Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:28]=[C:27]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([Cl:36])=[C:25]3[C:20]=2[CH2:21][CH2:22][CH2:23][O:24]3)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:46](Cl)(=[O:48])[CH3:47].Cl>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:28]=[C:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:46](=[O:48])[CH3:47])=[CH:32][CH:31]=3)[C:26]([Cl:36])=[C:25]3[C:20]=2[CH2:21][CH2:22][CH2:23][O:24]3)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccccc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C(C)=O)cc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
To a solution of the acetate 176 (500 mg, 0.85 mmol) in CH2Cl2 (20 mL) were added AlCl3 (691 mg, 5.18 mmol) and acetyl chloride (0.37 mL, 5.18 mmol) at 0° C. The mixture was warmed up to rt slowly and left at rt for 3 hours. The mixture was cooled to 0° C. and added aq. 1N HCl solution to quench the reaction. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 177 (540 mg, quantitative yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:18][CH:19]([Cl:22])[CH2:20]O>>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:20][CH:19]([Cl:22])[Cl:18])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Reactant: OCC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(Cl)Cl)C1(C)C

Procedure:
Using the procedure of Step F of Example 9, 4.8 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-hydroxy-3-oxo-1-propenyl]-cyclopropane-carboxylate and 2 ml of 2,2-dichloroethanol were reacted to obtain after elution with a 9-1 mixture of cyclohexane-ethyl acetate 5.6 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-dichloroethoxy)-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.CCN(C(C)C)C(C)C.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: Fc1cncc(Cl)c1I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cncc(Cl)c1N1CCNCC1
Temperature: 120 °C

Procedure:
In a 100 mL sealed reaction vessel/bomb, 3-chloro-5-fluoro-4-iodo-pyridine (5600 mg, 21.75 mmol) was taken up in NMP (12 mL). To the resulting clear brown solution was added DIPEA (3.373 g, 4.546 mL, 26.10 mmol) followed by piperazine (2.810 g, 32.62 mmol). The vessel was sealed and heated thermally at 120° C. for 18 hrs. The mixture was allowed to cool to RT and was concentrated in vacuo to afford a brown gum which was purified by chromatography on silica, eluting with a gradient of DCM-DCM:MeOH:NH3(90: 10:1) 100-0 to 0:100. Fractions containing clean product were collected and concentrated in vacuo to afford 1-(3-chloro-5-fluoropyridin-4-yl)piperazine as a cream solid. (3.52 g, 75%). MS (ES+) 216.0.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)[CH2:55][CH2:54]1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:53]3[CH2:58][CH2:57][CH:56]([C:59]4[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=4)[CH2:55][CH2:54]3)=[O:11])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Yield: 23049 %

Procedure:
A solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 222.3, 60 mg, 0.2 μmol), DIEA (0.11 ml, 0.63 mmol), HOBT (53 mg, 0.32 mmol, with 20% water), EDCI (60 mg, 0.32 mmol) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 47 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of ethyl acetate and washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel prep-TLC plate and developed using ethyl acetate/hexanes (1:1) to yield 21.0 mg (22%) of the title compound as a white solid. m/z (ES+) 456 (M+H)+. 1H NMR (400 MHz, Chloroform-d) 611.54-10.86 (br s, 1H), 7.60 (d, 2H), 7.38-7.20 (m, 4H), 5.04-4.92 (m, 1H), 4.06 (s, 3H), 4.14-4.00 (m, 1H), 3.62 (d, 1H), 3.15-3.03 (m, 1H), 2.93-2.76 (m, 2H), 2.38 and 2.30 (2 singlets, amide rotamers, ArCH3, 3H), 2.34-2.22 (m, 1H), 2.20-2.06 (m, 2H), 2.05-1.84 (m, 3H), 1.61-1.45 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)([OH:3])=[O:2]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2cccc(C(=O)O)c2)cc1
Yield: 47.6 %

Procedure:
A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H2 atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90% CH2Cl2) Rf 0.44 (streaking).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]([CH:16]=[CH2:17])=[C:4]([NH:18][CH3:19])[N:3]=1.[CH2:20]([Mg]Br)[CH:21]=[CH2:22].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH2:22][CH:21]=[CH2:20])[C:5]([CH:16]=[CH2:17])=[C:4]([NH:18][CH3:19])[N:3]=1
Reactant: C=Cc1c(NC)nc(Cl)nc1C(=O)c1ccccc1
Reactant: C=CC[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(O)(c1ccccc1)c1nc(Cl)nc(NC)c1C=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)(phenyl)methanone (142 mg) in THF (2.6 mL) at rt was added allylmagnesium bromide (1.0 M solution in THF, 1.1 mL) dropwise, and the reaction mixture was stirred at rt for 30 min. The reaction was worked up with EtOAc/sat. NH4Cl, and the crude product was purified by prep. TLC eluting with 30% EtOAc/Hexanes to give the title compound as a colorless oil (133 mg). LC-MS (M−H2O+H)+=298.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C@H:13]([CH3:17])[C:14](O)=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C@H:13]([CH3:17])[CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: C[C@@H](Nc1ccc(C(F)(F)F)c(Cl)c1)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](CO)Nc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.3 %

Procedure:
20.55 ml (20.55 mmol, 1 M in THF) of a borane-tetrahydrofuran complex solution was added dropwise at 0° C. to a solution of 2.20 g (8.20 mmol) of (R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propionic acid (22% ee) in 33 ml THF, then after 10 min the ice bath was removed and the solution stirred for 2.5 h at RT. After cooling, 14 ml of MeOH and 0.7 ml of H2SO4 were added, and after 30 min at RT and 1 h at reflux the reaction mixture was concentrated in vacuo. The residue was partitioned between 1 M aq. sodium hydroxide saturated with NaCl solution and EtOAc (3×). The organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated. Flash silica gel column (CH2Cl2/MeOH 99:1) afforded 1.94 g (93%) of the title compound as a 61:39 mixture of the (R) and (S) stereoisomers as yellow oil. MS: 252.04 (M−H−, Cl)
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]([O:39][CH2:40][C:41]([N:43](C)[C:44]1C=CC(N)=CC=1)=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][CH2:40][C:41]([N:43]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]2[N:11]=[C:6]([NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=2)=[CH:14][CH:15]=1)[CH3:44])=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(N)cc1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Product: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, 2-benzoxy-N-methyl-N-(4-aminophenyl)acetamide and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave 2-benzyloxy N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (MS calcd for C26H28N6O2 456.2, found [MH] 457.0).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[N:32](=[CH:40][CH2:41]Cl)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39].[H-].[Na+]>CN(C)C=O>[ClH:39].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[O:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:41][CH2:40][N:32]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=[CH:33]3)=[CH:28][CH:29]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reactant: ClCC=NCCCCCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(OCCN4C=CC=CC=C4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Yield: 71.2 %

Procedure:
Stir a solution of 4-[2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenol (160 mg, 0.39 mmol), 2-(hexamethyleneimino)-ethyl chloride hydrochloride (140 mg, 0.69 mmol), 60% sodium hydride (47 mg, 1.18 mmol) and N,N-dimethylformamide (2 mL) for 18 hours at ambient temperature, then evaporate under reduced pressure. Dissolve the residue in dichloromethane and wash with water, dry with solid magnesium sulfate and chromatograph on silica gel with dichloromethane/methanol mixtures. Combine the fractions containing product and add 1N hydrogen chloride in diethyl ether (0.30 mL). Concentrate the resulting solution under reduced pressure to give 160 mg of the title compound (69%). Mass spectrum (ion spray): m/z=546 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]([C:31]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:32]=1[CH:33]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:31]=3[O:29][CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(OC)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,4 dimethoxylbenzaldehyde. MS (ESI) m/z 529.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.CO.[H][H]>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1

Procedure:
A mixture of 15.3 g. (0.05 moles) of ethyl 3-nitro-4-cyclohexyl-phenylglyoxylate in 100 ml. methanol containing 0.05 mole citric acid and 1.5 g. of 5% palladium-on-carbon is shaken with hydrogen at 3 atm. pressure and 27° C until 3 moles of hydrogen are absorbed. The mixture is filtered, washed with methanol and the filtrate concentrated in vacuo to obtain ethyl 3-amino-4-cyclohexylphenylglyoxylate, isolated as the citrate salt.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:7]
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: Cc1c(Br)cccc1C(=O)O
Product: Cc1c(Br)cccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 3-bromo-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=491.1, tR (minutes, Method D)=0.84
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+]>C1COCC1>[CH2:16]([O:15][C:5]1[CH:6]=[CH:7][C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[CH:9][C:4]=1[C:3]([OH:20])=[O:2])[CH:17]([CH3:19])[CH3:18]
Reactant: CNS(=O)(=O)c1ccc(OCC(C)C)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OCC(C)C)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
To 3.3 mmol 2-isobutoxy-5-methylsulfamoyl-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 286.2 ([M−H]−, 100%)
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]O.P(Br)(Br)[Br:14]>COCCOC>[Br:14][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCCOc1ccc(Cl)cc1Cl
Solvent: COCCOC
Product: Clc1ccc(OCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.2 %

Procedure:
To a solution of 10.0 g of 2-(2,4-dichlorophenoxy)-1-ethanol in 1,2-dimethoxyethane (200 ml) was added dropwise a solution of 14 g of phosphorus tribromide in 1,2-dimethoxyethane (20 ml) under ice-cooling. The reaction solution was stirred at room temperature for 20 hours. After the reaction solution was concentrated, the residue was diluted with water and ethyl acetate. Saturated aqueous sodium hydrogencarbonate was added to the organic layer, and the resulting emulsion formed was subjected to Celite filtration. The filtrate was diluted with diethyl ether and saturated aqueous ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, to give 6.15 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][CH2:12][C:13](OCC)(OCC)OCC>C(O)C>[Cl:11][CH2:12][C:13]1[S:10][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2
Reactant: COc1ccc(N)c(S)n1
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CCO
Product: COc1ccc2nc(CCl)sc2n1
Temperature: 90 °C

Procedure:
3-Amino-6-methoxy-2-pyridinethiol (0.8 g, Maybridge Co.) and 2-chloro-1,1,1-triethoxyethane (1.26 g) were combined in ethanol (5 mL) and heated at 90° C. in a sealed tube for 2 hours. The mixture was allowd to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (2:1, dichloromethane:hexanes) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 4.00 (3H, s), 4.88 (2H, s), 6.88 (1H, d, J=8.7 Hz), 8.10 (1H, d, J=8.7 Hz); MS (DCI/NH3) m/z 215.0 (M+H)+.
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40]CC)=[O:39])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:38]([OH:40])=[O:39])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)CC(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)CC(C)C
Yield: 56.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-isovaleryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (296 mg) was dissolved in methanol (14 ml), aqueous lithium hydroxide monohydrate (62 mg) solution (7 ml) and tetrahydrofuran (7 ml) were added, and the mixture was refluxed for 45 minutes. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 160 mg of the titled compound.
Reaction SMILES: [CH4:1].[CH2:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>>[CH2:5]=[CH:6][C:7](=[CH2:2])[CH3:1].[CH2:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C
Solvent: C1CCCCC1
Product: C=CC(=C)C
Reaction time: 2 h

Procedure:
Activated charcoal (130 g), which had been exposed to a stream of fermentor off-gas, was placed into a 1000 mL flask along with a stir bar. Cyclohexane (563 mL) was added to the flask and the slurry was agitated for 2 hours. Vacuum was applied (100 mbar) via an in-line cryogenic trap (30 mL capacity, immersed in liq. nitrogen). Four fractions were collected and combined to yield an isoprene/cyclohexane solution (2.1 wt % isoprene, total volume=53.1 g). This solution was vacuum distilled at 100 mbar and a new isoprene/cyclohexane solution was collected (yield=10.1 g), which was dried over 3 A molecular sieves. GC analysis of this solution indicated an isoprene content of 7.7 wt. %.
Reaction SMILES: [OH-].[Na+:2].[N:3]1[S:4][N:5]=[C:6]2[CH:11]=[C:10]([C:12]3[C:13](=[O:43])[O:14][C:15]([OH:42])([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[C:16]=3[CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[C:20]([O:32][CH3:33])[CH:19]=3)[CH:9]=[CH:8][C:7]=12>CO>[N:3]1[S:4][N:5]=[C:6]2[CH:11]=[C:10]([C:12](=[C:16]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[C:20]([O:32][CH3:33])[CH:19]=3)[C:15]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:42])[C:13]([O-:43])=[O:14])[CH:9]=[CH:8][C:7]=12.[Na+:2]
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4nsnc4c3)=C2Cc2cc(OC)c(OC3CCCC3)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C(Cc2cc(OC)c(OC3CCCC3)c(OC)c2)=C(C(=O)[O-])c2ccc3nsnc3c2)cc1
Temperature: 25 °C

Procedure:
Equimolar amounts of 0.1N NaOH are added to a suspension of 30 mg of 3-(2,1,3-benzothiadiazol-5-yl)-4-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one in 1 ml of methanol and the mixture is stirred at room temperature. The solvent is removed, the residue is partitioned between water and diethyl ether, and the aqueous phase is then lyophilized. Sodium 2-(2,1,3-benzothiadiazol-5-yl)-3-(4-cyclopentyloxy-3,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-4-oxo-2-butenoate is obtained.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.CN(C)C=O.O.[C:15]1([CH3:23])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1>>[CH3:23][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1
Reactant: Cc1cc(C)cc(C)c1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(Cc2c[nH]cn2)c(C)c1

Procedure:
3.0 g of 4-chloromethylimidazole hydrochloride are suspended in 20 ml of mesitylene. 5 ml of dimethylformamide are added and the reaction mixture is refluxed for 12 hours, then cooled. 30 ml of water are added, the layers are separated, and the aqueous phase is washed with chloroform. The aqueous solution is then made alkaline with sodium carbonate solution and extracted with chloroform. The combined chloroform extracts are washed with water and evaporated to dryness. The residue, which is crude 4-(2',4',6'-trimethylbenzyl)imidazole, is converted to the hydrochloride by treatment with concentrated hydrochloric acid. The hydrochloride salt melts at 166°-169° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[CH:26]([CH3:28])[CH3:27]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: CC(C)COC(=O)Cl
Product: CCOC(=NC(=O)OCC(C)C)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and isobutyl chloroformate, there is obtained ethyl N-isobutoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 366 (11), 337 (13), 293 (20), 263 (88), 194 (100);
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12](=[O:18])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:19][NH2:20]>>[NH2:1][C:2]1[CH:11]=[C:10]([C:12]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([NH:20][CH3:19])=[O:6]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CN
Product: CCN(CC)C(=O)c1ccc(C(=O)NC)c(N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
In an autoclave a mixture of methyl 2-amino-4-(diethylcarbamoyl)benzoate (490 mg, 1.96 mmol) and methylamine solution (33% in ethanol; 25 ml, 200 mmol) was stirred for 24 hrs at 90° C. The reaction mixture was concentrated. The crude product was purified by silica gel chromatography using EtOAc as eluent, providing the title compound as white solid (341 mg, 70%).