Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([OH:14])=[O:13].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cc2ccccc2)c1
Temperature: 60 °C

Procedure:
24.4 g of the sodium salt of 2-chloro-5-nitrobenzenesulphinic acid are dissolved in 150 ml of ethanol under reflux conditions, and 35 g of benzyl chloride are gradually added. After 10 to 12 hours under reflux conditions the solution is cooled down to 60° C., and the precipitated salt is separated off by filtration. The solution, on cooling down to 0° C., yields 24.1 g of colourless crystals of benzyl 2-chloro-5-nitrophenyl sulphone.
Reaction SMILES: C1COCC1.Cl.[F:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][C:21](=[CH:24][O:25]C)[CH2:20][CH2:19]2)[CH:11]=[C:12]([F:15])[C:13]=1[F:14]>O>[F:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([CH:24]=[O:25])[CH2:20][CH2:19]2)[CH:11]=[C:12]([F:15])[C:13]=1[F:14]
Reactant: COC=C1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=CC1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
THF (100 ml) and 2N-hydrochloric acid (100 ml) were added to 4-(2'-(3",4",5"-trifluorophenyl)ethyl)methoxymethylenecyclohexane (20 g), followed by heating the mixture under reflux with stirring for 2 hours, adding to water (300 ml) after completion of the reaction, extracting with ethyl acetate (300 ml), drying the organic layer over anhydrous MgSO4 and concentrating under reduced pressure, to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethyl)cyclohexane carbaldehyde (17 g).
Reaction SMILES: [P:1](Cl)(=[O:20])([O:11][CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])[O:2][CH2:3][CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8].[CH3:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:29][O:30][PH:31]([O:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37])=[O:32])[CH2:27][CH3:28].C(C(CCCC)C[O:46]P(=O)(O)O)C.Cl>O>[O:2]([CH2:3][CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8])[P:1]([O:20][P:31]([O:33][CH2:34][CH:35]([CH2:36][CH3:37])[CH2:38][CH2:39][CH2:40][CH3:41])([O:30][CH2:29][CH:26]([CH2:27][CH3:28])[CH2:25][CH2:24][CH2:23][CH3:22])=[O:32])(=[O:46])[O:11][CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17].[CH3:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:3][O:2][PH:1]([O:11][CH2:12][CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH3:19])=[O:20])[CH2:9][CH3:10]
Reactant: CCCCC(CC)COP(=O)(Cl)OCC(CC)CCCC
Reactant: CCCCC(CC)COP(=O)(O)O
Agent: CCCCC(CC)CO[PH](=O)OCC(CC)CCCC
Agent: Cl
Solvent: O
Product: CCCCC(CC)COP(=O)(OCC(CC)CCCC)OP(=O)(OCC(CC)CCCC)OCC(CC)CCCC

Procedure:
The final major step in the process of this invention is the hydrolysis of the di-(2-ethylhexyl) phosphorochloridate to product DEHPA. This reaction is carried out using an excess amount of water over the stoichiometric amount. Dealkylation of the DEHPA to mono-(2-ethylhexyl) phosphoric acid by HCl at elevated temperatures is a side reaction that must be controlled to produce acceptable product. This dealkylation is minimized by adjusting the amount of water so that a final HCl content below about 11 wt. % is obtained. In general, the hydrolysis reaction is carried out at 80°-100° C. Considerable amounts (above 60 wt. %) of tetra-(2-ethylhexyl) pyrophosphate are formed in this process from the reaction of DEHPC with DEHPA. This lowers product purity and causes processing problems, such as poorer phase separation. This is overcome by extending the hydrolysis time to 4-6 hours to hydrolyze the pyrophosphate to DEHPA product. An alternative and preferred method to carry out the hydrolysis is to hydrolyze the mixture, as above described for about 2 hours at about 80° C. Then the aqueous layer containing the HCl is separated. A second hydrolysis, using the same amount of water as previously stated, is carried out at 95°-100° C. for about 3 hours.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.Cl.[CH3:19]OCOC.[OH-].[Na+]>CN(C)C=O.O.C1(C)C=CC=CC=1>[ClH:2].[Cl:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:19]1
Reactant: Clc1ccccc1CNCCc1cccs1
Reactant: COCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 0 °C
Reaction time: 11 h

Procedure:
N-(2-chlorobenzyl)-2-(2-thienyl)-ethylamine hydrochloride (29.2 g, 102 mmole), hydrogen chloride gas (4.5 g, 129 mmoles) and dimethoxymethane (33 ml, 388 mmoles) were combined in dimethylformamide (57 ml). The solution was refluxed and stirred for 11 hours. The dimethylformamide was removed under vacuum while keeping the temperature of the solution at 85° C. A solution of sodium hydroxide (11 g, 275 mmoles) in H2O (87 ml) and toluene (87 ml) was added to the residue and stirred at a temperature less than 55° C. for 30 minutes. The aqueous and organic layers were separated and the aqueous layer washed with toluene (85 ml). The toluene was combined with the organic layer and concentrated under vacuum to 50 ml. The solution was filtered to remove salts. Methanol (17 ml) and HCl gas were added to the solution at a temperature less than 40° C. until a pH of 1.5 was reached. The slurry was heated to a temperature less than 50° C. for one hour and cooled to 0° C. for one hour. The product was isolated, washed with 1:9 methanol/toluene and dried; yielding 87.6% real to real (corrected for assay of starting material) of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (ticlopidine hydrochloride). Characterizing HPLC data indicated 99.3% pure.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:20]([O-:23])(=[O:22])[CH3:21].[NH2:24][N+:25]1[CH:29]=[CH:28][N:27]([NH2:30])[C:26]=1[CH2:31][CH3:32]>C(O)(=O)C.C(O)C>[C:20]([O-:23])(=[O:22])[CH3:21].[C:20]([O-:23])(=[O:22])[CH3:21].[C:20]([O-:23])(=[O:22])[CH3:21].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[N:24][N+:25]3[CH:29]=[CH:28][NH:27][C:26]=3[CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:16]=[N:30][N+:27]3[CH:28]=[CH:29][NH:25][C:26]=3[CH2:31][CH3:32])=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[N:24][N+:25]3[CH:29]=[CH:28][NH:27][C:26]=3[CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: CCc1n(N)cc[n+]1N
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)N1CCN(c2ccc(C=N[n+]3cc[nH]c3CC)cc2)CC1
Reaction time: 18 h

Procedure:
1.95 g (7.4 mmol) of p-[4-(ethoxycarbonyl)-1-piperazinyl]benzaldehyde are added to a solution of 0.69 g (3.7 mmol) of 1,3-diamino-2-ethyl-imidazolium acetate in 10 ml of glacial acetic acid, the mixture is left to stand at room temperature for 18 hours, then diluted with 30 ml of ethanol and the product is crystallized out by the addition of ether. There is obtained 1,3-bis[[[p-(4-(ethoxycarbonyl)-1-piperazinyl]benzylidene]amino]-2-ethyl-imidazolium acetate diacetate of melting point 187°-188°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
In 50 ml of THF was dissolved 4.99 g of N-benzyloxycarbonyl-L-proline (20) and after adding thereto 2.23 g of triethylamine and 2.39 g of ethyl chloroformate, the reaction was maintained for 20 minutes under ice-cooling. To the reaction mixture was added 2.79 g of aniline and the reaction was performed for one hour under ice-cooling. The solvent was distilled off, the residue thus formed was dissolved in ethyl acetate, and the solution was washed, in succession, with an aqueous solution of 1N hydrochloric acid, a saturated aqueous sodium hydrogen, carbonate solution, and then a saturated aqueous sodium chloride solution. The organic layer thus formed was dried by anhydrous sodium sulfate and then concentrated to dryness. The residue was recrystallized from chloroform-ethyl acetate-hexane to provide 5.20 g of (S)-1-benzyloxycarbonyl-N-phenyl-2-pyrrolidinecarboxamide (93) having a melting point of 143°-144° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7][Br:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[Br-:8].[Cl:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1cc(CBr)c(Cl)s1
Solvent: c1ccccc1
Product: Clc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)s1
Product: [Br-]

Procedure:
2,5-Dichloro-3-bromomethyl thiophene (22 g., 90 mmoles) was mixed with 26 g. (99 mmoles) of triphenyl phosphine and 150 ml. of benzene. The mixture was heated to the reflux for 2-1/2 hours, cooled and filtered to give (2,5-dichloro-3-thenyl)triphenyl phosphonium bromide, m.p. 208°-215° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6]C=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[NH2:42][CH2:43][C:44]1[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:42][CH2:43][C:44]4[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6]1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(CC4CC4)C3=O)nc2C)cn1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 2-(aminomethyl)-5-methylpyrazine, the title compound was obtained as a white powder in 43% yield: mp 161-163° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 8.33 (s, 1H), 6.77 (t, J=4.8 Hz, 1H), 4.64 (d, J=4.8 Hz, 2H), 4.09-4.01 (m, 2H), 3.68-3.58 (m, 2H), 3.14 (d, J=7.2 Hz, 2H), 2.57 (s, 3H), 2.50 (s, 3H), 0.96-0.85 (m, 1H), 0.55-0.49 (m, 2H), 0.23-0.18 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.7, 155.2, 153.1, 152.5, 148.8, 143.4, 142.7, 117.2, 48.6, 42.3, 42.2, 42.1, 21.2, 17.3, 8.9, 3.5; MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[Cl:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=1[S:55](=[O:58])(=[O:57])[NH2:56].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:50]([C:49]4[CH:53]=[CH:54][C:46]([Cl:45])=[C:47]([S:55]([NH2:56])(=[O:57])=[O:58])[CH:48]=4)=[O:51])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3-sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 gradient to give 5-[(4-(1,3-benzodioxol-5-yl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl) carbonyl]-2-chlorobenzenesulfonamide as a solid (0.09 g, 17%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.17 (m, 2H), 6.94 (s, 1H), 6.81-6.86 (m, 2H), 5.93 (s, 2H), 4.74 (m, 1H), 4.11 (m, 1H), 3.52 (m, 1H), 3.30 (m, 4H), 2.52 (s, 3H), 2.44 (m, 2H), 2.39 (m, 1H), 2.18 (m, 1H), 1.80-2.04 (m, 12H), 1.70 (m, 2H). HRMS C36H40ClN5O5 m/z 690.2517 (M+H)Cal., 690.2538 (M+H)Obs..
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1>CN(C)C=O>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:4]([C:3]2[C:2](=[S:1])[NH:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=C(O)c1cccnc1S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N,N-dimethylformamide (660 mL), and carbonyldiimidazole (110 g, 0.70 mol) was added thereto under ice-cooling, and then the mixture was stirred at room temperature for 2 hours. Water (5.4 mL) was added thereto, the whole was stirred for 40 minutes. 3,5-Xylidine (76 mL, 0.61 mol) was added thereto, and the mixture was stirred for 16 hours at 60° C. The mixture was allowed to stand, water (1.3 L) was added thereto, and then the precipitated solid was filtered off. The solid was dried under reduced pressure at 45° C. to give 130 g of the title reference compound as a yellow solid. (Yield 89%)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[S:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]2[CH2:13][CH2:14][CH2:15][C:3]1=2.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(O)=O>O.C(O)(C)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:8][C:6]2[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]3[CH2:13][CH2:14][CH2:15][C:3]=3[C:2](=[O:1])[N:7]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)Cn1c2c(c(=O)[nH]c1=S)CCC2
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: O=CO
Product: O=C(O)Cn1c(SCc2ccc(F)cc2)nc(=O)c2c1CCC2
Temperature: 40 °C
Yield: 96.5 %

Procedure:
(4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid (30.0 g, 1.0 eq) was slurried in a mixture of water (162 mL) and isopropyl alcohol (30 mL). KOH solution (50% aqueous, 28.3 g, 1.90 eq) was added followed by a water line wash (15 mL) resulting in a solution. Then K2CO3 (2.75 g, 0.15 eq) was charged and the solution was heated to 40±3° C. Thereafter 4-fluorobenzyl chloride (18.2 g, 0.95 eq) was added, followed by a line wash of isopropyl alcohol (18 mL) and the reaction mixture was stirred at 40±3° C. until the reaction was deemed complete (˜2.5 hours). The reaction mixture was cooled to 20±3° C. and formic acid (3.1 g, 0.5 eq) was added resulting in crystallisation of the product within 30 minutes. A second charge of formic acid (10.4 g, 1.7 eq) was added over 1 hour and the slurry was stirred at 20±3° C. for at least one hour. The slurry was filtered to isolate the product, which was washed twice with a mixture of water (48 mL) and isopropyl alcohol (12 mL), then with isopropyl alcohol (60 mL) and dried in vacuo at 50° C. to yield the title compound as an off-white solid (40.6 g, 92%). 1H NMR (d6 DMSO) δ 1.95 (2H, m), 2.57 (2H, t), 2.85 (2H, t), 4.4 (2H, s), 4.7 (2H, s), 7.15 (2H, dd), 7.45 (2H, dd), ˜13.6 (1H, vbrs).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([Sn](C)(C)C)[CH2:33][CH2:32]2.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[O:11])=[C:2]([C:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=3)[CH:35]=2)[CH:7]=1
Reactant: COc1ccc(C(=O)c2ccc(OCCN3CCCCC3)cc2)c(Br)c1
Reactant: COc1ccc2c(c1)CCC([Sn](C)(C)C)=C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)cc1)=C2
Temperature: 100 °C
Reaction time: 5 h
Yield: 38.8 %

Procedure:
A suspension of (2-bromo-4-methoxyphenyl)[4-(2-piperidin-1-ylethoxy)phenyl]methanone (570 mg), (6-methoxy-3,4-dihydronaphthalen-2-yl)trimethyltin (542 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg) and copper(I) iodide (25 mg) in toluene (10 ml) was stirred for 5 hours at 100° C. under a nitrogen atmosphere. Ethyl acetate was added thereto, the insoluble material was removed by filtration, the solvent was evaporated in vacuo, and the resulting residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (263 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[OH-].[Na+]>O>[ClH:19].[ClH:19].[CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOCCNS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCCNS(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1
Product: Cl

Procedure:
31 Grams of 3-(2-ethoxyethylsulfamoyl)-4-chlorobenzoic acid and 30 g of N-methylpiperazine were heated for 4 hours at 140° C. Subsequently the excess base was eliminated in vacuo. The residue was dissolved in 0.2 l of water, and the solution was adjusted to a pH value of 9.5 by means of 2N NaOH. After evaporating the solution in vacuo, the residue was extracted with boiling ethanol, and the solution, which had been concentrated to 100 ml, was mixed with 100 ml of ethanolic HCl of 10% strength. After having been triturated and cooled, the final product crystallized within a short time and was dried at 60° C. after washing with ethanol.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([O:13]C)=O)[N:10]=2)[CH2:3]1.[Si:15]([O:32][CH:33]1[CH2:36][NH:35][CH2:34]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Al](C)C.C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:15]([O:32][CH:33]1[CH2:34][N:35]([C:11]([C:9]2[N:10]=[C:6]([N:4]3[CH2:3][CH:2]([OH:1])[CH2:5]3)[O:7][CH:8]=2)=[O:13])[CH2:36]1)([C:28]([CH3:31])([CH3:29])[CH3:30])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1coc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(O)C3)n2)C1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (500 mg, 2.52 mmol) (obtained as described in Reference Example 70(7)) in toluene (25 ml) was added a solution of 0.67 M 3-t-butyldiphenylsilyloxyazetidine (obtained as described in Reference Example 42(2))-trimethylaluminium in toluene (11.3 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred in an oil bath (80° C.) for 15 minutes. After checking the completion of the reaction, to the reaction mixture were added 10% aqueous acetic acid (20 ml) and ethyl acetate (50 ml) in an ice bath and the mixture was stirred at room temperature for 0.5 hours. To the reaction mixture was added ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (95:5→9:1) as the eluant to afford 1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]-3-hydroxyazetidine (1.24 g, yield 100%) as a pale brown solid.