Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:15](OCC)=[O:16].Cl>CN(C=O)C>[CH:15]([CH:7]([CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:16]
Reactant: CCOC=O
Reactant: CCOC(=O)CCC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
40.7 g of ethyl 3-cyclopentylpropionate are placed in 400 ml of DMF at from 0° to 5° C., 14.4 g of sodium hydride (80% in oil) are added. After dropwise addition of 200 ml of ethyl formate, the mixture is stirred at 25° C. for 24 h. The mixture is stirred into 1.6 l of 10% HCl, extracted with 800 ml of methylene chloride and distilled. 19.7 g (41%) are obtained of ethyl 2-formyl-3-cyclopentylpropionate of boiling point 117° C./12 min.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CS([C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2/[C:35](=[CH:40]\[O:41][CH3:42])/[C:36]([O:38][CH3:39])=[O:37])[CH:23]=1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:22]2[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3/[C:35](=[CH:40]\[O:41][CH3:42])/[C:36]([O:38][CH3:39])=[O:37])[CH:23]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(S(C)(=O)=O)ncn1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(OCc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 60 °C
Yield: 44.3 %

Procedure:
To a solution of 4-nitrobenzyl alcohol (666 mg) in DMF (8 ml) was added potassium carbonate (800 mg) followed by a solution of (E)-methyl 2-[2-(6-methanesulphonylpyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.0 g, prepared as described in Example 1) in DMF (3 ml). The reaction mixture was heated to 60° C. under an atmosphere of nitrogen for 5½ hours, cooled and then poured into water (40 ml). The resulting mixture was extracted with ether (×3) and the combined ether layers were dried and evaporated to yield an orange oil. Chromatography (eluent ether-hexane, 7:3) gave (E)-methyl 2-[2-(6-(4-nitrobenzyloxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (532 mg) as a glass which solidified on standing; m.p. 96-98° C.; 1H NMR: δ 3.55 (3H, s), 3.75 (3H, s), 5.50 (2H, s), 6.15 (1H, s), 7.15 (1H, d), 7.3 (3H, m), 7.45 (1H, s), 7.58 (2H, d), 8.22 (2H, d), 8.42 (1H, s) ppm; IR maxima: 1700, 1620, 1560, 1340 cm−1; mass spectrum m/e 437 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][C@@H:28]([O:32]C(=O)C5C=CC([N+]([O-])=O)=CC=5)[C:24]=4[N:25]=[CH:26][N:27]=3)[C:5]2=[CH:6][CH:7]=1.C(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][C@@H:28]([OH:32])[C:24]=4[N:25]=[CH:26][N:27]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)C4)c4cc(Cl)ccc43)c21
Agent: CC(C)(C)OC=O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)C4)c4cc(Cl)ccc43)c21

Procedure:
tert-butyl 5-chloro-1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was prepared by the procedures described in Example 3, Step 12, substituting tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate. LCMS (APCI+) m/z 357.1 [M+H−Boc]+; Rt=3.86.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][Br:13]
Reactant: COC(=O)c1cccc(F)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(F)c1CBr
Temperature: 25 °C
Yield: 266.1 %

Procedure:
A solution of 3-fluoro-2-methyl-benzoic acid methyl ester (3.64 g, 21.67 mmol) in carbon tetrachloride (100 mL) was treated with N-bromosuccinimide (3.85 g, 21.63 mmol) and benzoyl peroxide (0.1 g). The reaction mixture was then heated at reflux temperature and after 3 h the heat was removed and it was stirred at room temperature over the weekend. The reaction was then filtered to remove the solids and concentrated in vacuo to yield a light yellow oil. The reaction was then repeated with the remaining 3-fluoro-2-methyl-benzoic acid methyl ester (6.1 g, 36.3 mmol) in carbon tetrachloride using N-bromosuccinimide (6.5 g, 36.5 mmol) and benzoyl peroxide (0.1 g) heating at reflux. The reaction mixture was then filtered and concentrated in vacuo. The two material from the two reactions was combined and purified by flash column chromatography (silica gel, 10% diethyl ether/hexanes) to afford 2-bromomethyl-3-fluoro-benzoic acid methyl ester (14.22 g, 99%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.CO[C:21](C)(C)[CH3:22]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([O:2][CH3:1])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)[CH2:16][CH:17]=[CH:21][CH3:22]
Reactant: CO[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Reactant: COC(C)(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](OC)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.65 g of ethyltriphenylphosphonium bromide were suspended in 40 ml of tert.butyl methyl ether while gassing with argon. The suspension was treated at room temperature with 797 mg of potassium tert.butylate and stirred for 1 hour. The mixture was subsequently cooled to 0° C., treated dropwise within 3 minutes with a solution of 1.1 g of 3-[trans-4-(trans-4-methoxycyclohexyl)cyclohexyl]propionaldehyde in 15 ml of tert.butyl methyl ether and then left to warm slowly to room temperature while stirring. After 2 hours the pale yellow suspension was partitioned in diethyl ether/water. The aqueous phase was separated and washed three times diethyl ether. The organic phases were washed twice with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the yellow, solid crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 0.91 g of trans-4-(3-pentenyl)-1-(trans-4-methoxycyclohexyl)cyclohexane with a Z/E ratio of 86:11.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH:31]([S:39](Cl)(=[O:41])=[O:40])=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1(/[CH:32]=[CH:31]/[S:39]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
N-[2-({[(E)-2-Phenylethenyl]sulfonyl}amino)-5-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and β-styrenesulfonylchloride (48 mg, 0.239 mmol according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 499.2; Calcd 499.14; 1H-NMR δ 8.26 (d, 1H), 8.04 (d, 1H), 7.75–7.38 (m, 8H), 7.22 (d, 1H, J=15.4 Hz), 7.16 (d, 1H), 6.97 (d, 1H), J=15.4 Hz), 6.78 (dd, 1H), 6.68 (d, 1H), 3.68 (app t, 2H), 3.39 (app t, 2H), 3.28–3.21 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:36]([O:38][CH3:39])=[O:37])[N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)n1nc(C(=O)NC2CN(C)CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
To a solution of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (0.92 g) and triethylamine (0.77 g) in dichloromethane (30 ml), methyl chloroformate (0.48 g) is added dropwise at 0° C., and the mixture is stirred at 25° C. for 16 hours. The reaction mixture is washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.7 g) as an oil. The free base thus obtained is converted to the fumarate of the title compound in a usual manner, m.p. 158°-160° C. (recrystallized from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].[Cl-].[NH4+]>ClCCl>[CH3:12][C:9]1[C:8]2[C:7](=[O:13])[CH2:6][CH2:5][CH2:4][C:3]=2[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:10]=1
Reactant: Cc1ccc(N)c2c1C(=O)CCC2
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NS(C)(=O)=O)c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-amino-8-methyltetralone (De, B. Synth. Commun. (1988), 18, 481-486) (0.25 g, 1.4 mmol) in dichloromethane (7 mL) was treated with pyridine (0.35 mL, 4.3 mmol), treated with methanesulfonyl chloride (0.12 mL, 1.5 mmol), stirred at ambient temperature for 1.5 hours, treated with aqueous ammonium chloride solution (20 mL) and extracted with dichloromethane (4×25 mL). The combined dichloromethane extracts were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with ethyl acetate:hexanes 1:1 provided the desired product.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=[O:9].[CH3:11][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[ClH:1].[CH3:11][O:9][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH2:2])=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid hydrochloride (96 mg, 0.58 mmol) was dissolved in a 1:1 mixture of benzene and methanol (6 mL). The mixture was cooled to 0° C. A 2.0 M solution of (trimethylsilyl)diazomethane in hexanes (0.44 mL, 0.87 mmol) was added and the reaction was stirred at 25° C. for 30 min. The mixture was concentrated and dried in vacuo. The crude product was directly used in the next step.
Reaction SMILES: S(=O)(=O)(O)N.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15])[CH:10]=[O:11].Cl([O-])=[O:18].[Na+]>O.C(O)(C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15])[C:10]([OH:18])=[O:11]
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(C=O)cc(Cl)c1O
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(C(=O)O)cc(Cl)c1O
Temperature: 12 °C
Yield: 52 %

Procedure:
A solution of sulfamic acid (11.8 g, 121.5 mmol) in water (25 mL) was added with vigorous stirring to 3-chloro-4-hydroxy-5-methylbenzaldehyde (16.00 g, 93.8 mmol) in tert-butanol (100 mL). The mixture was cooled (˜12° C.) and a solution of sodium chlorite (12.00 g, 106.1 mmol) in water (25 mL) was added in 5 mL portions with vigorous stirring. The reaction was exothermic and the temperature at the end of the addition was approximately 50° C. The two layers were separated and the aqueous layer was extracted with ether (2×50 mL). The organic layers were washed with brine and evaporated to dryness. Water was added, and the mixture was stirred and filtered. The solid was dissolved in warm ether (250 mL), and the solution was dried, filtered, concentrated to 100 mL, and cooled in the freezer (approx. −20° C.). Filtration and washing with cold ether gave 3-chloro-4-hydroxy-5-methylbenzoic acid (9.10 g, 52%), as a yellow solid, mp 242–244° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH:38]1(Br)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: BrC1CCCCC1
Product: COc1ccc(CC2c3cc(OC4CCCCC4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with cyclohexyl bromide
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:28][C:29]1[C:33]([C:34]2[CH:35]=[C:36](C3C(C)=CC=C4C=3C=CC=N4)[C:37]3[NH:41][C:40](=[O:42])[NH:39][C:38]=3[CH:43]=2)=[C:32]([CH3:55])[O:31][N:30]=1>>[CH3:28][C:29]1[C:33]([C:34]2[CH:35]=[C:36]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C:3](=[O:21])[N:2]4[CH3:1])[C:37]3[NH:41][C:40](=[O:42])[NH:39][C:38]=3[CH:43]=2)=[C:32]([CH3:55])[O:31][N:30]=1
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Reactant: CN1C(=O)CCc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1-c1cc(-c2cccc3c2CCC(=O)N3C)c2[nH]c(=O)[nH]c2c1

Procedure:
5-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one was synthesized using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one and Cs2CO3 in a similar fashion as 6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example 2).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([C:12]([CH3:14])=[O:13])=[CH2:11]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[O:5])[CH2:11][CH2:10][C:12](=[O:13])[CH3:14]
Reactant: C=CC(C)=O
Reactant: O=Cc1ccccc1Br
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)c1ccccc1Br
Temperature: 70 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 90 g of bromobenzaldehyde, 41 g of methyl vinyl ketone, 24.2 g of 3-benzyl-4-methyl-5-hydroxyethylthiazolium chloride is added with 45 ml of triethylamine. A marked exothermicity is observed, at the end of which the reaction mixture is heated to 70° C. under stirring for 4 h. The resulting mixture is cooled and partitioned between 800 ml of ether and 400 ml of H2O. The aqueous phase is reextracted and the combined organic phases are washed with 10% HCl and with brine, then dried over Na2SO4 and the solvent is evaporated off. 110 g of an orange oil are obtained (93% yield). 1H NMR (CDCl3), δ: 2.22 (s, 3 H), 2.89 (t, 2 H), 3.15 (t, 2 H), 7.18-7.65 (m, 4 H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:18])=[C:7]([F:17])[CH:8]=2)[N:3]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:11]1[C:2]([N:20]([CH3:19])[CH2:21][CH2:22][C:23]#[N:24])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([F:17])=[C:6]([F:18])[CH:5]=2)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CNCCC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1N(C)CCC#N
Temperature: 20 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of 16.3 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline prepared as described in Example 1 and 10 g of N-methyl-N-β-cyanoethylamine in 160 cm3 of toluene are added 19.08 g of sodium carbonate. The suspension obtained is heated at reflux and then stirred for 4 hours at this temperature. The reaction mixture is subsequently cooled to approximately 20° C., followed by washing with 3 times 50 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 19.17 g of 3-ethoxycarbonyl-6,7-difluoro-2-(N-methyl-N-β-cyanoethylamino)quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[NH2:25][C:26]([NH2:28])=[O:27]>CN(C=O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:25]=[C:26]([NH2:28])[O:27][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: NC(N)=O
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3oc(N)nc3-c3ccc(F)cc3F)nn12
Temperature: 100 °C
Yield: 4 %

Procedure:
2-Bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.500 g, 1.26 mmol, Preparation #A.2) and urea (0.228 g, 3.80 mmol) were added to DMF (5 mL) then heated at about 100° C. for about 2 h. The mixture was cooled to ambient temperature then purified by RP-HPLC (Table 1, Method f). Concentration under reduced pressure of most of the organic solvent resulted in a precipitate which was collected by filtration and dried to give the title compound (0.018 g, 4%): LC/MS (Table 1, Method b) Rt=1.96 min; MS m/z: 357.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][NH2:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:49][O:48][CH3:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CON
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NOC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with methoxyamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H46Cl2N5O4 [(M+H)+] 694.2922, observed 694.2919.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:15]Cl)[C:6]1[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].[Cl:17][C:18]1[C:19]([CH3:24])=[N:20][NH:21][C:22]=1[CH3:23]>COCCOC>[Cl:1][CH2:2][C:3]([N:5]([CH2:15][N:20]1[C:19]([CH3:24])=[C:18]([Cl:17])[C:22]([CH3:23])=[N:21]1)[C:6]1[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4]
Reactant: CCc1cccc(C)c1N(CCl)C(=O)CCl
Reactant: Cc1n[nH]c(C)c1Cl
Solvent: COCCOC
Product: CCc1cccc(C)c1N(Cn1nc(C)c(Cl)c1C)C(=O)CCl
Temperature: 0 °C

Procedure:
21.4 parts by weight of 2-chloro-2'-methyl-6'-ethyl-N-chloromethyl acetanilide and 20.2 parts by weight of 4-chloro-3,5-dimethylpyrazole are refluxed for 10 hours in 100 parts by volume of glycol dimethyl ether. After cooling the mixture to 0° C., it is filtered, and the filtrate, concentrated to 23.8 parts by weight, is filtered with 600 parts by volume of chloroform through 50 parts by weight of silica gel. From the concentrated chloroform filtrate there is isolated 20.4 parts by weight of 2-chloro-2'-methyl-6'-ethyl-N-(4-chloro-3,5-dimethylpyrazol-1-yl-methyl)-acetanilide as an oil which completely crystallizes upon milling with 50 ml of petroleum ether (m.p. 66° C. from petroleum ether).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:49][CH:48]=2)(=O)=O)=CC=1.O.NN>CN(C=O)C.O>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N3C(=O)c4ccccc4C3=O)cc2)cc1
Reactant: Oc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of the 2-(1-trityl-1H-imidazol-4-yl)phenol (1.1 g, 2.73 mmol) in DMF (15 mL) was added NaH (83 mg, 3.28 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. 4-(1,3-dioxoisoindolin-2-yl)phenethyl 4-methylbenzenesulfonate (1.15 g, 2.73 mmol) was added to the mixture. After stirring overnight under a nitrogen atmosphere, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (2×20 mL), brine (20 mL) and dried. The solvent was removed under reduced pressure and, the crude product was dissolved in ethanol (15 mL) and treated with hydrazine hydrate (0.3 mL, 5.46 mmol). The mixture was heated at 80° C. for 2 h and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, 30%-50% EtOAc/hexanes as eluent) to afford the desired product as a yellow solid (862 mg, 60% over two steps). 1H NMR: 2.63 (t, 2H, J=7.6 Hz), 4.03 (t, 2H, J=7.6 Hz), 6.46 (d, 1H, J=8.4 Hz), 6.80 (dd, 2H, J=12.4 Hz, 8 Hz), 6.99 (t, 1H, J=7.6 Hz), 7.10-7.19 (m, 7H), 7.28-7.31 (m, 9H), 7.41 (s, 1H), 7.52 (s, 1H), 8.18-8.21 (m, 1H), 8.63 (s, 1H), 9.11 (s, 1H).