Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O1CCCC1.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(OCc2ccccc2)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(OCc2ccccc2)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixture of 2-benzyloxy-5-methoxymethoxybenzaldehyde (10.03 g), ethanol (50 mL) and tetrahydrofuran (100 mL) was added sodium tetrahydroborate (1.43 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give (2-benzyloxy-5-methoxymethoxyphenyl)methanol as a colorless oil (10.08 g, 97%).
Reaction SMILES: C([Si:5](C)([C:12]1([CH2:18][CH:19]([CH3:21])[CH3:20])SCCCS1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CC=C.[OH2:23]>CC#N.Cl[Hg]Cl>[CH2:11]([CH2:10][C:6]1([SiH2:5][C:12](=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)[CH2:6][CH:7]=[CH2:8]
Reactant: C=CCC[Si](C)(c1ccccc1)C1(CC(C)C)SCCCS1
Reactant: O
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: C=CCCCC1([SiH2]C(=O)CC(C)C)C=CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 44 (6.19 g, 17.7 mmol) in CH3CN (200 mL) was added water (10 mL) and HgCl2 (24 g, 88 mmol). After stirring overnight at rt, the mixture was concentrated and partitioned between water (100 mL) and hexane (200 mL). The organic layer was isolated and the aqueous layer extracted twice with 50 mL portions of hexane. The combined organic extracts were washed with saturated aqueous NaCl and dried over Na2SO4. Concennation to dryness in vacuo at rt gave quantitatively crude ketone 45 as a yellow oil. This ketone was used in the next reaction without further purification: Rf 0.75 (1/19 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.41-7.35 (m, 3H), 5.91-5.78 (m, 1H), 4.99 (dd, J=17.0, 1.7 Hz, 1H), 4.90 (dd, J=10.0, 1.7 Hz, 1H), 2.44 (d, J=6.7 Hz, 2H), 2.16-2.06 (m, 3H), 1.16-1.07 (m, 2H), 0.78 (pd, J=6.7 Hz, 6H), 0.51 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[N:17][C:12]2[O:13][CH2:14][CH2:15][NH:16][C:11]=2[CH:10]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C.O>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:19])[F:20])=[CH:10][C:11]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: FC(F)(F)c1ccccc1-c1cnc2c(c1)NCCO2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccccc4C(F)(F)F)cc32)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
In a 10 ml flask, 7-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (67 mg, 0.24 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (118 mg, 0.36 mmol) were dissolved in dichloromethane. Triethylamine (0.17 ml, 1.20 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(2-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (46 mg, 34%).
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11].[NH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[CH2:14]1.[BH4-].[Na+].O>CO>[ClH:11].[CH3:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([NH:12][CH2:9][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[OH:8])[CH2:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)CC(N)CC2
Reactant: O=CC(=O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2
Temperature: 4 °C
Yield: 20 %

Procedure:
An amount of 3.53 g of phenylglyoxal is reacted under stirring at room temperature for 3 hours with 5 g of 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride in 100 ml of methanol in the presence of 0.9 g of sodium borohydride. After cooling to 4° C., 4,3 g of sodium borohydride are added and the reacting mixture is left under stirring at room temperature for a night. After addition of 20 ml of water, the solution is stirred at room temperature for 15 minutes, then it is evaporated to dryness. The residue is dissolved in 300 ml of ethyl acetate and 60 ml of water; after filtration, the organic phase is separated, dried over magnesium sulfate, filtered and evaporated to dryness. The oil thus obtained is purified by flash-chromatography by using a mixture ethyl acetate/methanol 8/2 as eluant to obtain the 2-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol hydrochloride. Yield: 20% of the theoretical value.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]([CH3:44])[C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:27]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([N:36]([CH3:44])[CH3:35])[CH:38]=2)=[O:33])=[CH:20][CH:21]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CN(C)c1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(N(C)C)c4)cc3)c2cc1OC
Yield: 89.5 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 3-Dimethylaminoaniline (69 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 12 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 72 mg of the title compound (yield: 89%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.[NH2:14][C:15]([NH2:17])=[NH:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[CH:4]=[CH:3][N:14]=[C:15]([NH2:17])[N:16]=1
Reactant: N=C(N)N
Reactant: CN(C)C=CC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nccc(-c2ccco2)n1
Temperature: 100 °C
Reaction time: 21 h
Yield: 85.8 %

Procedure:
A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (5.0 g, 30.3 mmol), guanidine hydrochloride (5.8 g, 60.7 mmol) and potassium carbonate (8.4 g, 60.9 mmol) in N,N-dimethylformamide (50 ml) was stirred at 100° C. for 21 hours. After cooling as it was, the reaction mixture was diluted with ice water (250 ml). The resulting solid was collected by filtration and washed with water, to give the title compound (4.19 g, 86%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](C)([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.[Cl-].[CH2:30](C1C=CC=C(CCC)C=1[N+]1C=CN(C2C(CCC)=CC=CC=2CCC)C=1)CC.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:30][O:16][C:14]([CH:10]1[N:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CCCc1cccc(CCC)c1-n1cc[n+](-c2c(CCC)cccc2CCC)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(C)(C(=O)O)C1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 282.5 %

Procedure:
3-Methyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (120 mg, 0.49 mmol) and 2-Bromo-5-trifluoromethyl-pyridine (133 mg, 0.59 mmol) were dissolved in 2.0 mL of anhydrous toluene (degassed). In a separate, septum-equipped vial were placed tri(dibenzylideneacetone)dipalladium (0) (22 mg, 0.024 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (42 mg, 0.1 mmol) and sodium t-butoxide (57 mg, 0.59 mmol). This “catalytic” vial was equipped with a magnetic stir bar and flushed with dry nitrogen. The reactant solution was next transferred to the “catalytic” vial and the mixture was stirred at 100° C. for 5 h. After this period the mixture was combined with 20 mL of hexane/EtOAc (2:1) and was passed through a pad of Celite. The resulting filtrate was evaporated in vacuo and purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 110 mg (58%) of 4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.C(NC(C)C)(C)C.ClP(=O)(OCC)[O:28][CH2:29][CH3:30]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:30][CH:29]=[O:28])=[CH:5][CH:4]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: CC=NC(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(=CC=O)c2ccc(OC)cc2)cc1
Reaction time: 68 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction time was extended to 68 hours. The following reagents were used: 4,4'-dimethoxybenzophenone (24.2 g), diisopropylamine (32.2 mL) 1.55M n-butyl lithium in hexane (148 mL), acetaldehyde N-tertbutylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). The usual work up furnished 25.6 g of an orange oil which was crystallized from ether-hexane to give 22.7 g of 3,3-bis(4-dimethoxyphenyl)-2-propenal, as a yellow solid, mp 55°-57° C. The analytical specimen, mp 56°-57° C. Crystallized from the same solvent system, had been prepared in a previous experiment.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9](=[O:20])[C:10]3[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][S:12][C:11]=3[C:18](=[O:19])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].OC(C1SC2C(=O)C3C=CSC=3C(=O)C=2C=1)C>C(Cl)(Cl)Cl.CO>[OH:3][CH:1]([C:4]1[S:8][C:7]2[C:9](=[O:20])[C:10]3[C:14]([CH:15]([OH:17])[CH3:16])=[CH:13][S:12][C:11]=3[C:18](=[O:19])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc2c(s1)C(=O)c1c(C(C)=O)csc1C2=O
Agent: CC(O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)c1cc2c(s1)C(=O)c1c(C(C)O)csc1C2=O
Yield: 90 %

Procedure:
Compound 13 was reduced with NaBH4 as in the preparation of 10. Column chromatography on silica gel eluting with CHCl3:MeOH (100:1) gave 14 as a yellow solid (mp 218-219° C.) in a 90% yield. IR (KBr) 1650, 1670 (C═O), 3100-3500 (OH) cm−1; 1H NMR (DMSO-d6) δ 1.36 (d, J=6.0 Hz, 3H, C-7-CH3), 1.48 (d, J=6.0 Hz, 3H, C-2-CH3), 5.05 (s, 1H, C-2-OH), 5.33 (s, 1H, C-7-OH), 5.52 (m, 1H, C-7-CH), 6.17 (m, 1H, C-2-CH), 7.41 (s, 1H, H-3), 7.97 (s, 1H, H-6); 13C NMR (DMSO-d6) δ 24.8 (C-7-CH3), 25.5 (C-2-CH3), 64.1 (C-7-CH), 64.9 (C-2-CH), 120.7 (C-3), 130.1 (C-6), 174.7 (C-4), 175.3 (C-8); MS m/z 308 (M+); Anal. (C14H12O4S2) C, H.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18](Cl)(=[O:20])[CH3:19].Cl>O.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
To a cooled, stirred suspension containing 154 gms. of anhydrous aluminum chloride, 800 ml. of carbon tetrachloride and 200 gms of p-chlorobiphenyl add (dropwise) 91 gms of acetyl chloride. When the reaction temperature of the mixture reaches 10° C., add 60 ml of methylene chloride and allow the reaction mixture to slowly reach room temperature. Stir the mixture overnight. Pour the resulting mixture into 1 liter of crushed ice and water containing 100 ml. of conc. hydrochloric acid. Separate the organic phase, dry over anhydrous sulfate, filter, concentrate, and triturate the solid residue with 600 ml. of hexane to yield 1-(4'chloro[1,1']biphenyl-4-yl) ethanone, m.p. 100°-101° C.
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]2=[S:17])[CH:7]=[CH:8][C:9]=1[F:10]>C(#N)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]=[C:12]2[S:17][CH3:1])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=S
Reactant: CI
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCN=C1SC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.520 mL) was added to a mixture of ethyl 3-(3,4-difluorophenyl)-2-thioxopiperidine-3-carboxylate (500 mg) in acetonitrile (5 mL) at room temperature, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (530 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[CH:2].Cl.[CH3:13][O:14][NH2:15]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:15][O:14][CH3:13])=[O:7])#[CH:2]
Reactant: CON
Reactant: C#Cc1cccc(C(=O)O)c1
Agent: Cl
Product: C#Cc1cccc(C(=O)NOC)c1
Yield: 106.7 %

Procedure:
In a manner similar to that described for Example 478 (step 1), 3-ethynylbenzoic acid (0.1 g, 0.685 mmol) and O-methylhydroxylamine hydrogen chloride (0.057 g, 0.685 mmol) were reacted to give the title compound (0.128 g, 61%).
Reaction SMILES: [CH2:1]([C:5]1([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[O:10][C:9](=[O:11])[CH:8]([Cl:12])[C:7](=[O:13])[CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.Cl>CN(C=O)C.C(NC(C)C)(C)C.C(Cl)Cl.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.[Cu]I>[Cl:12][CH:8]1[C:7](=[O:13])[CH2:6][C:5]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)([CH2:1][CH2:2][C:3]#[C:4][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[O:10][C:9]1=[O:11]
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Reactant: Oc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Cl
Temperature: 90 °C

Procedure:
A solution of 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione (200 mg, 0.66 mmol) from Step 4 above, 3-iodophenol (145 mg, 0.66 mmol), bis(triphenylphosphine)palladium (II) dichloride (18 mg, 0.026 mmol), and copper (I) iodide (10 mg, 0.052 mmol) in DMF (0.66 mL) and diisopropylamine (0.66 mL) was sonicated for 1 minute and then heated to 90° C. for 20 minutes. The reaction was cooled to room temperature, and then diluted with 10 mL CH2Cl2 The reaction was then neutralized to a pH of 4 with 6 N HCl and the layers were separated. The aqueous layer was extracted with 3×10 mL CH2Cl2 and the organic layers were combined, and then dried over sodium sulfate. After filtering the solids, the organic layer was concentrated to a dark oil, which was used without further purification. MS (ESI): 359 (M−H), 361 (M+2−H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=C1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:18]([OH:20])=O)=[C:14]([CH2:16][CH3:17])[N:15]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1NCC#N>O1CCCC1>[CH3:10][C:11]1[S:12][C:13]([C:18]([NH:3][CH:4]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)[C:5]#[N:1])=[O:20])=[C:14]([CH2:16][CH3:17])[N:15]=1
Reactant: N#CCNc1ccco1
Reactant: c1c[nH]cn1
Reactant: CCc1nc(C)sc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCc1nc(C)sc1C(=O)NC(C#N)c1ccco1
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of imidazole (2.72 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2-methyl-4-ethyl-5-thiazolecarboxylic acid (1.71 g; 10 mmol) was added thereto at once, and stirring was continued for 30 minutes. To the mixture was added dropwise a solution of 2-(2-furyl)aminoacetonitrile (1.46 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude oil. The oil was purified by silica-gel column chromatography (eluent:n-hexane:ethyl acetate=2:1 volume) to give crude crystals. Recrystallization from n-hexane/ethyl acetate gave 1.58 g of 2-(2 -methyl-4-ethylthiazole-5-carboxamido)-2-(2-furyl)acetonitrile as colorless crystals. m.p., 125°-126° C. Yield, 57%.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13]CC)=O)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Br:8][C:6]1[N:7]=[C:2]2[N:25]([CH2:24][C@H:21]3[CH2:22][CH2:23][C@H:18]([O:17][CH3:16])[CH2:19][CH2:20]3)[C:11](=[O:13])[CH2:10][NH:9][C:3]2=[N:4][CH:5]=1
Reactant: CO[C@H]1CC[C@H](CN)CC1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(Br)nc32)CC1
Temperature: 150 °C

Procedure:
A solution of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (500 mg, 1.47 mmol), ((trans)-4-methoxycyclohexyl)methanamine (317 mg, 2.21 mmol) and diisopropylethyl amine (0.77 mL, 4.42 mmol) in anhydrous dimethylsulfoxide (8.0 mL) was placed in a microwave vessel (20 mL). The reaction was heated to 150° C. for 1 h. The reaction was poured into water, extracted with ethyl acetate (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dissolved in acetic acid (30 mL) and placed in a sealed tube. The reaction was heated to 120° C. overnight. The solution was cooled, concentrated under reduced pressure, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate (3×100 mL), dried over sodium sulfate, filtered and adsorbed onto silica gel. Purification by flash chromatography (50% ethyl acetate in hexanes) gave a light orange solid (400 mg, 1.12 mmol, 76% yield). MS (ESI) m/z 355.2 [M+]+, 357.2 {M+2]+.
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([N:11]1[CH2:16][CH:15]([CH3:17])[C:14](=O)[CH:13]([CH3:19])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].C([BH3-])#[N:21].[Na+]>CO>[NH2:21][CH:14]1[CH:15]([CH3:17])[CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH3:19]
Reactant: CCOC(=O)N1CC(C)C(=O)C(C)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CC(C)C(N)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (20 g) was added to the stirred solution of 1-carbethoxy-3,5-dimethyl-4-piperidinone (4.5 g, 22.5 mmol) in methanol (200 ml) and stirred for 3 hr. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (1.4 g, 22.5 mmol) was added to it. Cooling was removed and stirring was for 3 hr at 35° C. The reaction mixture was concentrated, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH ˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to give 4-amino-1-carbethoxy-3,5-dimethylpiperidine. The obtained 4-amino-1-carbethoxy-3,5-dimethylpiperidine was subjected to silica gel column chromatography. Elution with 5% methanol in chloroform furnished a solid, which was a mixture of stereoisomers, conformational analysis of which was not obtained.
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:7]2[CH:13]=[N:14][C:15]([Cl:17])=[N:16][C:6]1=2)[CH2:2][CH2:3][CH3:4].[CH3:18]N(C)C(=O)C.IC.[H-].[Na+]>O>[CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:18])[C:7]2[CH:13]=[N:14][C:15]([Cl:17])=[N:16][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)N(C)C
Reactant: CCCCN1CCC(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.102 g (0.0004 mole) of 9-butyl-2-chloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-44), 1 mL of N,N-dimethylacetamide and 0.037 mL (0.0006 mole) of iodomethane at 0 degrees was added 0.024 g (0.0006 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.094 g of 9-butyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-44) as an yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:16])[NH:13][C:14](=[O:15])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[N:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[N:1]/[C:2]2[CH:3]=[CH:4][C:5]3[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:7]4[C:6]=3[C:11]=2[CH:10]=[CH:9][CH:8]=4)=[CH:19][CH:18]=1
Reactant: Nc1ccc2c3c(cccc13)C(=O)NC2=O
Reactant: O=Cc1ccncc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1NC(=O)c2ccc(/N=C/c3ccncc3)c3cccc1c23
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3 g (14.13 mmol) of 4-aminonaphthalene-1,8-dicarboximide and 7.56 g (70.65 mmol) of 4-pyridinecarboxaldehyde in 180 mL of a 2:1 mixture of concentrated sulfuric acid and glacial acetic acid were stirred at 80° C. for 2 hours. The mixture was then poured onto ice and slowly neutralized or adjusted to a slightly alkaline pH (pH=about 8) with NaOH. The resulting precipitate was suction-filtered off, washed with copious amounts of water and then dried under vacuum. Yield: 2.28 g (54% of the theoretical), lustrous yellow powder. 1H-NMR (d6-DMSO/300 MHz): δ=6.46 (s, 1H); 7.52-7.56 (m, 2H, aromatic); 7.20 (d, J=5.7 Hz, 2H, pyridyl); 8.38 (m, 1H, aromatic); 8.65 (d, J=5.7 Hz, 2H, pyridyl), 8.71-8.73 (m, 2H, aromatic); 11.41 (s, 1 H, N—H).