Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:9]=3[NH:10]2)=[CH:6][CH:5]=1.[CH3:26]I.O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[CH2:16][C:15]([CH3:17])([CH3:18])[N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:9]=3[N:10]2[CH3:26])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]c3cc(Br)ccc3c2CC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)cc31)CC(C)(C)N(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
NaH (60% dispersion in oil, 42 mg, 1.1 mmol) was added to a solution of tert-butyl 7-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (200 mg, 0.528 mmol) in DMF (10 mL) under N2, and the resulting suspension was stirred at 25° C. for 30 min. MeI (0.05 mL, 0.8 mmol) was added to the suspension, and the resulting suspension was stirred at 25° C. for 1 h. H2O was added, and the resulting solid was collected by filtration. Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded the title compound (145 mg, 70%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.43 (d, J=1.5 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.3, 1.5 Hz, 1H), 4.62 (s, 2H), 3.61 (s, 3H), 2.77 (s, 2H), 1.52 (s, 6H), 1.49 (s, 9H).
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.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[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: O=Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Yield: 81.1 %

Procedure:
To a solution of 5-bromo-2-hydroxybenzaldehyde (5 g, 24.9 mmol) in acetone (200 mL) were added benzyl bromide (5.11 mL, 29.9 mmol), potassium iodide (KI, 2.07 g, 12.45 mmol) and potassium carbonate (K2CO3, 5.17 g, 37.4 mmol), followed by mixing at 70° C. for 2 hours under a reflux condition. The product thus obtained was diluted in ethyl acetate (EtOAc), washed with brine, and dried over magnesium sulfate (MgSO4) to concentrate it. The concentrate was purified using silica column chromatography (10% ethyl acetate/hexane) to afford the title compound (5.88 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]1[CH2:16][CH2:15][C:14](=O)[CH2:13]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][CH:14]1[CH2:15][CH2:16][CH:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH3:11])[CH:6]=2)[CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cn1cc(C2CCC(=O)C2)c2cc(F)ccc21
Product: Cn1cc(C2CCC(NCc3ccccc3)C2)c2cc(F)ccc21
Yield: 101.6 %

Procedure:
This compound was prepared in the same manner as for Intermediate 6, using 3-(5-fluoro-1-methyl-1H-indol-3-yl)-cyclopentanone (1.25 g, 5.19 mmol) and benzylamine (0.66 g, 6.2 mmol) to afford 1.7 g of the desired product as a mixture of cis and trans isomers. Flash chromatography on silica gel (3% 2 M NH3 in methanol/ethyl acetate) afforded 0.4 g (23%) of the cis isomer (first eluting) and 0.45 g (27%) of the trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:22]([CH3:25])([O-:24])=[O:23].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:13])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([CH2:25][N+:22]([O-:24])=[O:23])=[O:6]
Reactant: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1

Procedure:
This compound was obtained by carrying out the procedure as in Example 42 starting with 19 g (62.5 mmol) of 2-chloro-4-[(2-methylbenzyl)carbonylamino]benzoic acid obtained in step a), 3.18 g of nitromethane, 11 g (67.6 mmol) of diethyl cyanophosphonate, 16.8 g (167 mmol) of triethylamine in 205 ml of DMF dried over a molecular sieve. After chromatography on a silica column (eluent: dichloromethane-methanol 95:5) and recrystallization from a hexane-ethyl acetate mixture, 0.2 g (Yield=1) of a pale yellow powder is obtained.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH2:47][CH2:48][O:49][CH3:50])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH2:47][CH2:48][O:49][CH3:50])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:15][CH2:16][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:22]=2[CH2:23]1)[CH3:2]
Reactant: COCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCOC)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 6.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.3 mg) was obtained.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[N:12]=[CH:11][C:10]=1[C:23]#[N:24])[C:3]([O:5]CC)=[O:4].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:23]([C:10]1[CH:11]=[N:12][N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[C:9]=1[CH:8]=[CH:2][C:3]([OH:5])=[O:4])#[N:24]
Reactant: CCOC(=O)C(Cl)Cc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1C=CC(=O)O
Yield: 68.1 %

Procedure:
A stirred slurry of 0.35 gram (0.0009 mole) of ethyl 2-chloro-3-[4-cyano-1-(2,3,4-trichlorophenyl)-1H-pyrazol-5-yl]propionate and 0.24 gram (0.002 mole) of potassium carbonate in 35 mL of 50% aqueous ethanol was heated at reflux for one hour. The reaction mixture was then cooled and concentrated under reduced pressure, leaving a residue. The residue was dissolved in water, and the solution was washed once with methylene chloride. The aqueous layer was stirred and acidified by the dropwise addition of concentrated hydrochloric acid. Upon acidification, the mixture was stirred for one hour, and the resultant solid was collected by filtration. The solid was dried, yielding 0.21 gram of 3-[4-cyano-1-(2,3,4-trichlorophenyl)-1H-pyrazol-5-yl]acrylic acid; m.p. 215°-219° C. A small sample was recrystallized from ethanol and water to raise the m.p. to 226.5°-228.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH:30][CH2:31][CH3:32])=CC=1C(O)=O.N1CCCC1>>[CH2:31]([NH:30][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH3:32]
Reactant: CCNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CCNS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 43 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-ethylsulfamoyl-benzoic acid and pyrrolidine and obtained in 43% yield. MS (m/e): 202.2 (MH−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:14]1=[O:21]
Reactant: ClCc1ccccc1Cl
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccccc3Cl)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-chlorobenzylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60°-95° C.). M.p. 101°-104° C.
Reaction SMILES: C(OC[N:10]1[N:14]=[N:13][C:12]([C:15]2[S:16][C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:18]([CH3:20])[N:19]=2)=[N:11]1)C1C=CC=CC=1>CO.Cl>[CH3:20][C:18]1[N:19]=[C:15]([C:12]2[N:13]=[N:14][NH:10][N:11]=2)[S:16][C:17]=1[C:21]([NH:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:22]
Reactant: Cc1nc(-c2nnn(COCc3ccccc3)n2)sc1C(=O)NCc1cccnc1
Agent: Cl
Solvent: CO
Product: Cc1nc(-c2nn[nH]n2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 2-(2-(benzyloxymethyl)-2H-tetrazol-5-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (2.80 g, 6.65 mmol) in a mixture of methanol (20 mL) and hydrochloric acid (1 mL) was refluxed for 17 hours. The reaction mixture was cooled to ambient temperature and methanol was removed in vacuo. The residue was diluted with water (20 mL), basified with 1% sodium hydroxide and extracted with ethyl acetate (7 mL). The aqueous layer was cooled to 0° C. and acidified with 1% hydrochloric acid. The white solid obtained was filtered and dried in air to afford the title compound in 80% yield (1.60 g): mp>200° C. (decomposition); 1H NMR (300 MHz, DMSO-d6) δ 9.08 (t, J=5.8 Hz, 1H), 8.59 (br s, 1H), 8.51 (br s, 1H), 7.89-7.82 (m, 1H), 7.52-7.42 (m, 1H), 5.04 (br s, 1H), 4.47 (d, J=5.8 Hz, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.2, 156.6, 152.6, 147.9, 147.4, 137.4, 135.7, 128.2, 124.6, 41.1, 17.4; MS (ES−) m/z 300.3 (M−1).
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11](C2(O)CCCCC2)[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:6]1.[OH:29][C:30]1(C(C2C=CC3C(=CC=CC=3)C=2)C(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:1].[ClH:1].[CH3:3][NH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]2[OH:29])[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(c2ccc3ccccc3c2)C2(O)CCCCC2)C1
Reactant: CN[C@@H]1CCN(CC(c2ccc3ccccc3c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CN[C@@H]1CCN(CC(c2ccc3ccccc3c2)C2CCCCC2O)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-[2-[(3R)-3-(methylamino]pyrrolidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {(3R)-1-[(1-hydroxycyclohexyl)(2-naphthyl)acetyl]pyrrolidin-3-yl}carbamate. MS m/z 353; HRMS: calcd for C23H32N2O+H+, 353.25874; found (ESI, [M+H]+), 353.2583.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([N:14]1[C:18](=[O:19])[C:17](=[C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:22]=3[S:21]2)[S:16][C:15]1=[N:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[NH:40][CH2:41][CH3:42])[C:35]#[N:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:44][C:45]([O:47][CH3:48])=[O:46]>CC(=O)CC>[CH3:48][O:47][C:45](=[O:46])[CH2:44][O:30][C:27]1[CH:28]=[CH:29][C:22]2[S:21][C:20](=[C:17]3[S:16][C:15](=[N:31][C:32]4[CH:33]=[C:34]([C:35]#[N:36])[CH:37]=[CH:38][C:39]=4[NH:40][CH2:41][CH3:42])[N:14]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:18]3=[O:19])[N:24]([CH3:25])[C:23]=2[CH:26]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OCC(=O)OC)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 75 °C

Procedure:
To a suspension of K2CO3 (41 mg, 5 equiv) in 2-butanone (2 mL) were added the product of Example 57 (31 mg, 0.06 mmol) and methyl 2-bromoacetate (7 μL, 1.2 equiv). The resulting suspension was heated at 75° C. overnight. After cooling, the reaction mixture was filtered, and the filtrate was evaporated to give a crude material, which was purified by chromatography on silica gel, eluting with MeOH-DCM (0:100 to 3:97) to give the title compound (5 mg). 1H-NMR (CDCl3): δ 7.63 (1H, d), 7.28-7.39 (6H, m), 7.13 (1H, d), 7.08 (1H, d), 6.84 (1H, dd), 6.62 (1H, d), 5.13 (2H, s), 4.98 (1H, t), 4.88 (2H, s), 3.79 (3H, s), 3.68 (3H, s), 3.05 (2H, m), 0.99 (3H, t); MS(ESI): 586 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])=[N+:2]=[N-:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(F)ccc1C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
2-Azido-4-fluoro-benzoic acid (3.01 g, 17 mmol; Barral, Karine; Moorhouse, Adam D.; Moses, John E. Organic Letters (2007), 9(9), 1809-1811) was dissolved at ambient temperature in thionyl chloride (27.3 ml) under an argon atmosphere. The reaction mixture was heated to 80° C. for 1.5 h and brought to dryness under reduced pressure to give 2-azido-4-fluoro-benzoyl chloride as orange oil. 2-Azido-4-fluoro-benzoyl chloride was dissolved at ambient temperature in CH2Cl2 (23 ml) under an argon atmosphere. 4-Chloro-phenylamine (2.12 g, 17 mmol; [106-47-8]) was added and the reaction mixture was stirred at ambient temperature for 14 h. Saturated aqueous NaHCO3 solution was added until a pH of 8 was adjusted, the layers were separated and the aqueous layer was extracted two more times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from heptane/CH2Cl2 to give the title compound (3.08 g, 11 mmol; 64%) as off-white crystals. MS: m/e=291.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:17]([C:15]1[C:2]([Cl:1])=[C:3]([Cl:16])[C:4]2[O:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]=2[CH:14]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCC(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a stirred solution of ethyl 6,7-dichloro-2,3-dihydro-2-benzofurancarboxylate (13.4 g, 0.05 mole) and butyryl chloride (10 ml, 0.09 mole) in CH2Cl 2 (30 ml) cooled to 5° C. in an ice bath was added aluminum chloride (22.5 g, 0.17 mole) over a 10 minute period. The reaction mixture was stirred for 1 hour at 25° C. then for 20 minutes at reflux. The reaction mixture was poured into ice water, extracted into ether, washed with water and the ether evaporated in vacuo. The residue was treated with 10 N sodium hydroxide (100 ml) and the resultant sodium salt filtered and suspended in dilute hydrochloric acid which was extracted with ether (206 ml), washed with water, dried over magnesium sulfate, evaporated to 50 ml and treated with hexane to give 12.0 g of 5-butyryl-6,7-dichloro-2,3-dihydro-2-benzofurancarboxylic acid which melted at 124°-125° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].C([O:13][C:14]1[C:24]2[CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[O:19][C:18]=2[CH:17]=[C:16]([O:29]C(=O)C)[CH:15]=1)(=O)C.[OH-].[Na+]>C(Cl)Cl.CO>[C:5]([C:26]1[CH:27]=[CH:28][C:20]2[O:19][C:18]3[CH:17]=[C:16]([OH:29])[CH:15]=[C:14]([OH:13])[C:24]=3[CH2:23][CH2:22][C:21]=2[CH:25]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(c1)Oc1ccccc1CC2
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(c1)CCc1c(O)cc(O)cc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of aluminum chloride (1 g, 7.5 mmol) in anhydrous methylene chloride (3 mL) was added propionyl chloride (668 μL, 7.7 mmol) and stirred at room temperature for one hour. This solution was added dropwise to a solution of 10,11-dihydrodibenz[b,f]oxepin-1,3-diol diacetate (62) (300 mg, 0.96 mmol) in methylene chloride (5 mL) at 0° C. and stirred at room temperature for one hour. To the reaction solution was added dropwise methanol (10 mL) at 0° C. and a 20% sodium hydroxide aqueous solution (3 mL) was added thereto and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into hydrochloric acid-ice water and extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1), and recrystallization was carried out from ethyl acetate and hexane to obtain 190 mg (yield 70%) of skin-colored needles of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C=O.[CH2:25](I)[CH3:26]>O>[CH2:25]([N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1)[C:15](=[O:17])[CH3:16])[CH3:26]
Reactant: CCI
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 1 h

Procedure:
A mixture of 4.0 g of N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide, 0.85 g of sodium hydride (50% in oil) and 300 ml of dry dimethylformamide, under argon, was stirred for 1 hour then 1.42 ml of ethyl iodide was added. After stirring for 2.5 hours, 0.5 equivalent of sodium hydride and 1.1 equivalent of ethyl iodide were added. This mixture was stirred overnight, poured into 1 liter of water and extracted with five 100 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo, giving 3.6 g of the desired compound as tan crystals, mp 105°-110° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: COC(=O)c1ccccc1
Reaction time: 15 h

Procedure:
A 0.5 mM solution of benzoic acid containing 0.2 mM chloromethane and buffered at pH 4.0 with 20 mM citrate buffer was incubated with 0.035 g of fungal mycelium (Phellinus ribis NCWRF. FPRL 42 or CBS 175.29) for a period of 15 hours at a temperature of 25° C. Methyl benzoate was formed at a rate of 77 nanomoles/g fungal mycelium/hour.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([C:27]1[N:31]=[C:30]([CH3:32])[O:29][N:28]=1)([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:19][C:20]([C:27]3[N:31]=[C:30]([CH3:32])[O:29][N:28]=3)([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(C)(N)c1noc(C)n1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CCOC(=O)C(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(C)n1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c) and ethyl 2-amino-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (example 147a) as starting materials and isolated (508 mg, 86%); MS (ESI, m/z): 443.5 (M+H+).
Reaction SMILES: [NH:1](/C(=C\C([O-])=O)/C([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18](Cl)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH:1](/[C:18](=[CH:17]\[C:25]([O:27][CH2:28][CH3:29])=[O:26])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cl)C(Cl)C(=O)OCC
Reactant: O=C([O-])/C=C(\Nc1ccccc1)C(=O)[O-]
Product: CCOC(=O)/C=C(\Nc1ccccc1)C(=O)OCC

Procedure:
The crude yield (14.7 g) assays as 63.1% anilinofumarate. This is a 73% yield based on aniline as the limiting reagent or 66.5% yield based on the real diethyl dichlorosuccinate charged.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[CH3:57].[N:58]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:67]([O:66][C:64]([N:58]1[CH2:63][CH2:62][N:61]([C:48]2[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=2[CH3:57])[CH2:60][CH2:59]1)=[O:65])([CH3:70])([CH3:68])[CH3:69]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
In a first flask 0.135 g of palladium acetate (0.135 g, 0.602 mmol) and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (0.375 g) were suspended in 5 mL of toluene and stirred at 70° C. for 30 min. In a second flask, 2-bromo-1-methyl-4-nitrobenzene (1 g, 4.63 mmol), tert-butyl piperazine-1-carboxylate (1.12 g, 6.02 mmol and sodium tert-butoxide (1.068 g, 11.11 mmol) were added to 5 mL of toluene and stirred for 30 min. at 60° C. To this mixture was added the contents of the first flask, and stirring was continued for 3 h at 60° C. The solvent was evaporated, the residue purified via silica gel chromatography with dichloromethane-methanol (0 to 100%) to yield the title compound (0.145 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5](=[NH:13])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:18][CH:19]=O.C(=O)(O)[O-].[Na+]>CC(O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:18]=[CH:19][N:13]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: N=C(Nc1ccccc1)c1cccc(I)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Ic1cccc(-c2nccn2-c2ccccc2)c1

Procedure:
To a 500 mL round bottom flask was added 3-iodo-N-phenylbenzimidamide (7.84 g, 24.34 mmol), 2-chloroacetaldehyde solution (50%, 6.7 mL, 48.7 mmol), sodium bicarbonate (4.09 g, 48.7 mmol), and 150 mL 2-propanol. The reaction mixture was heated at reflux for 3 h under nitrogen. The solvent was removed under vacuum and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with water, brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 20-40% ethyl acetate/hexane (4.67 g, 55%).