Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][O-:12].[Na+].I[CH3:15].O>CN(C=O)C.CO>[CH3:11][O:12][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: C[O-]
Reactant: CI
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccnc(OC)c1
Temperature: 130 °C
Reaction time: 14 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2-chloroisonicotinic acid (10.0 g) in DMF (150 mL) was added a 28% solution of sodium methoxide in methanol (38.6 mL), and the mixture was stirred at 130° C. for 14 hr. Iodomethane (15.9 mL) was added to the reaction mixture at 80° C., and the mixture was stirred at 80° C. for 5 min. Water was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (8.57 g) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[C:11]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].CCO>N1CCCCC1.O>[Br:10][C:7]1[CH:6]=[C:3]2[C:2](=[N:9][CH:8]=1)[N:1]=[C:23]([CH3:24])[C:22]([C:21]([NH:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:28][CH:27]=1)=[O:26])=[CH:4]2
Reactant: Nc1ncc(Br)cc1C=O
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1nc2ncc(Br)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Yield: 54.5 %

Procedure:
2-Amino-5-bromonicotinaldehyde (0.50 g, 2.49 mmol) and N-(4-tert-butylbenzyl)-3-oxobutanamide (0.62 g, 2.49 mmol) were suspended in piperidine (1.0 ml) and EtOH (1.0 ml) in a high-pressure vial. The mixture was heated at 120° C. for 4.5 hours and then cooled to room temperature. The reaction was diluted with water (40 ml) and extracted with CH2Cl2 (3*30 ml). Combined organics were washed with water (30 ml), dried over MgSO4 and evaporated. The crude product was purified by flash chromatography using CH2Cl2/CH3OH (20:1) as eluent to give 0.56 g (54%) of 6-bromo-N-(4-tert-butylbenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide as yellow solids.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 9.1 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester in 50 ml of DMF, 3.7 g of HOBT and 4.7 g of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was used in the next reaction step. Yield: 12.6 g.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])[N:7]([CH2:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2c(C)noc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)noc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
To a solution of ethyl 4-{4-chloro-2-[(3,5-dimethylisoxazol-4-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}butanoate (400 mg, 0.90 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (62 mg, 2.68 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hr. Additional lithium borohydride (62 mg, 2.68 mmol) was added and the mixture was warmed to 50° C. for 4 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to give the title compound (193 mg, 0.47 mmol, 53%) as a colorless solid.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:13]2=[O:37])[CH2:8]1)(C)(C)C.O>FC(F)(F)C(O)=O.ClCCl>[OH:6][C@@H:7]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:13]2=[O:37])[CH2:8]1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@@H]3CC[C@@H](O)C3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
(−)-(1R,3R)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (148 mg, 0.27 mmol) (from Example 27e supra) was dissolved at 0° C. in a 25% trifluoroacetic acid in dichloromethane solution (5 mL) that contained water (300 μL). After stirring for 30 minutes the reaction mixture was partitioned between ethyl acetate and 0.5 N aqueous sodium hydroxide. The pH of the aqueous layer was adjusted to 12 via the addition of solid sodium hydroxide. The organic layer was then collected, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by silica gel column chromatography using a 0–100% ethyl acetate in hexanes to 0–40% tetrahydrofuran in ethyl acetate gradient followed by a precipitation out of dichloromethane with excess pentane afforded (+)-(1R,3R)-1-(3-hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 92 mg, 86%).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)=[CH:11][CH:10]=1.C(Cl)Cl>O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2=[C:13]3[C:18]=1[CH:17]=[CH:16][CH:15]=[C:14]3[C:2](=[O:3])[C:23]1[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(-c2cc3ccccc3o2)c2ccccc12
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c3c(cccc13)C(=O)c1c-2oc2ccccc12
Reaction time: 1.5 h

Procedure:
Alternatively, 3-methoxy-7-oxo-7H-benzo[b]-phenaleno[2,1-d]furan was prepared by addition of 0.38 ml. (45 mmol.) of oxalyl chloride followed by 1.2 ml. (0.01 mol.) of stannic chloride to a solution of 1 g. (37 mmol.) of 2-(4-methoxynaphthyl)benzofuran in 100 ml. of methylene chloride at 0°. The reaction mixture was stirred for 1.5 hours at 0° then poured into water. The layers were separated and the organic phase was washed with 10% aqueous sodium carbonate, dried (MgSO4) and evaporated to dryness. The residue was chromatographed on silica with chloroform as eluant to give the product.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.S(=O)(=O)(O)O.[CH2:21](O)[CH:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH2:21]([O:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:4]=1[NH2:1])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)c1ccc(N)cc1N
Temperature: 25 °C

Procedure:
To a mixture of 212 g of 2,4-dinitrobenzoic acid in 300 ml of toluene were added 38 g of concentrated sulfuric acid and 230 ml of isobutyl alcohol. The mixture was refluxed for 10 hrs and the resulting water removed by azeotropic distillation. After this period the mixture was cooled to room temperature and washed with 1000 ml of an aqueous 5% NaHCO3 solution followed by two 500 ml water washings. The toluene was removed at reduced pressure and the resulting dark oil was washed with hexane to yield 252 g of isobutyl-2,4-diaminobenzoate, a fluffy white crystalline solid, mp 54°-55° C.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>>[CH3:19][CH:18]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[C:1](=[O:14])[NH:2][CH2:3][CH2:4][C:5]1=2)[CH3:20]
Reactant: CC(C)Br
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Agent: [H-]
Agent: [Na+]
Product: CC(C)n1c2c(c3ccccc31)C(=O)NCC2
Yield: 28.4 %

Procedure:
2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-1-one (931 mg) was treated with sodium hydride (73% dispersion in oil; 328 mg) and was then stirred with 2-bromopropane (615 mg) at room temperature for 72 h. Purification by FCC eluting with System A (200:8:1) gave a foam (324 mg) which was further purified by recrystallisation from ethyl acetate: hexane (1:1) to give the title compound (249 mg), t.l.c. (System A, 100:8:1) Rf 0.58.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH2:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:6]([C:7](=[O:9])[C:27]2[CH:28]=[CH:29][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=2)[C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CCc1ccccc1
Reactant: COC(=O)c1cc(Cl)c(C(=O)O)cc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cc(Br)c(C(=O)OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-chloro-4-(methoxycarbonyl)benzoic acid (1.21 g, 4.15 mmol) in dry dichloromethane (22.5 mL) was added dropwise oxalyl chloride (0.43 mL, 4.96 mmol) followed by N,N-dimethylformamide (1 mL). After being stirred for 2 h at room temperature, the reaction mixture was evaporated and the residue was dissolved in dry dichloromethane (20 mL) at room temperature under agron. After cooling to −5° C., ethylbenzene (0.46 g, 4.35 mmol) was added. Then AlCl3 (1.72 g, 12.8 mmol) was added portionwise and the reaction temperature was kept between −5° C. and 0° C. After being stirred at the same temperature for two hours, the reaction mixture was poured onto ice water and extracted with dichloromethane (100 mL). The combined organic layers were washed with 1 M HCl (60 mL), water (30 mL) and brine (60 mL), and dried over anhydrous Na2SO4 Concentration under reduced pressure provided the title compound as a yellow solid. Yield: 1.37 g (87%). 1H-NMR (CDCl3, 300 MHz): δ 7.89 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.64 (s, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 3.98 (s, 3H), 2.70 (q, J=7.8 Hz, 2H), 1.27 (t, J=7.8 Hz, 3H).
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3](OC)=[O:4].[NH2:9][C:10](N)=[S:11].C([OH:17])CCC>>[CH3:8][C:2]1([CH3:7])[S:11][C:10](=[O:17])[NH:9][C:3]1=[O:4]
Reactant: COC(=O)C(C)(C)Br
Reactant: NC(N)=S
Reactant: CCCCO
Product: CC1(C)SC(=O)NC1=O
Temperature: 110 °C
Reaction time: 5 h

Procedure:
41.4 mmoles of methyl 2-bromo-2-methyl-propionate and 4.56 mmoles of thiourea are dissolved in n-butanol (90 mL) and stirred at 110° C. for 5 hours. The solvent is evaporated to dryness and the residue is taken up in ethanol (120 ml) and HCl (2N, 120 mL) and then heated at reflux for 16 hours. The ethanol is evaporated off and the mixture is diluted with water (120 ml) and then extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over magnesium sulphate, filtered and evaporated to dryness. The crystals obtained are washed with pentane, filtered off and dried in vacuo to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:19]([C:22]1[CH:31]=[C:30]([C:32]([NH:34][NH2:35])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])([O-:21])=[O:20].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:35][NH:34][C:32]([C:30]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([N+:19]([O-:21])=[O:20])[CH:31]=3)=[O:33])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]
Yield: 87.8 %

Procedure:
From 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.70 mmol, 200 mg) synthesized in Synthetic Example 1, methyl 2-nitro-4-hydrazinocarbonylbenzoate (0.70 mmol, 167.8 mg) of Reference Synthetic Example 40 and tosylic acid monohydrate (36.2 mg, 0.21 mmol), 311.1 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a yellow solid (yield 88%).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[Na+].C([O:24][CH2:25][CH3:26])(=O)C.[CH3:27]CCCCC>CC(C)=O.[Cl-].[Na+].O>[CH2:1]([O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[CH:27][C:25](=[O:24])[CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCOc1ccccc1C=O
Reactant: CCCCCC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCOc1ccccc1C=CC(C)=O

Procedure:
2-(nonyloxy)benzaldehyde (62 g) dissolved in acetone (500 mL) was treated with aqueous sodium hydroxide (100 mL, 1M) at room temperature for 18 h. Brine and ethyl acetate/hexane (1:1 parts by volume) was then added. Concentration of the organic phase followed by crystallization from hexane gave 4-(2-nonyloxyphenyl)-3-butene-2-one (53 g).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])=[CH:4][C:3]=2[O:2]1.[Cl:15][CH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:18]1>>[ClH:15].[ClH:15].[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][CH:17]([CH2:16][N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:12]5[O:13][CH2:1][O:2][C:3]=5[CH:4]=4)[C:9]3=[O:14])[CH2:18]2)[CH:26]=1
Reactant: O=C1NCCc2cc3c(cc21)OCO3
Reactant: ClCC1CCN(CCCc2cccnc2)C1
Product: Cl
Product: O=C1c2cc3c(cc2CCN1CC1CCN(CCCc2cccnc2)C1)OCO3

Procedure:
Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(pyrid-3-yl)-propyl]-pyrrolidine analogously to Example 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][N:14]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:17]([C:16]2[CH:15]=[N:14][C:13]([Cl:12])=[CH:21][CH:20]=2)=[O:18])[CH:5]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COC(=O)c1cccc(NC(=O)c2ccc(Cl)nc2)c1

Procedure:
3-[(6-Chloro-pyridine-3-carbonyl)-amino]-benzoic acid methyl ester was prepared from 3-amino-benzoic acid methyl ester and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H11N2O3Cl [M+H]+: 291.0531. Found: 291.0531.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1([CH3:23])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[O:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:14][C:13]1([CH3:15])[C:9]([CH3:8])([CH3:23])[O:10][B:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:18][CH:17]=2)[O:12]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethyl bromoacetate (0.60 mL) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 g) and potassium carbonate (0.94 g) in N,N-dimethylformamide (5 mL), and the mixture was stirred overnight at 80° C. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to afford the title compound (1.33 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Solvent: CC(C)=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1

Procedure:
In a manner similar to that of Example 75(a), by reacting g (150 mmol) of 5-bromo-2-hydroxy-benzaldehyde and 17.8 ml (150 mmol) of benzyl bromide in 300 ml of acetone, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 22.8 g (52%) of the expected product are obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1>[C:3]([C:2]1([CH2:1][CH2:8][CH2:7][CH2:6][CH3:11])[CH2:4][C:9]2[C:10]([CH3:10])([CH3:2])[CH2:11][CH2:6][C:7]([CH3:1])([CH3:9])[C:8]=2[CH2:3]1)#[CH:4]
Reactant: [Li]CCCC
Reactant: CCCCCC
Solvent: C1CCOC1
Product: C#CC1(CCCCC)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.6 g of this dibromide were dissolved in 10 ml of THF, cooled to −78° C. and treated dropwise with 1.8 ml of a 1.6 molar solution of butyl lithium in hexane. After stirring at −78° C. for 1 hour and at room temperature for 1 hour, the reaction mixture was poured on ice/saturated aqueous ammonium chloride solution and extracted with hexane. The organic phase was dried (Na2SO4) and the solvent evaporated to yield 0.4 g of 2-ethynyl-4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene as yellowish oil.
Reaction SMILES: [Na].N1C=CN=N1.Br[CH:8]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:9]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11]>C(#N)C>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:9]([S:10]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])=[CH:8][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Agent: [Na]
Agent: c1c[nH]nn1
Solvent: CC#N
Product: CC(C)(C)C(=O)C=C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
Sodium ethylate was prepared by dissolving 2.3 g of metallic sodium in 100 ml of 99% ethanol, which was then mixed with 6.9 g of triazole and stirred for 30 minutes. The mixture was evaporated to dryness under reduced pressure to give sodium salt of triazole. Thus prepared sodium salt of triazole (0.91 g) was added to a solution of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one (4.78 g) in acetonitrile (50 ml), and refluxed for 1 hour. After cooling, the mixture was added to 200 ml of ice water and extracted with ethyl acetate. The organic layer was then treated in the same manner as that of the method A to give 3.77 g of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonyl-1-penten-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Cl.Cl[CH2:12][CH2:13][NH2:14].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][CH:8]=1
Reactant: NCCCl
Reactant: COc1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cccc(SCCN)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
A mixture of 3-methoxybenzenethiol (5 g), 2-chloroethylamine hydrochloride (1.1 eq.) and Cs2CO3 (2.2 eq.) in CH3CN (60 mL) was stirred at 60° C. for 20 h. To the reaction mixture, EtOAc (100 mL) was added, and washed with H2O (2×30 mL). The organic phase was concentrated under reduced pressure to give product 20 (Yield: 6.2 g, 95%), which appeared to be pure by TLC and NMR and was used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([C:10]#N)=[CH:3]1.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=[O:24].[Na+].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10]=[O:24])=[CH:3]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC1(C)C=C(C#N)C(C)(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)C=C(C=O)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
To the mixture of the product of Example 10f (500 mg, 3.07 mmol) in dry dichloromethane (12.5 mL) at −78° C. was added diisobutyl aluminum hydride (6.5 mL, 6.14 mmol) and the reaction was warmed to room temperature and stirred for approximately 2.5 hours. Wet sodium sulfate was added to quench the reaction. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a colorless oil. (360 mg, Yield: 71%). 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 6.33 (s, 1H), 1.55-1.49 (m, 4H), 1.20 (s, 6H), 1.10 (s, 6H) ppm.