Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1.[Na+].[I-]>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CCCN1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1 g, 6.2 mmol), 1-(3-chlorophenyl)piperazine (1.22 g, 6.2 mmol) anhydrous Na2CO3 (0.33 g, 3.1 mmol) and NaI (0.093 g, 0.6 mmol) in dry DMF (5 ml) was stirred at 70° C. for 14 hrs. The reaction mixture was cooled, poured on water (20 ml) and the separated residue was extracted with CHCl3 (2×25 ml). The extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 1.50 g (75%) . IR (Neat): 3020, 2820, 1660, 1590, 1450, 1210, 730. 1H NMR (CDCl3): 1.30-2.60(m, 12H, 3', 4', 2, 1 & 2×N--CH2), 2.40-3.50(m, 8H, 5', 3 & 2×N--CH2), 6.40-7.20(m, 4H, ArH). MS: m/z 321 (M+) 323 (M+2).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([C:15]2[S:19][C:18]([NH:20][C:21](=[O:23])[CH3:22])=[N:17][C:16]=2[CH3:24])=[CH:11][C:10]=1[NH:25]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClCCl>[NH2:25][C:10]1[CH:11]=[C:12]([C:15]2[S:19][C:18]([NH:20][C:21](=[O:23])[CH3:22])=[N:17][C:16]=2[CH3:24])[N:13]=[N:14][C:9]=1[Cl:8]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c(Cl)nn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1nc(C)c(-c2cc(N)c(Cl)nn2)s1
Temperature: 0 °C

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a stirred mixture of N-[5-(6-chloro-5-tritylaminopyridazin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (300 mg), methanol (0.5 mL) and dichloromethane (4 mL) that had been cooled to 0° C. The resultant mixture was heated to 55° C. for 5 hours. The mixture was evaporated and the residue was basified to pH8 by the addition of a saturated aqueous sodium bicarbonate solution. The resultant solid was isolated and washed with diethyl ether. The solid was dissolved in dichloromethane and a 7M methanolic ammonia solution was added. The mixture was evaporated to give N-[5-(5-amino-6-chloropyridazin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide as a solid; Mass Spectrum: M+H+ 282.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1.[Si:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:29]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1)(=[O:31])[CH3:30].[Si:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCc1c[nH]c2ccccc12
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)n1cc(CCCO)c2ccccc21

Procedure:
A solution of the indole 2 (29 g, 86 mmol), CH2Cl2 (450 mL), 1,8-diazobicyclo[5.4.0]undec-7-ene (38 mL, 0.26 mol), 4-dimethylaminopyridine (1.0 g, 8.5 mmol), and acetic anhydride (32 mL, 0.34 mol) was stirred for 1 week at ambient temperature. The reaction mixture was concentrated and then diluted with ether. The ether was then washed with H2O, 5% KHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 5% ethyl acetate/hexanes) gave the acylated product 3 (27 g) as a yellow oil.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([CH:47]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:48][NH2:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(O)(C)C>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:49][CH2:48][CH:47]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: NCC(Cc1ccccc1)Cc1ccccc1
Solvent: CC(C)O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(Cc4ccccc4)Cc4ccccc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Yield: 80.4 %

Procedure:
A solution of ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) (0.25 g, 0.38 mmol) and 2-benzyl-3-phenylpropylamine (0.16 g, 0.76 mmol) in isopropanol (10 ml) was stirred at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1 by volume) to afford the title compound as a yellow foam (0.26 g, 83%).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O.Cl.[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][NH:33][CH3:34])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:15]([F:37])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:9].[Cl:12][C:13]1[CH:36]=[CH:35][C:16]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][N:33]([CH3:34])[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[O:8])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:15]([F:37])[CH:14]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CNCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 144.7 %

Procedure:
Isonicotinoyl chloride (36 mg, 0.2 mmol) was added to a suspension of 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(methylamino)ethoxy)quinazoline hydrochloride hydrate (90 mg, 0.1 mmol), (prepared as described for the starting material in Example 54), in methylene chloride (3 ml) and triethylamine (80 mg, 0.8 mmol) was then added dropwise. The mixture was stirred for 30 minutes at ambient temperature and the solvent was then removed by evaporation. The residue was partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was dissolved in methylene chloride/methanol and 3M ethereal hydrogen chloride (0.5 ml) was added. The suspension was diluted with ether, the precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(4-pyridylcarbonyl)amino)ethoxy)quinazoline hydrochloride (75 mg, 67%). 1H NMR Spectrum: (DMSOd6; CF3COOD; 95° C.) 3.1(s, 3H); 3.8-3.9(br s, 2H); 4.1(s, 3H); 4.4-4.6(br s, 2H); 7.4-7.45(m, 2H); 7.55(dd, 1H); 7.65(t, 1H); 7.9-8.0(br s, 2H); 8.28(s, 1H); 8.8(s, 1H); 8.95(s, 2H) MS-ESI: 482 [MH]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:30][Si:31]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34]>C1(C)C=CC=CC=1>[CH2:36]([O:35][Si:31]([CH2:30][O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([O:38][CH2:39][CH3:40])[O:32][CH2:33][CH3:34])[CH3:37]
Reactant: CCO[Si](CO)(OCC)OCC
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCO[Si](COC(=O)C=Cc1ccc(OC)cc1)(OCC)OCC

Procedure:
100 g of p-methoxycinnamic acid (Aldrich) was dissolved in 500 mL of toluene and 118 g of dicyclohexylcarbodiimide (DCC) (Aldrich) was added. After adding 100 g of hydroxymethyltriethoxysilane (Gelest), the toluene solution was stirred for about 18 hours at about 40° C. After evaporating the solvent under reduced pressure and adding 200 mL of acetone, insoluble byproduct (dicyclohexylurea) was removed by filtering. After removal of acetone, triethoxysilylmethyl-(p-methoxycinnamate) was obtained. The new product could be identified by thin-layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:16][CH2:17][CH:18]=[C:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:33][C:20]1=2.[I-].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][CH:18]=[C:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[N:29][C:24]=3[CH2:23][O:22][C:21]3[CH:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:33][C:20]2=3)[CH2:12][CH2:13]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC1(c2ccccc2Cl)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(C)(c3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 12 h
Yield: 24.6 %

Procedure:
A solution of 4-(2-Chloro-phenyl)-4-methyl-piperidine (0.29 g, 1.38 mmol) in isopropanol (5 mL) was treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.19 g, 0.50 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 12 hr, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.062 g (25%) of the title compound, 1H-NMR (CDCl3) ∂: 1.10 (3H, s), 1.58 (6H, s), 1.78 (2H, m), 1.90 (1H, m), 2.10 (2H, m), 2.40 (8H, m), 5.30 (2H, brs), 6.18 (1H, t), 6.79 (1H, m), 6.92 (1H, m), 7.19-7.39 (6H, m), 7.42 (1H, m), 7.55 (1H, m), 8.55 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:29][CH2:30][NH2:31]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:29][CH2:30][NH:31][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:13][C@@H:11]3[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]3[CH2:15]2)[CH:17]=[N:18][CH:19]=1)=[O:23]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NCCc4ccc(Cl)c(Cl)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3,4-dichlorophenethylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 505 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]3[CH:20]=[CH:21][S:22][C:18]=3[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[S:22]1[C:18]2[CH:17]=[CH:16][N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][CH2:10]3)[C:19]=2[CH:20]=[CH:21]1
Reactant: c1ccc(CN2CCC(c3nccc4sccc34)CC2)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CCC(c2nccc3sccc23)CC1
Reaction time: 12 h

Procedure:
1 g of the product obtained in Step E is added dropwise to a suspension of 93 ml of ethyl chloroformate and 0.89 g of K2CO3 in 5 ml of toluene. After 12 hours at ambient temperature, the reaction mixture is diluted with water, extracted with toluene and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 95/5) enables the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]1([S:27]([O:30][CH2:31][C:32](=O)[CH3:33])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:32]([CH3:33])[CH2:31][OH:30])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]1([S:27]([O-:30])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)COS(=O)(=O)c1ccccc1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Product: CC(CO)=NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Product: O=S(=O)([O-])c1ccccc1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with 2-oxopropyl benzenesulfonate to give 7-bromo-2-[(2-hydroxy-1-methylethylidene) hydrazino]-5-phenyl-3H-1,4-benzodiazepine, benzenesulfonate (ester).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:41]([CH2:44]C)CC)C.[OH2:46]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:21][C:44](=[O:46])[NH:41][CH:9]2[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cc1ccc(F)cc1)C(O)c1ccc(F)cc1
Reactant: O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(F)cc2)C(c2ccc(F)cc2)O1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of (2RS,3RS)-3-(4-fluorophenyl)-2-(4-fluorobenzyl)-3-hydroxypropionic acid (13.8 g, 47.2 mmol) in tetrahydrofuran (150 ml) were added diphenylphosphoryl azide (13.2 ml, 61.4 mmol) and triethylamine (9.2 ml, 66.1 mmol) and the mixture was stirred for 30 min. The mixture was further heated under reflux for 4 hrs. and allowed to stand at room temperature. Water (200 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel and evaporated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to give (4RS,5SR)-5-(4-fluorophenyl)-4-((4-fluorophenyl)methyl)-1,3-oxazolidin-2-one (12.8 g, 94%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(COc2cccnc2N)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccccc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.91 g, 0.0083 mol), phenyl isothiocyanate (1.4 g, 0.01 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.18 g (72%), m.p. 123°-125 ° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH:10]([NH2:13])([CH3:12])[CH3:11].[OH-].[Na+].[CH2:16]([NH2:18])[CH3:17]>CC(C)=O.O>[CH3:17][CH2:16][NH:18][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([NH:13][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCN
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCNc1nc(Cl)nc(NC(C)C)n1
Temperature: 35 °C

Procedure:
Using the apparatus and general procedure described in Illustrative Embodiment IA, a 30.5% by weight solution of cyanuric chloride in acetone was charged to a batch reaction vessel. A less than stoichiometric amount of isopropylamine (the molar ratio of cyanuric chloride to isopropylamine was 1.04) was charged over a period of one hour and then sufficient 20% by weight sodium hydroxide in water was added over a period of 40 minutes to bring the pH of the aqueous phase to 8.0. The temperature of the reaction mixture during both reaction steps was controlled at 10° C. Hydrolysis of the excess cyanuric chloride was effected by reducing the pH to 6.0 and heating the reaction mixture to 35° C. for a period of 0.5 hours. Aqueous sodium hydroxide solution was added as necessary to maintain the pH of the reaction mixture at 6.0. At the conclusion of this reaction step, the pH was increased to 8.0 and ethylamine as a 68% solution in water was added over a period of 30 minutes. Sufficient 20% by weight sodium hydroxide solution was added over a period of 45 minutes to produce a pH of 8.5. The temperature of the reaction mixture was maintained at 35° C. during this reaction sequence. Crude atrazine was isolated from the reaction mixture by precipitation with water. The molar yield of atrazine was 94.3% based on isopropylamine charged to the reaction. The composition of the crude atrazine was determined by gas-liquid chromatography and is given below.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCC1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Benzyl-3,3-dimethyl-piperidin-4-one (WO 01/00577 A2) (5.0 g, 23 mmol) was dissolved in MeOH (25 ml), cooled to 0° C. and sodium borohydride (1.0 g, 25 mmol) was added portionwise. The reaction was allowed to reach room temperature and stirred overnight after which time the solvent was removed under vacuum, the residue redissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated to afford the title compound (4.9 g, 97%). MS: 220.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:19]1[CH2:23][CH2:22][CH2:21][C:20]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:39])[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33](Br)[CH:32]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:39])[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([C:20]2[CH2:21][CH2:22][CH2:23][C:19]=2[C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:32]=1)[CH3:28]
Reactant: CCOC(=O)c1cc(Br)ccc1F
Reactant: OB(O)C1=C(c2cc(C(F)(F)F)ccc2OCc2ccccc2)CCC1
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)ccc1F

Procedure:
Prepared by general procedure C(iii) but using 2-(2-benzyloxy-5-trifluoromethylphenyl)cyclopentene-1-boronic acid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and 3-bromo-6-fluorobenzoic acid ethyl ester instead of 2-chloropyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7]([Mg]Br)[CH:8]=[CH2:9]>C(OCC)C>[CH3:1][C:2]([CH3:6])([CH:3]([OH:4])[CH2:9][CH:8]=[CH2:7])[CH3:5]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)C=O
Solvent: CCOCC
Product: C=CCC(O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylacetaldehyde (10.2 mL, 90.9 mmol) in diethyl ether (200 mL) at 0° C. was added allylmagnesium bromide (100 mL, 1M in ether). The reaction mixture was stirred at 0° C. for 1 hour. The resulting mixture was quenched with saturated ammonium chloride and extracted with diethyl ether. The organic extracts were washed with brine, dried over Na2SO4 and filtered. The solvent was carefully removed under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][C:4](=C(C)C)[CH:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)=[O:16].C(O)(C)C>C(OCC)(=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C:4](=[O:16])[CH:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C=O
Reactant: CCOC(=O)C1C(=C(C)C)CC[C@H]1C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C(=O)CC[C@H]1C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(2R)-Ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (24 g, 0.122 mol) in ethyl acetate (100 mL) was cooled to −68° C. with dry ice/isopropanol. Ozonized oxygen (5-7 ft3 h− of O2) was bubbled through the solution for 3.5 hours. The reaction mixture was flushed with nitrogen at room temperature until the color disappeared. The ethyl acetate was removed under vacuum and the residue was dissolved in 150 mL of acetic acid and cooled by ice water, and zinc powder (45 g) was added. The solution was stirred for 30 minutes and then filtered. The filtrate was neutralized with 2N NaOH (1.3 L) and NaHCO3. The aqueous phase was extracted with ether (3×200 mL). The organic phase was combined, washed with water, dried and concentrated to afford (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.21 (m, 2H), 2.77 (d, J=11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2.10 (m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:39])(C[Si](OC(C)C)(C)C)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:19][CH:18]=2)[C:13]1=[O:30])[CH3:11].[C:40](=O)([O-])[OH:41].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:39])([CH2:40][OH:41])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:30])[CH3:11]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 68.9 %

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (0.88 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 10 ml), to which 1.57 ml of 30% aqueous hydrogen peroxide and 0.128 g of sodium hydrogencarbonate were added. The mixture was heated at 70° to 80° C. for 90 minutes, cooled and extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of water, an aqueous solution of Na2S2O3 (25 ml×2) and 25 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:3) and recrystallized from diisopropyl ether to give 0.5 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (yield: 69%) as colorless powdery crystals.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([NH2:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:11][B-:12]([F:15])([F:14])[F:13].[CH2:16]([O+](CC)CC)[CH3:17]>C(Cl)Cl>[F:11][B-:12]([F:15])([F:14])[F:13].[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[NH:9])[O:8][CH2:16][CH3:17]
Reactant: CC[O+](CC)CC
Reactant: Cc1ccccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a degassed suspension of o-toluamide (1.35 g, 9.788 mmol) in methylene chloride (5 mL) was added triethyloxonium tetrafluoroborate (9.788 mL, 9.788 mmol, 1 M in methylene chloride). After the clear solution was stirred at room temperature overnight, it was concentrated in vacuo. The residue was triturated in methylene chloride and diethyl ether. The white solid was filtered off and washed with diethyl ether to afford ethyl 2-methyl-benzimidate tetrafluoroborate (1.4 g, 80%). It was used without further purification.