Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH3:31])=O)(=O)OC.O.[NH2:33][NH2:34]>>[CH3:31][C:21]1[N:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:24][C:20]=1[C:18]1[N:34]=[N:33][C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=2[CH:17]=1
Reactant: O=C1CCCCCCC1=O
Reactant: NN
Reactant: COP(=O)(CC(=O)c1sc(-c2ccccc2)nc1C)OC
Solvent: O
Product: Cc1nc(-c2ccccc2)sc1-c1cc2c(nn1)CCCCCC2

Procedure:
light brown solid. MS (ESI): 335.1 (M+). Prepared from cyclooctane-1,2-dione, [2-(4-Methyl-2-phenyl-thiazol-5-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:39][CH:38]=2)[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH2:30])=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(Cl)Cl>[I:18][CH:29]1[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]([C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:42]=2)[C:24]2[C:23](=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)[CH2:30]1
Reactant: C=CC(c1ccccc1)C(c1ccc(OC)cc1)c1ccc(OC(=O)C(C)(C)C)cc1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(I)C(c1ccccc1)C2c1ccc(OC(=O)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (65.8 mg, 0.177 mmol) was suspended in methylene chloride (3.4 mL), and cooled in a dry ice-acetone bath to −78° C. To this, a methylene chloride (1.8 mL) solution of 1-(4-methoxyphenyl)-2-phenyl-1-(4-pivaloyloxyphenyl)-3-butene (4, 56.0 mg, 0.135 mmol) was added, and further, boron tribromide diethyl ether complex (0.015 mL, 0.118 mmol) was added divided into 3 portions. After this, and after stirring for 1 hr at −78° C., the reaction was stopped by adding a saturated ammonium chloride solution (5 mL), and after returning to room temperature, extraction was performed three times with diethyl ether (10 mL). The organic layers were combined and washed with a saturated sodium chloride solution (10 mL), dried with anhydrous sodium sulfate, and concentrated. The residue was purified with thin layer chromatography (toluene), and the subject compound (5, 51.6 mg) was obtained as a slightly yellow oily substance (yield 71%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[C:29]=1[OH:30])[CH:25]=O)[CH3:20].[NH2:34][C:35]([NH2:37])=[O:36].Cl>C(O)C>[CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:37][C:35](=[O:36])[NH:34][CH:25]([C:24]3[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[C:29]([OH:30])=[C:22]([O:21][CH2:19][CH3:20])[CH:23]=3)[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)Cc2ccccc2)cc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(N(C)C)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 17.8 %

Procedure:
To a solution of 1-(4-(dimethylamino)phenyl)-2-phenylethanone (80 mg, 0.32 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (63 mg, 0.32 mmol), and urea (60 mg, 0.96 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl solution, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 54 (27 mg, yield 16.3%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.29 (s, 1H), 8.51 (s, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.23 (s, 1H), 7.07-6.97 (m, 5H), 6.83 (d, J=7.2 Hz, 2H), 6.58 (d, J=8.4 Hz, 2H), 5.07 (d, J=2.4 Hz, 1H), 4.05 (q, J=6.8 Hz, 2H), 2.88 (s, 6H), 1.34 (t, J=6.8 Hz, 3H); MS (ESI): m/z 475.0 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]([N:19]=[C:20]=[S:21])([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[S:21])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)N=C=S
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=S)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
24.93 g of 4-amino-1-benzylpiperidine are dissolved in 300 ml of dichloromethane and then 16.7 ml of tert-butylisothiocyanate are added dropwise and at room temperature. The reaction mixture is stirred at room temperature for 5 hours and then water is added and the mixture is allowed to settle. The organic phase is separated, dried over sodium sulphate and evaporated. The residue obtained is crystallized from petroleum ether in order to give white crystals which melt at 137° C.; yield: 88%.
Reaction SMILES: [O-]CC.[Na+].[Na].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([CH3:13])[CH:12]=1.[C:17]1([CH2:23][CH2:24]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[N+:14]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:11]=1[CH3:13])([O-:16])=[O:15]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: BrCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cc(OCCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
To a sodium ethoxide solution prepared from 15 g (0.652 Mol) of sodium and 500 ml of anhydrous ethanol were added, successively, 100 g (0.653 Mol) of 5-hydroxy-2-nitrotoluene and 90 ml (121.95 g=0.659 Mol) of 2-phenylethylbromide and the mixture was refluxed for 5 hours. A further 50 ml (0.366 Mol) of 2-phenylethylbromide were added and again the mixture was refluxed for 10 hours. The solvent was distilled off in vacuo, the residue was taken up in ether and extracted several times with dilute sodium hydroxide solution. The ethereal phase was evaporated down, the residue was stirred thoroughly with 400 ml of petroleum ether 35/60. The resulting crystals were suction filtered and washed with petroleum ether. Yield: 95.2 g (57% of theory) of slightly yellowish crystals, Mp. 70-72° C. IR (CH2Cl2): 1340, 1515 (NO2) cm-1
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[K+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)[N:11]=[CH:10][CH:9]=1)#[N:13]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1c(C#N)ccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1c(C#N)ccnc1-c1cnn(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A mixture of methyl 2-chloro-4-cyanonicotinate (730 mg, 3.71 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (927 mg, 4.46 mmol), trans-dichlorobis(triphenylphosphine)palladium (261 mg, 0.371 mmol) and potassium fluoride (2697 mg, 14.85 mmol) in DME (15 mL) was stirred at 120° C. for 1 h under microwave irradiation. The mixture was filtered through Celite, and the filtrate was diluted with H2O and EtOAc. The organic phase was washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a pale yellow solid (470 mg, 52.3%). 1H NMR (500 MHz, CDCl3) δ ppm 3.97 (s, 3H), 4.03 (s, 3H), 7.41 (d, J=4.88 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 8.79 (d, J=4.88 Hz, 1H). [M+H] calc'd for C12H10N4O2, 243; found, 243.
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[Na+:19].[Na+]>O>[Cl-:1].[Na+:19].[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]
Reactant: O=S(=O)([O-])[O-]
Reactant: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)O
Product: [Cl-]
Reaction time: 1 h

Procedure:
Glucosamine sulfate sodium chloride was prepared by the following procedure. A one-liter, three-necked flask equipped with a thermometer, stirrer, heating mantle and condenser was charged with 1720 g of purified water and 431.5 g (2.0 moles) of glucosamine hydrochloride. The glucosamine hydrochloride promptly went into solution, with stirring (the dissolution of the glucosamine hydrochloride was endothermic in nature). After stirring for a few minutes, 142 g (1.0 mole) of sodium sulfate was added to the solution and stirring was continued for about one hour at 35-40° C. to complete the reaction.
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][CH:15]=[CH2:16])=[C:9]([CH:12]=1)[CH:10]=O.O1CCOCC1>>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][CH:15]=[CH2:16])=[C:9]([CH:12]=1)[CH:10]=[N:2][OH:3]
Reactant: NO
Reactant: C=CCOc1ccc(Br)cc1C=O
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOc1ccc(Br)cc1C=NO

Procedure:
A 0.16 mol/L hydroxylamine hydrochloride/1 N sodium hydroxide solution was sent as a first fluid from the center at a ratio of supply pressure/back pressure of 0.15 MPa/0.07 MPa, a rotation speed of 500 rpm, and a sending temperature of 15° C., and a 0.12 mol/L 5-bromo-2-allyloxybenzaldehyde/dioxane solution was introduced as a second fluid into a space between the processing surfaces at 15 mL/min. The first fluid and the second fluid were mixed in a thin film fluid, and then a solution obtained after processing was discharged from the space between the processing surfaces at 30 mL/min. As a result of HPLC analysis, substantially complete conversion to 5-bromo-2-allyloxybenzaldoxime was observed.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][S:16][C:15]=3[CH:26]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH2:27]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][S:16](=[O:27])[C:15]=3[CH:26]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)SCC(c2ccccc2)O3)nc1
Reactant: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)S(=O)CC(c2ccccc2)O3)nc1

Procedure:
To 5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine (214 mg) in methanol (80 ml) at 60° C., NaIO4 (total 2.5 eq) was added in small portions until disappearance of the starting material. The mixture was poured into water and precipitate was filtered and washed with water. The crude product was purified by column chromatography using heptane-ethyl acetate (1:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 9.02 (d, 1H, J 2.8 Hz), 8.51 (dd, 1H, J 9.1, 2.8 Hz), 7.45-7.56 (m, 6H), 7.32 (dd, 1H, J 9.0, 2.8 Hz), 7.21 (d, 1H, J 9.0 Hz), 7.10 (d, 1H, J 9.1 Hz), 5.77 (dd, 1H, J 12.0, 1.5 Hz), 3.34 (dd, 1H, 14.4, 1.5 Hz), 3.13 (dd, 1H, 14.4, 12.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.[F:14][C:15]([F:29])([CH:26]([F:28])[F:27])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1C=O.[BH4-].[Na+].[CH2:32](O)C>>[F:1][C:2]1[CH:3]=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:32][C:24]3[CH:23]=[CH:22][CH:19]=[C:18]([O:17][CH2:16][C:15]([F:14])([F:29])[CH:26]([F:27])[F:28])[CH:25]=3)=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: CCO
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: O=Cc1ccccc1OCC(F)(F)C(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Fc1ccc2c(CCNCc3cccc(OCC(F)(F)C(F)F)c3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 6-fluorotryptamine hydrochloride (90 g, 0.419 mol) and water (900 ml). Add an aqueous solution of NaOH (2N, 230 ml) and dichloromethane (900 ml). After 1 hour, separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic layers, wash water, dry over MgSO4, and evaporate to a residue. Combine the residue and toluene (200 ml) and evaporate to give 78.45 g of a brown oil. Combine the above 78.5 g with another 41.4 g batch to provide 6-fluorotryptamine. Combine 6-fluorotryptamine (119.85) and ethanol (3.325 L), add 2,2,3,3-tetrafluoropropoxybenzaldehyde (176 g, 0.745 moles, 1.2 equiv.) and 150 g of molecular sleve 3 Å. Heat to reflux. After 2 hours, cool to RT room temperature and add NaBH4 (35.2 g, 0.93 mol, 1.5 equiv.). After 1 hour, filter through celite and wash with 500 ml of ethanol. Evaporate the filtrate under reduced pressure to give an oily residue. Partition the residue between water and dichloromethane. Separate the layers, extract the aqueous later with dichloromethane, combine organic layers, wash with brine and dry over MgSO4. Filter and evaporate under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4][OH:5].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C1(NC2CCCCC2)CCCCC1>CC(C)=O>[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)([O:5][CH2:4][C:3]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:15])=[O:14]
Reactant: Cc1cccc([N+](=O)[O-])c1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OCc2c(C)cccc2[N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 37.9 %

Procedure:
A 100 mL round bottomed flask equipped with a dropping funnel was charged with 2.50 g of 2-methyl-6-nitrobenzyl alcohol and 3.14 g of tosyl chloride dissolved in 30 mL of dry acetone under argon. To the mixture was added dropwise 3.30 mL of dicyclohexylamine dissolved in 5 mL of dry acetone while cooling so as to keep the temperature below 15° C. The reaction mixture was brought to room temperature and stirred for 1 day. The mixture was filtered to remove dicyclohexylamine hydrochloride, the solvent removed under vacuum, and the residue chromatographed over silica gel using carbon tetrachloride as the eluent. The product was recrystallized from methylene chloride/pentane to give 1.82 g (38% yield) of white crystals.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:7]=1.[C:25]1([CH2:31][C@H:32]([NH2:35])[CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>>[NH2:35][C@@H:32]([CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][NH:34][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(NC(=O)c2ccccc2)c1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(NC(=O)c2ccccc2)c1=O

Procedure:
N-(2-Chloro-1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-5-yl)-benzamide (0.07 mmol) was stirred as a solution with 3-phenyl-propane-1,2(S)-diamine (0.15 mmol) and diisopropylethylamine (0.1 mmol) at 0° C. for 2 h. The material was purified on reverse phase HPLC. M+1=455.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[C:20](#[N:24])[CH:21]([CH3:23])[CH3:22].Cl>O1CCCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:21]([CH3:23])([CH3:22])[C:20]#[N:24])=[CH:13][CH:14]=1
Reactant: CC(C)C#N
Reactant: COc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C#N)cc1
Yield: 52 %

Procedure:
Add potassium bis(trimethylsilyl)amide (39.90 g, 200 mmol) to a stirred solution of 4-fluoroanisole (15.0 mL, 133 mmol), isobutyronitrile (49.0 mL, 539 mmol) and anhydrous tetrahydrofuran (150 mL). Heat the reaction to reflux under nitrogen for 72 h. Cool the reaction to room temperature, pour it into 1 N hydrochloric acid (300 mL), and extract with diethyl ether (3× 100 mL). Wash the diethyl ether extracts with brine (100 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to yield 12.13 g (52%) of 2-(4-methoxy-phenyl)-2-methyl-propionitrile: TLC: Rf in 10% ethyl acetate/hexanes: 0.30; 1H NMR (CDCl3): 7.40-7.37 (m, 2H), 6.92-6.90 (m, 2H), 3.81 (s, 3H), 1.70 (s, 6H).
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6](=[S:24])[CH:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2].[CH2:25](N(C(C)C)C(C)C)[CH3:26].BrCC>O1CCOCC1>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([S:24][CH2:25][CH3:26])=[C:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Solvent: C1COCCO1
Solvent: CCBr
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(CC)C2S1

Procedure:
To a solution of 0.5 g of 4-nitrobenzyl 6-ethyl-7-oxo-3-thioxo-4-thia-1-azabicyclo[3,2,0]heptane 2-carboxylate in 2 ml of dioxane was added, in one batch, 0.57 ml of N-ethyldiisopropylamine, then 0.10 ml of bromoethane. When the reaction was complete, the solution was evaporated in vacuo and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the title product. (Yield 0.300 g)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.O.[NH2:13][NH2:14]>C(O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH:13][NH2:14])=[O:10]
Reactant: COC(=O)Cc1cnccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1cnccn1
Temperature: 120 °C
Yield: 80 %

Procedure:
In a 25 mL sealed tube, methyl 2-(pyrazin-2-yl)acetate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.33 g, 4 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 2-(pyrazin-2-yl)acetohydrazide (0.2 g) which was used without further purification in the following step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][OH:19])=[N:13][C:12]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)=[CH:11]2.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([NH:20][C:12]2[N:13]=[C:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]3[C:10]([CH:11]=2)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=3)=[N:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(CO)nc(Nc3cc(C)[nH]n3)cc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
MsCl (1.0 g) in 20 mL CH2Cl2 was added slowly to a mixture of [6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-methanol (11.0 g) and Et3N (1.42 g) in 50 mL CH2Cl2 at 0° C. The reaction mixture was stirred at r.t. for 3 h, and then washed with saturated NaHCO3 (aq) and NaCl(aq). The organic layer was dried over Na2SO4, and concentrated to give the crude product.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].Cl.CN(C)CCCN=C=NCC.O.O[N:26]1[C:30]2[CH:31]=CC=[CH:34][C:29]=2N=N1.C[N:36]1[CH2:41][CH2:40]O[CH2:38][CH2:37]1>C(Cl)Cl>[CH:30]([N:26]1[CH2:40][CH2:41][N:36]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)=[O:9])[CH2:37][CH2:38]1)([CH2:29][CH3:34])[CH3:31]
Reactant: CN1CCOCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reaction time: 24 h
Yield: 71.6 %

Procedure:
The product of Example 6 (3.2 g) and 4-formylbenzoic acid (2.102 g) were suspended in DCM (130 mL) under nitrogen. 1-{3-(Dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (3.96 g), 1-hydroxybenzotriazole hydrate (3.06 g) and N-methylmorpholine (9.432 g) were added in sequence to the above suspension. The reaction mixture was stirred under nitrogen for 24 h. DCM (100 mL) was added, the resulting mixture was washed with 10% aqueous NaOH solution (2×50 mL) and water (2×100 mL), and the separated organic phase was dried over anhydrous MgSO4, and concentrated under reduced pressure to yield the crude product (3.75 g). Chromatography of the residue on silica gel (2-5% 2 M methanolic ammonia/DCM) yielded the title compound (2.75 g).
Reaction SMILES: [C:1](=[C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4]1)=O.[CH2:13]([Li])CCC.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[C:20]1(/[CH:13]=[CH:1]/[C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1=CC=CC(=C=O)C1
Reactant: CCCCCC
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2ccccc2)c1

Procedure:
Using the procedure of Preparation H1, 2.37 g of triphenyl benzyl phosphonium chloride (Aldrich), 1.0 g of methyl 3-carbonylbenzoate and 2.44 ml of 2.5M solution of n-butyl lithium in hexane in 50 ml (total) of tetrahydrofuran gave 208 mg of the titled product, m.p. 108°-109° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CO
Reactant: CC(C)(C)CC(N)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)CC(C)(C)C

Procedure:
2-Amino-4,4-dimethyl-pentanoic acid (1.00 g, 6.84 mmol) was suspended in 50 mL of methanol and cooled in an ice bath. Thionyl chloride (1.82 g, 15.0 mmol) was added dropwise, at which time all the acid went into solution. The reaction was then removed from the ice bath and heated to reflux for 3.5 h. The reaction mixture was concentrated in vacuo and the resulting solid (1.10 g) was used in the next step without further purification. MS, m/z 159.9=M+1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[S:9])[NH2:8])[CH:2]=1.Br[CH2:11][C:12](OCC)=[O:13]>C1(C)C=CC=CC=1.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:9][CH:11]=[C:12]([OH:13])[N:8]=2)[CH:2]=1
Reactant: NC(=S)c1cccnc1
Reactant: CCOC(=O)CBr
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Oc1csc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine-3-carbothioamide (20 g, 0.145 mol) was dissolved in a mixture of toluene (145 ml) and DMF (116 ml). Ethyl bromoacetate (24.2 g, 0.145 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 hours. The precipitated yellow compound was filtered, washed with water and dried to give 2-(3-pyridyl)thiazol-4-ol as hybromide salt.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[S:12]1[C:20]2C(=O)C=[CH:17][NH:16][C:15]=2[CH:14]=[CH:13]1>C(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:17][N:16]=[C:15]2[CH:14]=[CH:13][S:12][C:20]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1cc[nH]c2ccsc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccnc2ccsc12
Temperature: 0 °C
Yield: 103.9 %

Procedure:
In a 250 mL round-bottomed flask 100 mL of methylene chloride and dimethylformamide (6.1 mL, 78.6 mmol) were combined and cooled to 0° C. Oxalyl chloride (57 mL, 114 mmol) was added dropwise over several minutes. 4H-Thieno[3,2-b]pyridin-7-one (5.4 g, 35.7 mmol) was added and the solution was heated to reflux. After 2 hours the flask was cooled to room temperature and the resulting solid was filtered and dried in vacuo to afford 6.29 g (100%) of 7-chloro-thieno[3,2-b]pyridine as a yellow solid. 1H NMR (400 MHz, DMSO) d 8.67 (d, 1H), 8.29 (d, 1H), 7.66 (d, 1H), 7.61 (d, 1H); LC-MS: 171 (MH+); HPLC RT: 4.19.