=C=O)c1
Reactant: Cc1ccccc1C
Reactant: [N-]=C=O
Product: CCC(CO)(CO)CO

Procedure:
As the oil phase component, 14 g of trimethylolpropane and xylene diisocyanate adduct (Takenate D-110N, produced by Mitsui Takeda Chemicals, Inc., a 75 mass % ethyl acetate solution), 2.0 g of Ethylenic Double Bond-Containing Compound (A) and 0.12 g of Pionin A-41C (produced by Takemoto Yushi Co., Ltd.) were dissolved in 16.67 g of ethyl acetate. As the aqueous phase component, 37.5 g of an aqueous 4 mass % PVA-205 solution was prepared. The oil phase component and the aqueous phase component were mixed and emulsified in a homogenizer at 12,000 rpm for 10 minutes. The resulting emulsified product was added to 25 g of distilled water and the obtained mixture was stirred at room temperature for 30 minutes and then stirred at 40° C. for 2 hours. The thus-obtained microcapsule solution was diluted with distilled water to a solid content concentration of 15 mass %. The average particle diameter was 0.2 μm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[I:21]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[C:11]([I:21])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2cncc(F)c2)s1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1sc(-c2cncc(F)c2)nc1I
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 2-(5-fluoropyridin-3-yl)thiazol-5-ylcarbamate (1.50 g, 5.08 mmol) in acetonitrile (50 mL) at 0° C. was added N-iodosuccinimide (2.40 g, 10.67 mmol). The mixture was stirred at 0° C. for 5 min and diluted with ethyl acetate and water. The organic phase was separated and rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a dark solid. This solid was passed through a bed of silica gel (100 g) eluting with 10% ether in hexanes (600 mL) to give tert-butyl 2-(5-fluoropyridin-3-yl)-4-iodothiazol-5-ylcarbamate as a pale yellow solid (1.80 g, 84% yield): mp 148-149° C.; 1H NMR (300 MHz, CDCl3) δ 8.87 (t, J=1.5 Hz, 1H), 8.47 (d, J=2.7 Hz, 1H), 7.93 (ddd, J=9.0, 2.5, 1.9 Hz, 1H), 7.08 (s, 1H), 1.57 (s, 9H). ESIMS m/z 422.1 (M+1), 420.2 (M−1),
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(CO)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)ccc1Br
Yield: 93 %

Procedure:
To a solution of 2-bromo-5-hydroxymethyltoluene (87.4 g) in methylene chloride (350 ml) were added, under ice-cooling with stirring, trietylamine (72.7 ml) and 4-dimethylaminopyridine (DMAP)(500 mg), and then thereto was added t-butyldimethylsilyl chloride (65.5 g). The mixture was stirred at 0° C. for 15 minutes, and stirred at room temperature for 3 hours. The reaction mixture is filtrated, and the filtrate was concentrated under reduced pressure. To the residure was added water (100 ml), and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled away. The residue was purified by a reduced pressure distillation (110° C. to 115° C./0.4 mmHg) to give the title compound (127.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:32]=1[C:33](Cl)=[O:34].C(N(C(C)C)CC)(C)C>ClCCl.O>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:33]([C:32]2[C:31]([Cl:30])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:40])=[O:34])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (19.0 mmol, 8.37 g) and 2,6-dichlorobenzoyl chloride (21 mmol, 4.4 g) in dichloromethane (90 mL) was added diisopropylethylamine (32.3 mmol, 5.6 mL) at room temperature. The solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, it was diluted with water (100 mL) and the two layers were separated. The aqueous phase was extracted with dichloromethane (100 mL) and the combined extracts were washed with brine (200 mL). The dried (MgSO4) solution was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with (hexane:ethyl acetate:dichloromethane, 1:1: 1) to obtain 11.54 g (99%) of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester as a colorless solid, mp 200-202° C. HRMS: Obs. mass, 613.1367. Calcd. mass, 613.1363 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[N:25]=[C:24](I)[CH:23]=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:22]3[CH:23]=[CH:24][N:25]=[C:20]([S:19][CH3:18])[N:21]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]c(-c3ccc(F)cc3)nc2n1
Reactant: CSc1nccc(I)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
KN(TMS)2 (688 mg 3.65 mmol) in toluene (3.5 ml) is added at 0° C. to a solution of 2-(4-fluorophenyl)-5-aminoimidazo[4,5-b]pyridine (684 mg 3 mmol) in DMF (10 ml). After stirring 1 h at room temperature, 2-methylthio4-iodopyrimidine (832 mg 3.3 mmol) in toluene (3.3 ml) is added dropwise and heated for 18 h at 120° C. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by SiO2 chromatography (acetone/cyclohexane 20/80 to 60/40) and renders the title compound as a yellow foam (300 mg 27%)
Reaction SMILES: [C:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].[CH:25]([C:27]1[C:36]2[O:37][C:38]3([C:48]([CH3:50])([CH3:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]3[CH3:51])[CH:39]=[N:40][C:35]=2[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)=O>ClCCl>[CH3:4][O:3][C:1]([CH:5]=[CH:25][C:27]1[C:36]2[O:37][C:38]3([C:48]([CH3:50])([CH3:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]3[CH3:51])[CH:39]=[N:40][C:35]=2[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)=[O:2]
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C=Cc1cc2ccccc2c2c1OC1(C=N2)N(C)c2ccccc2C1(C)C

Procedure:
0.34 g (1 mmol) of carbomethoxymethylene triphenylphosphorane and 0.36 g (1 mmol) of the compound of Example 1 are heated to reflux in 20 ml of dichloromethane for 18 hours. The solvent is evaporated off. The product is purified on a silica column (80/20 pentane/ethyl acetate eluent).