Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N:19]2[CH:23]=[N:22][N:21]=[CH:20]2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH2:33])[CH3:32])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N:19]2[CH:20]=[N:21][N:22]=[CH:23]2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:32])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-n1cnnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1-n1cnnc1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (10 mg, 0.050 mmol), 1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanamine (15 mg, 0.045 mmol), and N,N-diisopropylethylamine (0.016 mL, 0.091 mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H19ClFN8 (M+H)+: m/z=449.1. found: 449.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[S:5].C(Cl)(=O)C([Cl:15])=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[S:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)c(C(O)=S)c1
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(C(=S)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-5-methylthiobenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 2-chloro-5-methylthiobenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32][OH:33]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:30][CH2:31][CH2:32][OH:33])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:20])[F:21])[C:4]=2[N:3]=1
Reactant: OCCCBr
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCO)c(=O)n2CCCC(F)(F)F
Temperature: 60 °C
Yield: 69.2 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione (1.0 g, 3.0 mmol) in DMF (15 ml) was treated with caesium carbonate (1.16 g, 3.6 mmol) and 3-bromo-1-propanol (0.3 ml, 3.3 mmol). The mixture was heated at 60° C. for 4 h and then cooled and evaporated. The residue was partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography using a gradient elution from cyclohexane to EtOAc. Product-containing fractions were combined and evaporated to give the title compound as a colourless oil (0.82 g, 75%).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1>CO>[CH3:1][C@@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:12]=[N:11][N:10]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (527 mg, 1.236 mmol, Intermediate 13) in methanol was added 4M hydrogen chloride in 1,4-dioxane (7 mL, 28.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give white crystals. The crude product was poured onto a 5 g SCX cartridge, washed with methanol (2 column volumes) and eluted with ammonia in methanol (2 column volumes). The ammonia in methanol fractions were concentrated and dried in vacuo to yield the title compound as a yellow oil (389 mg).
Reaction SMILES: [N:1]1[NH:2][C:3]([NH2:6])=[CH:4][CH:5]=1.[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][C:13]=1[Cl:14]>C(O)(=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[C:17]([C:18]([F:21])([F:19])[F:20])[N:2]3[N:1]=[CH:5][CH:4]=[C:3]3[N:6]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Nc1ccn[nH]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc2ccnn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2H-pyrazol-3-ylamine (4.0 g, 48 mmol) and 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (11.4 g, 40 mmol) in acetic acid (80 mL) was heated at reflux for 4 h. The solution was poured into ice-cold 10% aqueous ammonia and the mixture was stirred at 0° C. for 0.5 h. The solid was isolated by filtration, triturated with EtOH (40 mL), and dried to give 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine as a pale-yellow solid. MS (ISP) 332.1[(M+H)+]; mp 130-131° C.
Reaction SMILES: [C:1](=[O:22])([O:19][CH2:20][CH3:21])[O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14](OCC)=[O:15]>C(OCC)(=O)C.O>[C:1](=[O:22])([O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH2:12][NH:13][C:14]2=[O:15])[O:19][CH2:20][CH3:21]
Reactant: CCOC(=O)NCCc1cccc(OC)c1OC(=O)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Oc1c(OC)ccc2c1CCNC2=O
Temperature: 142.5 °C
Reaction time: 0.33 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed polyphosphoric acid (PPA, 150 g). This was followed by the addition of 2-[2-[(ethoxycarbonyl)amino]ethyl]-6-methoxyphenyl ethyl carbonate (20 g, 64.24 mmol, 1.00 equiv) at 145° C. The resulting solution was stirred for 20 min at 140-145° C. The reaction mixture was cooled to room temperature with a water/ice bath. The resulting solution was diluted with 500 mL of ethyl acetate and 500 mL of water. The resulting mixture was washed with 3×300 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.5 g (9%) of ethyl 6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl carbonate as a gray solid. MS (ESI) m/z 266 ([M+H]+).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: O=C(N[C@H]1CCN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.C(OC(=O)[NH:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([Cl:47])=[C:42]([N+:44]([O-])=O)[CH:43]=1)(=[O:38])=[O:37])(C)(C)C>>[NH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([Cl:47])=[C:42]([NH:44][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:43]=1)(=[O:37])=[O:38]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NCCNS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and [2-(4-amino-5-chloro-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (example B.17) according to general procedure II and subsequent removal of the protecting group with trifluoroacetic acid in dichloromethane at 0° C. for 3 h. Orange solid. MS (ISP) 595.0 [(M+H)+]; mp 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][C:7]1=[O:12].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]2[CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([OH:18])=[C:8]2[C:7]1=[O:12]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: O=C1CNCCN1Cc1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1cccc(Cl)c1)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3-chlorobenzyl)piperazin-2-one (3.97 g, 17.67 mmol) and diethyl ethoxymethylenemalonate (4.01 g, 18.55 mmol) in toluene (60 mL) was heated in a sealed tube at 80° C. overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (200 mL), cooled to 0° C. under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 21.2 mL, 21.2 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and the solid precipitated was filtered to provide the title compound.
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH3:29])[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)[CH3:8])=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:44].O1CCOCC1>>[ClH:44].[ClH:44].[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:2]=[CH:3][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([N:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH3:29])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[CH3:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccc3)cc2)cc1)N(CC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(c1ccccc1)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
Reaction and post-treatment were carried out according to Example 4 using 353 mg of ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy]ethoxy]phenyl]-2-(N-phenyl-N-ethylamino)propionate obtained in Example 11 and 2 ml of a 1N aqueous sodium hydroxide solution. The product thus obtained was further treated with a 4N hydrogen chloride-dioxane solution to obtain 280 mg of hydrochloride of the desired compound as an amorphous powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:16](=[O:17])[O:15][CH:14]2[CH2:18][CH:19]=[CH:20][CH:13]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:31](Br)[CH:32]=[CH2:33]>C1COCC1>[CH2:33]([C@:12]1([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:16](=[O:17])[O:15][C@H:14]2[CH2:18][CH:19]=[CH:20][C@H:13]12)[CH:32]=[CH2:31]
Reactant: C=CCBr
Reactant: O=C1OC2CC=CC2C1Cc1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@]1(Cc2ccc3ccccc3c2)C(=O)O[C@H]2CC=C[C@@H]21

Procedure:
Analogously to the procedure of Example 3, the title compound was prepared from 0.79 g (3 mmol) of the compound from Example 7, 3 ml of 1 molar lithium bis(trimethylsilyl)-amide solution in THF and 0.36 g (3 mmol) of allyl bromide in 10 ml of THF. Chromatographic purification was carried out using a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100:4. Yield: 684 mg (74.8%) of a pale yellow oil; Diastereomeric purity: >99% de (HPLC). MS (DCI/NH3) [m/e]: 322 (100, M+NH4+) 1H-NMR (200 MHz; CDCl3): δ[ppm]=2.24 (dd,1H); 2.37 (dd,1H), 2.72 (m,2H), 3.16 (d,1H), 3.28 (d,1H), 3.48(m,1H), 5.03 (dd,1H), 5.05 (m,1H), 5.12 (dd,1H), 5.78 (ddt,1H), 5.89 (m,1H), 6.04 (m,1H), 7.4-7.5 (br m,3H), 7.75 (s,1H), 7.8 (m,3H)
Reaction SMILES: Br[CH:2]([CH3:5])[CH:3]=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=1>C(OCC)(=O)C>[CH3:5][C:2]1[N:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]2=[N:6][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(Br)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc2ccc([N+](=O)[O-])cn12

Procedure:
Operations similar to Production Example 1-(2) were conducted using 2-bromopropionaldehyde and 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution to provide the title compound as yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCc1ccccc1
Product: O=Cc1ccc(OCCCCc2ccccc2)cc1
Yield: 63 %

Procedure:
Following the process described in example 18 (point A), starting from 4-hydroxybenzaldehyde and 4-phenyl-1-butanol, the title compound was prepared (63% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:27][N:28]([C:30](=[O:33])[CH2:31][CH3:32])[NH2:29].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCCl>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][N:28]([CH3:27])[C:30](=[O:33])[CH2:31][CH3:32])=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CCC(=O)N(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(=O)N(C)NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br

Procedure:
Prophetically, (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid can be reacted with N-methylpropionohydrazide in the presence of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl) and DMAP in 1,2-dichloroethane (DCE) to furnish the title molecule (Org. Lett. 2004, 6, 929-931).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](=O)[CH2:13]Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:20]([NH:23][C:24]([NH2:26])=[S:25])(=[O:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)C>[C:20]([NH:23][C:24]1[S:25][CH:13]=[C:12]([C:11]2[CH:16]=[CH:17][C:8]([O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:26]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)NC(N)=S
Reactant: O=C(CCl)c1ccc(OCc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Yield: 65.6 %

Procedure:
A 1.0 g portion of 4-(4-chlorobenzyloxy)phenacyl chloride, together with 440 mg of 1-acetylthiourea and 279 mg of sodium acetate, was stirred in 15 ml of ethanol under reflux for 2 hours. After cooling, the precipitated crystals were recovered by filtration, thus yielding 800 mg (65.6%) of 2-acetylamino-4-[4-(4-chlorobenzyloxy)phenyl]thiazole. m.p., 239°-240° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15])[C:7]([OH:9])=[O:8])([O-])=O.S(=O)(=O)(O)O.[CH3:21]O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15])[C:7]([O:9][CH3:21])=[O:8]
Reactant: CO
Reactant: CCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=S(=O)(O)O
Product: CCCc1ccc(C(=O)OC)cc1N
Reaction time: 6 h

Procedure:
To 3-nitro-4-propylbenzoic acid (31.0 g) were added sulfuric acid (1.0 g) and methanol (300 ml) and the mixture was heated under reflux for 24 hr. After cooling, 5% Pd-C (0.60 g) was added to the reaction mixture and the mixture was stirred under a hydrogen atmosphere (normal pressure) for 6 hr. The reaction mixture was filtered through Celite and concentrated. To the residue was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with toluene. The toluene layer was dried over sodium sulfate and concentrated to give the object compound (28.7 g) as an brown oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:18]([CH2:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:19](=O)[CH2:20][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([OH:35])[C:31]([OH:34])([CH3:33])[CH3:32])=[CH:26][N:25]=2)=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:48].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[CH:1]1([S:4]([C:7]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:18]([C:19]2[NH:48][C:22]([C:24]3[N:25]=[CH:26][C:27]([CH:30]([OH:35])[C:31]([CH3:33])([OH:34])[CH3:32])=[CH:28][CH:29]=3)=[CH:21][CH:20]=2)[CH2:37][CH:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COc1ccc2c(cnn2C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C(O)C(C)(C)O)cn2)c1S(=O)(=O)C1CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(cnn2C(CC2CCOCC2)c2ccc(-c3ccc(C(O)C(C)(C)O)cn3)[nH]2)c1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.7 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl]-1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.37 g), ammonium acetate (0.23 g), acetic acid (0.34 mL) and ethanol (10 mL) was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted from hexane-ethyl acetate (1:1-0:1, volume ratio) to give the title compound (60 mg, yield 17%) as a colorless amorphous solid. MS: 595 (MH+).
Reaction SMILES: [CH2:1]([C:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[CH2:10][N:11]([C:14](=[O:26])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[CH2:12][CH2:13][C:8]=2[C:7](=[O:27])[O:6]1)[CH:2]([CH3:4])[CH3:3].O.[Sn](Cl)Cl>CO>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1/[CH:16]=[CH:15]/[C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:27])[O:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:9]=2[CH2:10]1)=[O:26]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)/C=C/c1ccccc1[N+](=O)[O-])CC2
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)/C=C/c1ccccc1N)CC2
Temperature: 25 °C

Procedure:
A solution of (E)-3-isobutyl-5-(3-(2-nitrophenyl)acryloyl)-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (25 mg, 0.092 mmol) and tin(II)chloride hydrate (83 mg, 0.369 mmol) was heated in methanol (15 mL) for 2 hours. The reaction mixture was cooled to room temperature, concentrated to dryness, and re-dissolved in ethyl acetate (20 mL). The organic solution was washed with sat. NaHCO3 solution (5 mL), brine (5 mL), dried (MgSO4), and concentrated. Purification by column chromatography (4 g, SiO2, 0 to 5% chloroform/methanol/ammonium hydroxide 80:18:2 in dichloromethane) provided (E)-5-(3-(2-aminophenyl)acryloyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.83-1.01 (m, 6H), 1.62-1.75 (m, 1H), 1.84 (dd, J=14.69, 7.16 Hz, 1H), 2.35 (dd, J=14.69, 4.52 Hz, 1H), 2.43-2.55 (m, 2H), 3.51 (m, J=5.70 Hz, 1H), 3.82-4.00 (m, 3H), 4.09 (d, J=19.59 Hz, 1H), 4.84 (d, J=19.21 Hz, 1H), 6.66-6.86 (m, 3H), 7.18 (t, J=7.54 Hz, 1H), 7.29-7.48 (m, 6H), 7.83 (d, J=15.07 Hz, 1H); MS m/z 417 (M+H)+, 439 (M+23)+, 415 (M−H)−.
Reaction SMILES: CN(C=O)C.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH2:17][OH:18])[CH:16]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>C(OCC)(=O)C>[N:22]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH2:17][OH:18])[CH:16]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1CO
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCCOc1ccc([N+](=O)[O-])c(CO)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
DMF (7.5 mL) was added to (5-(3-chloropropoxy)-2-nitrophenyl)methanol (635 mg, 0.00258 moles) and sodium azide (252 mg, 0.00387 moles) in a flask, and the resulting mixture was heated to 70° C. and stirred overnight. The reaction was diluted in ethyl acetate (100 mL) and washed twice with water (75 mL each) and once with brine (75 mL). The organic layer was dried with anhydrous magnesium sulfate, which was filtered out. The filtrate was concentrated on a rotary evaporator and dried in vacuo overnight to yield (5-(3-azidopropoxy)-2-nitrophenyl)methanol as a yellow solid (yield 88%). H NMR (400 MHz, CD2Cl2) δ 8.16 (d, J=9.1 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 6.91 (dd, J=9.1, 2.8 Hz, 1H), 4.98 (s, 2H), 4.18 (t, J=6.0 Hz, 2H), 3.53 (t, J=6.6 Hz, 2H), 2.12-2.06 (m, 2H). 13C-NMR (100 MHz, CD2Cl2) δ 163.99, 141.22, 128.43, 114.97, 113.93, 66.15, 63.26, 48.68, 29.13 HRMS m/z: calculated for C10H12N4O4 [M+H]+, 253.0931. found, 253.0939.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Na].[CH2:8]([OH:11])[CH2:9][CH3:10]>>[CH2:8]([O:11][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][CH3:10]
Reactant: CCCO
Reactant: Ic1cccs1
Agent: [Na]
Product: CCCOc1cccs1
Yield: 13.5 %

Procedure:
Iodothiophene (59 g, 281 mmole) and cupric oxide (11.2 g, 141 mmole) were placed in propanol (420 g) containing sodium (19.7 g, 857 mmole). The mixture was stirred at reflux for 48 hours and then filtered. The filtrate was added to cold water and the water extracted with ethyl ether. The ether layers were combined, dried over magnesium sulfate, filtered, concentrated, and then vacuum distilled from over sodium at 50° C. and 10 torr to provide 5.4 g of product.