Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=O)[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[NH2:24][OH:25].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[N:24][OH:25])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCC1CCC(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCC1CCC(=NO)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Temperature: 95 °C

Procedure:
A mixture of [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid (3.4 g, 0.01 mole), hydroxylamine hydrochloride (2.1 g, 0.03 mole) and pyridine (40 ml) were heated at 95° C. for 40 hours, poured into ice-water and hydrochloric acid, extracted with ether, washed with water, dried over magnesium sulfate and evaporated in vacuo. After recrystallization from toluene (120 ml) the [2,3-dichloro-4-(6-ethyl-3-(hydroxyimino)-1-cyclohexen-1-yl)-phenoxy]acetic acid hemitoluene solvate melted at 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([NH2:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCN
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCNCCOc1ccc(Cl)cc1Cl

Procedure:
In 20 ml of ethanol was dissolved 2.70 g (10.0 millimoles) of 2-(2,4-dichlorophenoxy)ethyl bromide, and 1.06 g (10.0 millimoles) of anhydrous sodium carbonate and 3.87 g (30.0 millimoles) of n-octylamine were added to the solution. The mixture was refluxed for 6 hours on an oil bath. After cooling, the reaction mixture was poured into 100 ml of water and extracted with 20 ml of chloroform three times.
Reaction SMILES: [C:1]([Cl:4])(=O)C.Cl.[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C@H:10]([C:17]([OH:19])=[O:18])[NH:11][CH2:12]2>CO>[ClH:4].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C@H:10]([C:17]([O:19][CH3:1])=[O:18])[NH:11][CH2:12]2
Reactant: CC(=O)Cl
Reactant: O=C(O)[C@H]1Cc2c(Br)cccc2CN1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H]1Cc2c(Br)cccc2CN1
Temperature: 25 °C
Reaction time: 36 h
Yield: 100.4 %

Procedure:
Dissolve dimethyl (3R)-5-bromo-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate (27.55 g, 84.0 mmol) in 5N hydrochloric acid (330.6 mL, 1.65 mol) and heat to reflux for three days. Concentrate under reduced pressure to give a white solid. Wash the solid with diethyl ether and dry under vacuum at 40° C. overnight to give (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1:1) (20.8 g, 71.1 mmol). Add acetyl chloride (50.6 mL, 711.0 mmol) to a 0° C. mixture of (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1:1) (20.8 g, 71.1 mmol) in methanol (474 mL). Warm to room temperature and stir for 36 hours. Concentrate under reduced pressure and dry to give the title compound (21.9 g, 71.4 mmol). MS (m/z): 270 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([F:9])([F:8])[F:7])C>C1(C)C=CC=CC=1>[C:14]([O:13][C:11](=[O:12])[NH:10][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)([CH2:4][OH:3])[C:6]([F:7])([F:8])[F:9])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(CO)(c1cccc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an at −7° C. stirred solution of 5 g (11.73 mmol) 2-(3-bromo-phenyl)-2-tert-butoxycarbonylamino-3,3,3-trifluoro-propionic acid ethyl ester in 50 ml toluene were added 58.7 ml of a 1.7M solution of DibalH in toluene. The mixture was stirred overnight at rt and quenched with an aqueous tartaric acid solution. The mixture was extracted with EtOAc and the organic phase was washed with brine, dried with MgSO4.H2O and evaporated. Purification via chromatography on silica gel (c-hexane/15-50% TBME) gave the desired product as a colorless resin.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH2:26]([NH:29][CH2:30][CH2:31][OH:32])[CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][N:29]([CH2:30][CH2:31][OH:32])[C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:23]
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OCCNCCO
Product: CC1(C)c2cc(C(=O)N(CCO)CCO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and N,N-diethanolamine.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1>>[C:35]([O:34][C:32](=[O:33])[CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:12](=[O:13])[C:11]([CH3:15])([CH3:16])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:26][CH2:27]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CC1CCNCC1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Product: CC(C)(C)OC(=O)CC1CCN(C(=O)C(C)(C)C(NC(=O)c2ccc(C#N)cc2)c2ccccc2)CC1
Yield: 60.2 %

Procedure:
The same procedure as in Example 2-(6-2) was performed with N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine (0.5 g, 1.55 mmol) using t-butyl 4-piperidine acetate (0.93 g, 4.66 mmol) to yield an oil of N-4-cyanobenzoyl-β-phenylα,α-dimethyl-β-alanyl-4-piperidineacetic acid t-butyl ester (470 mg, 60.2%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Pb](=O)=O>C1(C)C=CC=CC=1>[OH:8][C:5]1[C:6]([C:6]2[C:5]([OH:8])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(O)cn1
Agent: O=[Pb]=O
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(-c2nc(C)ccc2O)n1
Yield: 9.3 %

Procedure:
6-Methyl-3-hydroxypyridine (23.9 g, 0.219 moles), lead dioxide (98.3 g, 0.411 moles) and toluene (1 liter) were combined and refluxed for five hours. The hot solution was filtered and evaporated to dryness. The residue was refluxed with hexane and filtered while hot. The solution was evaporated to dryness giving the product as a yellow powder.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:24]([C@H:25]2[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C@@H:27]([CH2:34][OH:35])[O:26]2)=[CH:23][CH:22]=[CH:21][C:5]=1[CH2:6][C:7]1[CH:16]=[C:15]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14]2)[C:8]=1C(OC)=O.C(OCC)(=O)C.Cl>CO>[CH:8]1[C:9]2[C:15]([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:7]=1[CH2:6][C:5]1[C:4]([F:3])=[C:24]([C@@H:25]2[O:26][C@H:27]([CH2:34][OH:35])[C@@H:28]([OH:33])[C@H:29]([OH:32])[C@H:30]2[OH:31])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1c(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2F)cc2cccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2F)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 60.3 %

Procedure:
10% aqueous solution of sodium hydroxide (2 ml) was added to a solution of methyl 2-[2-fluoro-3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylate (19 mg) in methanol (2 ml). The mixture was refluxed with heating for 2 hours. The reaction mixture was neutralized by adding a 4 M ethyl acetate solution of hydrochloric acid and the solvent was evaporated under reduced pressure. Acetonitrile (5 ml) and a 4 M ethyl acetate solution of hydrochloric acid (1 ml) were added to the resulting residue and the mixture was refluxed with heating for 30 minutes. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)-2-fluorophenyl]-D-glucitol (10 mg).
Reaction SMILES: Cl.[CH3:2][C:3]([NH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[C:21]([O:33]CC2C=CC=CC=2)[C:20]=1[CH3:41])=[O:18])([CH3:14])[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7](O)[C:6]=1[CH3:13].C[OH:43]>[Pd]>[CH3:14][C:3]([NH:15][CH2:16][CH:17]([C:19]1[C:20]([CH3:41])=[C:21]([OH:33])[C:22]([OH:25])=[CH:23][CH:24]=1)[OH:18])([CH3:2])[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:43])=[CH:7][C:6]=1[CH3:13]
Reactant: CO
Reactant: Cc1ccc(O)c(C)c1CC(C)(C)NCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1C
Agent: [Pd]
Agent: Cl
Product: Cc1cc(O)cc(C)c1CC(C)(C)NCC(O)c1ccc(O)c(O)c1C

Procedure:
7 g of 2-[1,1-dimethyl-2-(2,6-dimethylhydroxyphenyl)ethylamino]-1-(3,4-dibenzyloxy-2-methylphenyl)ethanone hydrochloride in 125 mL of methanol is hydrogenated using 2 g of palladium on charcoal (5%). After separation of the catalyst, the solvent is distilled off. The solid that crystallizes out is stirred into acetonitrile, suction filtered, and washed. Yield: 3.5 g of hydrochloride; melting point: 182° C.–183° C. (decomposition).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](=[N:13][OH:14])[NH2:12])=[CH:9][CH:8]=1.[C:17]([O:21][C:22]([NH:24][CH:25]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29][CH2:30][C:31](O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(#N)C.N1C=CC=CC=1.[Cl-].[Na+].O>[C:17]([O:21][C:22](=[O:23])[NH:24][CH:25]([C:26]1[CH:36]=[CH:35][CH:34]=[C:28]([O:29][CH2:30][C:31]2[O:14][N:13]=[C:11]([C:10]3[CH:15]=[CH:16][C:7]([CH2:6][CH:2]4[O:3][CH2:4][CH2:5][O:1]4)=[CH:8][CH:9]=3)[N:12]=2)[CH:27]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC(=O)O)c1
Reactant: NC(=NO)c1ccc(CC2OCCO2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2nc(-c3ccc(CC4OCCO4)cc3)no2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-((1,3-dioxolan-2-yl)methyl)-N′-hydroxybenzimidamide (0.747 g, 3.35 mmol) and 2-(3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)phenoxy)-acetic acid (Example 59 Step 2, 1.0 g, 2.79 mmol)) in acetonitrile (5 mL), was added 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.8 g, 4.18 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with pyridine (1 mL) and heated at 150° C. for 30 minutes in a microwave. The reaction was diluted with saturated brine and extracted with ethyl acetate (×3). The combined organic fractions were dried with magnesium sulphate, and the solvent evaporated at reduced pressure. Material used directly in the next step without further purification (1.01 g, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[O:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC.O>[CH3:15][O:10][CH2:11][CH2:12][O:13][CH2:14][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(Br)c(C)c1
Reactant: C1COCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCCCCC
Product: COCCOCc1ccc(C)cc1C
Temperature: 100 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a mixture of 4-bromo-m-xylene (30 mg, 0.16 mmol, containing 2-bromo-m-xylene) and 1,4-dioxane (2 ml) were added water (0.2 ml), cesium carbonate (0.16 mg, 0.49 mmol), potassium (2-methoxyethoxymethyl) trifluoroborate (64 mg 0.32 mmol), palladium (II) acetate (3.6 mg, 0.016 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (13 mg, 0.032 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 12 hours. After the reaction mixture was allowed to cool at room temperature, to the reaction mixture was added water and hexane. The organic layer was washed with an aqueous saturated sodium chloride solution, and the organic layer was separated. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (hexane 100%) to obtain the title compound (32 mg, 0.16 mmol, 71%) as a mixture of 2-(2,6-dimethylbenzyloxy)ethyl methyl ether derived from 2-bromo-m-xylene contained in a raw material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][N:19]=[N+]=[N-])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1>[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(C)c1-c1cccc2c1CC(CN=[N+]=[N-])O2
Agent: [Pd]
Product: Cc1cccc(C)c1-c1cccc2c1CC(CN)O2
Yield: 93 %

Procedure:
Treatment of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.27 g, 5.55 mmol) with sodium azide (1.44 g, 22.23 mmol) generally according to the procedure described for Intermediate 98 gave 1.41 g (91%) of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.141 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.36 g (93%) of (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 254-256° C.; Anal. calcd. for C17H19NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 69.03; H, 7.05; N, 4.66.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCCCCC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: CCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1.08 g. of benzylalcohol, 1.16 g. of caproic acid, 2.20 g. of 2,2'-dipyridyl disulfide and 50 ml. of methylene chloride is added dropwise a solution of 2.62 g. of triphenyl phosphine in 20 ml. of methylene chloride while stirring at room temperature. After completion of the addition, the mixture is stirred at room temperature for an additional 3 hours. The reaction mixture is treated with the same procedure as in Example 1 (1) to give 1.9 g. of the desired product boiling at 75°C/0.2 mmHg.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([OH:22])=O)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:27][O:26][N:25]([CH3:24])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)n1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(6-Methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 1.27 g (12.7 mmol) of N,O-dimethylhydroxylamine hydrochloride, 9 mL (6.5 g, 64.7 mmol) of triethylamine and 9.2 mL (9.83 g, 15.5 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 50 mL acetonitrile to give 2.30 g of the product as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][CH2:7][C:8](Br)=[O:9]>ClCl.C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:8](=[O:9])[CH2:7][Br:6])[CH3:2]
Reactant: CCNCC
Reactant: O=C(Br)CBr
Agent: ClCl
Solvent: ClCCl
Product: CCN(CC)C(=O)CBr
Reaction time: 2 h

Procedure:
N,N-diethylbromoacetamide was prepared as follows: Diethylamine (1.54 mL, 14.9 mmol) and TEA (2.49 mL, 17.9 mmol) were dissolved in 75 mL CH2 Cl2, then bromoacetyl bromide (1.29 mL, 14.9 mmol) was added dropwise. After 2 h, the reaction was diluted with CH2Cl2, washed with water (2×), and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 45% EtOAc/hexanes) provided N,N-diethylbromoacetamide as a lachrymatory yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=1[NH:8][NH2:9])#[N:2].Cl>CO.C(OCC)(=O)C>[NH2:2][C:1]1[C:3]2[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=2[NH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)c1cc(C#N)c(NN)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc2c(N)n[nH]c2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.5 %

Procedure:
A mixture of tert-butyl 4-cyano-5-hydrazinothiophene-2-carboxylate (1.0 g, 4.2 mmol) and hydrochloric acid (0.7 mL of a 37% solution) in methyl alcohol (15 mL) was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with an aqueous solution of sodium bicarbonate. Organic layer was separated, dried over anhydrous sodium sulfate and evaporated to afford 0.9 g of the title compound.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl>C(O)C.[OH-].[Na+]>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:2]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1

Procedure:
A 3.15 g sample of methyl 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoate is refluxed for 8 hours in 100 ml of ethyl alcohol and 2.5 ml of 10N sodium hydroxide. The cooled reaction mixture is acidified with hydrochloric acid and the desired product collected and dried to give 2.9 g of the desired product as a solid m.p. 246°-249° C. M+H=318 .
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:20][C:4]=2[NH:3]1.[CH3:29][C:30](OC(C)=O)=[O:31]>C1COCC1>[C:30]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]#[C:21][C:19]2[CH:18]=[CH:17][C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=4)[C:12]#[N:13])[CH2:8][C:2](=[O:1])[NH:3][C:4]=3[CH:20]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Solvent: C1CCOC1
Product: CC(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Yield: 96.3 %

Procedure:
Prepared from 3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 140) (55 mg, 0.15 mmol) by treatment with Ac2O (0.017 mL, 0.165 mmol) in THF (3 mL) at 23° C. for 1 h. Obtained as a sand solid (59 mg).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[Cl:32][C:33]1[CH:38]=[C:37](Cl)[N:36]=[C:35]([CH3:40])[N:34]=1>C1COCC1>[Cl:32][C:33]1[CH:38]=[C:37]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:28][CH2:29][CH2:30][CH3:31])[N:36]=[C:35]([CH3:40])[N:34]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(Cl)nc(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium solution, 1.6 M in hexane (0.184 mL, 2.200 mmol, Aldrich, St. Louis, Mo.) was added to a solution of diisopropylamine (0.314 mL, 2.200 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Tributyltin hydride (0.527 mL, 2.000 mmol, Aldrich, St. Louis, Mo.) was added dropwisely. The solution was stirred at 0° C. for 15 min. The mixture was cooled down to −78° C., 4,6-dichloro-2-methylpyrimidine (326 mg, 2.000 mmol, Aldrich, St. Louis, Mo.) in THF (2 mL) was then added and the mixture was stirred at −78° C. for 8 h. The mixture was quenched by saturated aqueous KF (4 mL), and extracted with EtOAc (30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give 4-chloro-2-methyl-6-(tributylstannyl)pyrimidine as a light-yellow oil. The crude material was used directly in the next step without purification.
Reaction SMILES: [OH-].[Na+].[CH:3]1([OH:10])[CH2:8][CH2:7][CH:6](O)[CH2:5][CH2:4]1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:10][CH:3]1[CH2:4][CH2:5][CH:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8]1
Reactant: OC1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)CC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
Sodium hydroxide (5.7 g, 0.14 mol) was dissolved in water (6 ml) and 1,4-cyclohexanediol (cis/trans=6/4) (15.0 g, 0.13 mol) was added, which was followed by stirring at room temperature for 30 minutes. Then, tetrabutylammonium bromide (20.8 g, 0.065 mol) and t-butyl bromoacetate (24.5 ml, 0.13 mol) were added, and the mixture was stirred at room temperature for one hour. The reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column Chromatography (n-hexane/ethyl acetate=5/1-2/1) to give 2.13 g of t-butyl (4-hydroxycyclohexyl)acetate as a transparent oil (7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Temperature: 60 °C
Yield: 73.4 %

Procedure:
A solution of N-t-butoxycarbonyl-5-methoxycarbonylisoindoline (D12) (2.11 g) in MeOH (10 ml) was treated with 1M NaOH and heated at 60° C. for 1 h. The mixture was cooled to rt and the MeOH evaporated. The aqueous was washed with diethyl ether (2×20 ml), then acidified with 5% citric acid solution and extracted with diethyl ether (2×20 ml). The combined extracts were washed with water (2×20 ml), brine (20 ml), dried (MgSO4) and evaporated to give the title compound (D13) (1.47 g). MS electrospray (+ion) 264 (MH+). 1H NMR δ (CDCl3): 8.02 (2H, m), 7.35 (1H, m), 4.75 (2H, s), 4.71 (2H, s), 1.53 (9H, s).