Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24].C([O-])([O-])=O.[Na+].[Na+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2; 1.5 g; 5.0 mmol) was dissolved in toluene (35 mL) an DMF (2 mL). To this solution was added 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (204 mg, 250 μmol), followed by 3-chloro-4-fluorophenylboronic acid (CAN 144432-85-9; 959 mg, 5.5 mmol) and 2M-Na2CO3 (20.0 mL 40.0 mmol). The reaction mixture was heated to 90° C. and stirred for 4 h, cooled and poured into 100 mL ice water, acidified with 45 mL 2N—HCl and extracted ethyl acetate. The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The crude material was crystallized from heptane:ethyl acetate (5:1) to yield 1.1 g (63%) of the title compound as light grey solid; LC-MS (UV peak area/ESI): 97%, 348.0066 (M−H)−.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[F:24])=[C:5]([F:25])[C:4]=1[F:26].[I:29]Cl>C(#N)C>[F:25][C:5]1[C:4]([F:26])=[C:3]([I:29])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[F:24]
Reactant: ClI
Reactant: CCCc1ccc(-c2ccc(-c3ccc([Si](C)(C)C)c(F)c3F)c(F)c2)cc1
Solvent: CC#N
Product: CCCc1ccc(-c2ccc(-c3ccc(I)c(F)c3F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
The total amount of the terphenyl 9 is dissolved in 4 ml of absolute acetonitrile and reacted with 1.2 ml (6 mmol) of a 5 M solution of ICl in acetonitrile, and the mixture is stirred at room temperature for 1 hour. The residue is crystallised at −20° C. for 2 hours. The supernatant solution is subsequently sucked off, and the product which remains is washed with 2 M Na2S2O5 (10 ml) and water (10 ml) and dried in an oil-pump vacuum (yield: 54%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[N+:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])c3ccccc23)C1
Yield: 87.7 %

Procedure:
The compound was prepared from tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (3.56 g, 19 mmol) and 4-nitro-1-naphthol (3 g, 15.9 mmol). Yield: 5 g (88%) of the title compound as yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (d, J=7.03 Hz, 9H) 2.22-2.38 (m, 2H) 3.54-3.83 (m, 4H) 5.18 (br s, 1H) 6.74 (d, J=8.53 Hz, 1H) 7.56 (t, J=7.78 Hz, 1H) 7.71 (t, J=7.78 Hz, 1H) 8.29 (d, J=8.53 Hz, 1H) 8.33 (d, J=8.53 Hz, 1H) 8.72 (d, J=8.53 Hz, 1H). MS (ESI+) for C19H22N2O5 m/z 376.2 (M+NH4)+, 303.2 (M−tBu)+. HPLC 100%, RT=2.768 min (System A1, 10-97% MeCN over 3 min).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15](N)=[O:16]>>[C:15](=[O:16])([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[NH2:14]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: NC(N)=O
Product: NC(=O)Oc1ccc(-c2ccccc2)cc1
Yield: 90 %

Procedure:
6298 g of 4-phenyl phenol and 444 g of urea were charged into an autoclave (Toyo Koatsu Inc., Japan) equipped with a thermometer, stirrer, reflux condenser and gas feed tube and having an internal volume of 12 L followed by stirring at normal pressure while bubbling nitrogen gas with a capillary tube at the rate of 100 L/hr and carrying out the reaction at 140° C. When a portion of the reaction liquid was removed 10 hours later and analyzed by liquid chromatography, the formation of (4-phenylphenyl) carbamate was confirmed. The yield was about 90% based on the charged amount of urea.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=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>ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:25])=[CH:27][CH:28]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc2ncccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2ncccc2c1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 6-aminoquinoline (500 mg, 3.47 mmol) and 4-benzyloxybenzoic acid (792 mg, 3.47 mmol) in dichloromethane (25 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.84 g, 4.16 mmol) and triethylamine (0.58 mL, 4.16 mmol), and the solution was stirred overnight at room temperature. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (218 mg, 18%) was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16]N(C=O)C.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1>C(Cl)Cl.CO>[CH3:16][O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol) in CH2Cl2 (250 mL) at 0° C. was added DMF (0.100 mL) followed by (COCl)2 (2M in CH2Cl2, 36.23 mL, 72.46 mL) over a period of 10 min. The reaction was stirred at 0° C. for 1 h and then at room temperature for 30 min. The reaction solvent was removed under a reduced pressure, dried under high vacuum and again suspended in CH2Cl2 (250 mL). The solution was cooled to 0° C., were added pyridine (4.8 mL, 48.03 mmol) followed by MeOH (10 mL, excess) and stirred overnight. The extractive work-up with CH2Cl2 gave the expected 2-methoxycarbonyl-5-nitrobenzofuran (R926609). 1H NMR (CDCl3): δ 8.66 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65 (s, 1H), 4.01 (s, 3H); LCMS: ret. time: 26.94 min.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[CH:12]2)C1C=CC=CC=1.[OH-].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].S(OC)(OC)(=O)=O>C(O)C>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: COS(=O)(=O)OC
Product: Cn1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(Ref: Taborsky, R. G.; Delvigs, P; Palaic, D; Bumpus, F. M. J. Med. Chem. (1967), 10(3), 403-7). To a solution of 5-benzyloxy-1-methyl-1H-indole (2 g, 8.9 mmol) in ethanol (20 mL) was added potassium hydroxide (0.62 g, 11.2 mmol). The resulting solution was allowed to stir at room temperature for 10 mins before evaporating the ethanol in vacuo. The residue was taken up in acetone (75 mL) and sodium sulfate (6.4 g, 44.8 mmol) was added, followed by dimethyl sulfate (0.87 mL, 8.9 mmol) via syringe. The solution was stirred for 0.5 h, then filtered and evaporated in vacuo. The resulting residue was then taken up in ethanol (50 mL) and 10% palladium on charcoal (0.4 g) was added. This solution was stirred under a hydrogen atmosphere for 4 h, then filtered through celite and the solvent evaporated in vacuo. This material was purified by flash chromatography, eluting silica gel with hexane:ethyl acetate (100:0 to 50:50) to give the product. (0.48 g, 37%); δH (300 MHz, CDCl3) 7.15 (1H, d, Ar), 7.01 (2H, m, Ar), 6.8 (1H, m, Ar), 6.32 (1H, m, Ar), 3.73 (3H, s, NCH3).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1.C>C(O)(=O)C>[CH2:12]([C:4]1[S:3][C:2]2[N:1]=[C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]3[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:13]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc(CC)sc1N
Solvent: CC(=O)O
Product: CCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1

Procedure:
A mixture of 2-amino-5-ethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966), 2.0 g (0.01 mol) and 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 1.6 g (0.01 mol) is heated in an oil bath at 180°-185° C. for six hours. The mixture is cooled, dissolved in hot glacial acetic acid, activated charcoal (Darco G-60, Matheson, Coleman and Bell) added and the hot suspension filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled and 0.33 g of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid is collected; mp 255°-257° C. after recrystallization from methanol.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc2nc(SCCCCCO)[nH]c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2nc(SCCCCCBr)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
1.4 g of the compound obtained in Example 14a and 2.8 g of carbon tetrabromide were added to 15 ml of tetrahydrofuran and then gradually added with 2.2 g of triphenylphosphine. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:2) to obtain 1.18 g of the title compound as yellow crystals (yield: 67%).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:16](=[O:41])[NH:17][CH2:18][P:19]([O:39][CH3:40])([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.[CH2:43]([O:50][C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@H:54]1[C:55]([OH:57])=O)=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N1CCOCC1)C.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CO.Cl.CN(C)C=O.[Pd]>[CH3:40][O:39][P:19]([CH2:18][NH:17][C:16]([C@@H:11]([NH:10][C:55]([C@@H:54]1[CH2:58][CH2:59][CH2:60][N:53]1[C:51]([O:50][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:52])=[O:57])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:41])([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)OC
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 112.7 %

Procedure:
0.75 g of benzyl[(S)-1-[[[methoxy[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinyl]methyl]carbamoyl]-3-methylbutyl]carbamate was dissolved in 60 ml of methanol containing 1.4 ml of 1M hydrochloric acid. The solution was hydrogenated over 0.1 g of 10% palladium-on-charcoal for 4 hours. After filtration and evaporation, the residue was re-evaporated three times with 30 ml of toluene each time in order to remove water. The white residue obtained was dissolved in 10 ml of dimethylformamide and the solution was cooled to 0° C. 0.375 g of N-benzyloxycarbonyl-L-proline, 180 mg of N-ethylmorpholine and 0.4 g of hydroxybenzotriazole were added and, after all of the solids had dissolved, 0.345 g of N,N'-dicyclohexylcarbodiimide was added. After stirring at room temperature for 18 hours, the solvent was removed by evaporation. The residue was triturated with 30 ml of ethyl acetate and the mixture was filtered in order to remove dicyclohexylurea. The filtrate was washed twice with 30 ml of saturated sodium hydrogen carbonate solution each time, dried over anhydrous sodium sulfate and evaporated to give a colorless gum which was purified by flash chromatography on silica gel using 15% methanol in ethyl acetate for the elution. There was obtained 0.98 g of benzyl(S)-2-[[(S)-1-[[[methoxy[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinyl]methyl]carbamoyl]-3-methylbutyl]carbamoyl]-1-pyrrolidinecarboxylate in the form of a white foam.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].CN(C=O)C.Cl>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.O.N1C=CC=CC=1>[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][C:8]([CH3:12])([CH3:9])[CH3:7])=[O:10]
Reactant: COc1cccc(C(=O)O)c1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cccc(C(=O)OC(C)(C)C)c1OC
Temperature: 40 °C
Reaction time: 1 h
Yield: 166 %

Procedure:
Add thionyl chloride (67.6 mL, 928 mmol) dropwise to a solution of 2,3-dimethoxybenzoic acid (132 g, 714 mmol) and DMF (1.32 mL) in toluene (528 mL) maintained at 40° C. Stir the solution for 1 h at 40° C. after the addition is complete. Concentrate the mixture in vacuo and dissolve the residue in dichloromethane (528 mL). Warm the mixture to reflux and add tert-butyl alcohol (203.4 mL). Add pyridine (86.6 mL) dropwise over 5 min followed by addition of N,N-dimethylpyridin-4-amine (4.36 g, 35.7 mmol) and stir the mixture 1 h while cooling to ambient temperature. Dilute the mixture with water (200 mL) and acidify the mixture (pH=2) with 2 N hydrochloric acid. Separate the phases and wash the organic phase with 0.5 N hydrochloric acid (2×30 mL). Wash the organic phase with 15% potassium carbonate, water, and brine. Concentrate the organic phase in vacuo to yield the title compound (141.2 g, 83%) as a white solid. ES/MS m/z 165 [M-(C4H9O)]+.
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][CH2:23][C:24](=O)[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:4]2[CH2:5][CH2:6][N:1]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:2](=[O:8])[C:3]=2[C:24]([CH3:25])=[CH:23]1
Reactant: CC(=O)CNc1ccccc1Cl
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccccc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Temperature: 25 °C
Yield: 21 %

Procedure:
To a solution of [1,1′]bipiperidinyl-2,4-dione, from Step 4 (2.49 g, 12.7 mmol) in dry toluene (240 ml) at room temperature were added 1-(2-chlorophenylamino)propan-2-one (2.33 mg, 12.7 mmol) from Step 5 followed by a catalytic amount of p-TSA. The reaction mixture was boiled under reflux with a Dean-Stark trap, and 90 ml toluene was collected in the trap. Then 1 molar equivalent of p-TSA was added and the reaction mixture was boiled under reflux overnight. After cooling to room temperature, the reaction mixture was evaporated and purified by flash chromatography (heptane:EtOAc gradient) to give 0.93 g (21%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].C(O)(=O)C[SH:12].[OH-].[Na+]>CS(C)=O>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[SH:12]
Reactant: Clc1ccc(Cl)c(Br)c1
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Sc1cc(Cl)ccc1Cl
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a 300 ml four-necked flask equipped with a stirrer, a thermometer and a condenser were charged 24.9 g (0.110 mol) of 1-bromo-2,5-dichlorobenzene, 13.19 g (0.143 mol) of thioglycolic acid, 12.06 g (0.286 mol) of 95% sodium hydroxide and 100 g of dimethylsulfoxide, followed by stirring at 120° C. for 4 hours. After cooling until 100° C., 2,5-dichlorothiophenol salt produced as the side product was treated with 5.13 g (0.044 mol) of sodium monochloroacetate at the same temperature for 1 hour. Then, after distilling off the dimethylsulfoxide under reduced pressure, 100 g of water was added to 54.5 g of the residue. After dissolving the residue therein at 100° C., the solution was cooled for crystallization and filtered to yield sodium 2,5-dichlorophenylthioglycolate, which was then dissolved in 100 g of water with heating and acidized with concentrated hydrochloric acid, filtered and dried to yield 23.5 g of a light yellowish white powder of 2,5-dichlorophenylthioglycolic acid. The yield based on 1-bromo-2,5-dichlorobenzene was 90.0%.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[NH:22][NH2:23].C(N(CC)CC)C>CCO>[CH2:26]([O:25][C:21](=[O:24])[NH:22][N:23]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3ccccc3)n(NC(=O)OCc3ccccc3)cc2n(C)c1=O
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (1.15 g, 3.41 mmol), benzyl carbazate (commercial) (2.83 g, 17.05 mmol) and triethylamine (1.426 ml, 10.23 mmol) were combined in EtOH (15 ml) and the mixture heated at reflux for 15 mins. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was partitioned between water and DCM and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was triturated with Et2O and cooled in ice until precipitation occurred. The precipitate was collected by filtration, affording the title compound as a white solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][O:23][CH2:22][CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([N:13]([CH3:12])[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:9])[CH2:19][CH2:18]2)=[CH:27][CH:28]=1
Reactant: CNC1CCN(CCCOCCc2ccc(F)cc2)CC1
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C(=S)Nc1ccccc1)C1CCN(CCCOCCc2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 736 mg (5.44 mmol) of phenyl isothiocyanate in 15 ml of ethanol is treated with 2 g (5.44 mmol) of the preceding hydrochloride 22.3 and then 1.51 ml (10.9 mmol) of triethylamine. After stirring for 1 h, the mixture is evaporated to dryness and treated as in Example 1.1 to give 1.88 g (Yd: 81%) of compound of formula 22.4:
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)CCCCC>>[C:2]1([N:15]2[C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:18][C:16]2=[O:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1O
Reactant: NC(=O)Nc1ccccc1
Solvent: CCCCCCO
Product: O=c1[nH]c2c(n1-c1ccccc1)CCCC2
Yield: 29.6 %

Procedure:
A mixture of 4.5 g (39.4 mmol) of 2-hydroxycyclohexanone, 7.5 g (55 mmol) of phenylurea and 7 ml of hexanol is stirred under reflux for 20 hours. The mixture is concentrated under vacuum and the solid residue is recrystallized from acetone, and 2.5 g of product, m.p.=220° C., are recovered. Yield—29.6%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:21][C:22]#[N:23].CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([CH2:21][O:11][C:10](=[O:12])[C@@H:9]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)#[N:23]
Reactant: C=CCCC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)O
Reactant: N#CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Compound 93d (0.494 g, 1.324 mmol) was dissolved in DMF (10 ml), and 2-bromoacetonitrile (0.63 g, 5.30 mmol) and DIPEA (0.341 g, 2.65 mmol) were slowly added at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to afford (S)-3-(3-iodo-phenyl)-2-pent-4-enoylamino-propionic acid cyanomethyl ester (Compound 93e) (0.392 g, 72%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[I:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)cc1I
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
3-Iodo-4-methylphenyl amine (10 g, 43 mmol) was dissolved in 6 N HCl (40 ML), cooled to 0° C., and vigorously stirred throughout the procedure. Sodium nitrite (2.9 g, 1.03 equiv.) was dissolved in water (5 mL) and this solution was added to the reaction in a dropwise fashion. After 30 min, tin (II) chloride dihydrate (22.8 g, 1 mol) in 6 N HCl (100 mL) was added via addition funnel, and the reaction slurry was stirred at 0° C. for 3 h. The pH was adjusted to 14 with 40% aqueous sodium hydroxide solution and the aqueous mixture was extracted with EtOAc, (6×50 mL), dried (MgSO4), and concentrated to give 3-iodo-4-methylphenylhydrazine (7 g, 57%). This material was used directly without further purification.