Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.Cl.[NH2:22][CH2:23][C:24]([O:26]CC)=O.Cl.[C:30]1(NCC(OCC)=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([CH:23]2[N:22]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:3]3[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]=3[NH:1][C:24]2=[O:26])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOc1cc(N)c(C(=O)c2ccccc2)cc1OC
Reactant: CCOC(=O)CNc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1)C(=O)N2
Yield: 55 %

Procedure:
By replacing (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa) in example XXIIaa by (2-amino-4-ethoxy-5-methoxyphenyl)(phenyl)methanone XXIak, and ethyl glycinate hydrochloride by ethyl phenylglycinate hydrochloride, and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 168–169° C. 1H-NMR (DMSO, 200 MHz): d 1.38–1.42 (m, 3H, CH3), 3.65 (s, 3H, OCH3), 3.98–4.18 (m, 2H, CH2), 4.76 (s, 1H, CH), 6.78 (s, 1H Ar), 6.88 (s, 1H Ar), 7.38–7.58 (m, 10H Ar), 10.49 (s, 1H, NH).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[C:17]=[S:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20]>C(OCC)C.C(O)(C)C>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[S:18])[N:22]([CH2:21][CH2:19][OH:20])[C:1]2([OH:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1N=C=S
Solvent: CCOCC
Solvent: CC(C)O
Product: OCCN1C(=S)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Using the general procedure already described above, a solution containing 10.92 grams (40 moles) of 2-benzoyl-4-chlorophenylisothiocyanate in about 100 ml of ethyl ether was added dropwise to a stirred solution of 2.83 grams (44 moles) of ethanolamine in 200 ml of isopropanol. The reaction mixture was stirred overnight. The 6-chloro-3,4-dihydro-4-hydroxy-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinethione precipitated as a white solid. The product was washed with a mixture of ethyl ether and isopropanol to give the final product which had a melting point of 238°-240° C. Final yield was 93%.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH3:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[CH3:40][O:41][C:42]1[N:47]=[C:46]([C:48](=[O:50])[CH3:49])[CH:45]=[CH:44][CH:43]=1>>[OH:39][C:29]1([CH2:49][C:48]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([O:41][CH3:40])[N:47]=2)=[O:50])[C:28]2[C:32](=[CH:33][CH:34]=[C:26]([CH3:25])[CH:27]=2)[N:31]([CH2:35][CH2:36][CH3:37])[C:30]1=[O:38]
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Reactant: COc1cccc(C(C)=O)n1
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2cccc(OC)n2)c2cc(C)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-methyl-1-propylindoline-2,3-dione and 1-(6-methoxypyridin-2-yl)ethanone (commercially available from Fisher Scientific). 1H-NMR δ 7.74 (m, 2H), 7.19 (s, 1H), 7.11 (d, 1H), 6.98 (d, 1H), 6.77 (d, 1H), 5.27 (bs, 1H), 4.03 (s, 3H), 3.65 (m, 3H), 3.49 (d, 1H), 2.30 (s, 3H), 1.74 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(CC(=O)c2ccccc2Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CC(=O)c2ccccc2Cl)cc1
Yield: 96.7 %

Procedure:
A mixture of 18.78 g of methyl 4-[2-(2-chlorophenyl)-2-oxoethyl]benzoate in 288.8 ml of CH3OH, 72.2 ml of water and 5.2 g of NaOH is refluxed for 3 hours then acidified with 2 N citric acid. The reaction mixture is evaporated in vacuo to remove the CH3OH. The aqueous phase is extracted with CH2Cl2 and acidified with 1 N HCl. The resulting solid is collected and dried under vacuum to give 17.27 g of the desired product, m.p. 168-172° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][NH:8]1.ClC1C2C(=CC(OC)=C(OC3CCC4(OCCO4)CC3)C=2)N=CN=1.[F:54][C:55]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:56]=1[NH2:57]>C(#N)C.C(N(CC)CC)C>[F:54][C:55]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:56]=1[NH:57][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH3:29])=[C:14]([O:17][CH:18]3[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][CH2:27]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2
Reactant: Cc1ccc(F)c(N)c1
Agent: COc1cc2ncnc(Cl)c2cc1OC1CCC2(CC1)OCCO2
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3cc(C)ccc3F)c2cc1OC1CCC(=O)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
6 ml phosphorus oxychloride are added dropwise to 12.1 g 3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4,5]decan-8-yl-oxy)-7-methoxy-quinazoline in 120 ml acetonitrile and the mixture is heated to an internal temperature of 40° C. Then 9.3 ml triethylamine are added dropwise and the reaction mixture is refluxed for 3 hours. The mixture is cooled to ambient temperature and after standing overnight half the solution of the intermediate product (4-chloro-6-(1,4-dioxa-spiro[4,5]decan-8-yl-oxy)-7-methoxy-quinazoline, see Example IX) is combined dropwise with 2.7 ml of 2-fluoro-5-methylaniline in 5 ml acetonitrile. The reaction mixture is heated to 40° C. for 3 hours, then cooled and evaporated down. The residue is mixed with water and stirred. The precipitate formed is suction filtered and divided between 1M sodium hydroxide solution and dichloromethane. The organic phase is separated off, dried, evaporated down and stirred with diisopropylether. The solid is suction filtered and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCCCC1CCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCCCCCC1CCCC1)C(=O)OCC

Procedure:
11.5 g of 8-cyclopentyl-2-methyleneoctanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 22.1 g of (6-cyclopentylhexyl)-malonic acid ethyl ester, 2.8 g of paraformaldehyde, 22 ml of pyridine and 1 ml of piperidine.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:9]2)C.O=[C:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[C:16]1([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([CH2:5][C:4]([OH:3])=[O:22])=[CH:14][C:13]=3[NH:15][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)Cc1cc(N)c2[nH]c(-c3ccccc3)cc2c1
Product: O=C(O)Cc1cc(NC2CCOCC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
2-(2-Phenyl-7-amino-1H-indol-5-yl)-acetic acid ethyl ester prepared as an intermediate in the process of Example 31 and 4-oxo-tetrahydropyran were reacted according to the same procedures as Step B of Example 1 and Example 30 to give the title compound.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].[CH3:27][C:28](CC(O)=O)=[O:29]>N1C=CC=CC=1>[CH3:21][C:20]([O:19][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([O:18][C:28]([CH3:27])=[O:29])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:1][CH:2]=1)=[O:22]
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Reactant: CC(=O)CC(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of daidzein (2.0 g, 7.9 mmol), acetic anhydride (10 ml) and pyridine (2 ml) was heated on an oil bath at 105-110 C. for 1 h. After cooling the mixture to room temperature, it was stirred for a further 30 min during which time the diacetate crystallised from the solution. The product was filtered, washed thoroughly with water and recrystallised from methanol to yield daidzein diacetate as colourless prisms (2.4 g, 90%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[OH-].[CH2:16]([N+](C)(C)C)[C:17]1[CH:22]=CC=[CH:19][CH:18]=1.ClC(C)(C)C#C>O.ClCCl>[CH3:16][C:17]1([CH3:22])[CH:18]=[CH:19][C:10]2[CH:11]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=[CH:8][C:9]=2[O:12]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Oc1ccc(C2CCCC2)cc1
Agent: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)C=Cc2cc(C3CCCC3)ccc2O1

Procedure:
4-Cyclopentylphenol (10.0 g), and sodium hydroxide pellets (3.7 g) were stirred in water (60 ml) and dichloromethane (60 ml). Benzyltrimethylammonium hydroxide (75 ml, 40% solution in methanol) was added to the solution, followed by 3-chloro-3-methylbutyne (12.63 g) and the reaction mixture stirred under reflux condenser, with sonication. The layers were separated, and the aqueous phase extracted with chloroform. The combined organic layers were evaporated, and the residue taken up in ether. The ether solution was washed with 10% sodium hydroxide solution, and brine and dried over anhydrous magnesium sulphate. Filtration and evaporation gave a pale brown oil (10.89 g) which was refluxed in o-dichlorobenzene (22 ml) under nitrogen for 2 h. Evaporation and chromatography of the resulting brown oil (9.3 g) gave the title benzopyran (4.18 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCCCN2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (2.36 g, 13.6 mmol), the hydrochloride salt of the hexahydro-pyridazine (5.0 g, 41 mmol) and anhydrous potassium carbonate (11.3 g, 82 mmol) in N,N-dimethylacetamide (20 ml) was stirred at 115-120° C. under nitrogen for 3 days. A sample was analyzed by NMR showed complete conversion of the starting material. The resultant mixture was cooled to room temperature, poured onto cold water (200 mL), stirred vigorously and incubated at 4° C. overnight. The resulting brown precipitate was collected by filtration, washed well with water and dried on the filter funnel. This was then slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-Nitro-5-(tetrahydro-pyridazin-1-yl)-phenylamine (1.9 g, 62.5%). The crude product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15]=O.[Cl-].[K+].N>O.C1COCC1>[NH2:10][C@H:11]([C:12]([OH:14])=[O:13])[CH2:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: C=O
Reactant: NCC(=O)O
Reactant: c1ccc2[nH]ccc2c1
Agent: N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 30 °C

Procedure:
A 100 g of the frozen cells of Escherichia coli K-12 SH1001 prepared in Preparation Example 2 and 100 g of the frozen cells of Escherichia coli K-12 YK3005 (FERM BP-1736) prepared in Preparation Example 4 were suspended in 500 ml of the reaction solution (adjusted to pH 9.5 with 25% ammonia)containing 0.1 g of indole, 7.5 g of glycine, 1.6 g of formalin (formaldehyde content: 37%), 100 mg of PLP, 1.0 g of THF and 3.8 g of KCl, and then water was added to the suspension to make its total amount 1,000 ml. This suspension was fed into a 3-liter fermentor (mfd. by Able Inc.) and reacted with stirring at 30° C. During the reaction, pH of the reaction solution was adjusted to maintain at 9.5 with 25% ammonia. Indole was added continuously or intermittently so that the indole concentration in the reaction solution wouldn't exceed 2 mmol/l while monitoring the indole concentration by a high-performance liquid chromatograph (mfd. by Shimazu Corp.). Further, glycine and formaldehyde were added continuously or intermittently so that the L-serine concentration wouldn't exceed the designated levels for the respective test sections shown in Table 2 while monitoring the L-serine concentration in the reaction solution by a high-performance liquid chromatograph(mfd. by Shimazu Corp.). Glycine was added in a total amount of 22.5 g. The L-tryptophan concentration in the reaction solution was monitored by a high-performance liquid chromatograph (mfd. by Shimazu Corp.). The yields of L-tryptophan based on glycine are shown in Table 2.
Reaction SMILES: O1CCCC1.[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[CH:7]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([NH2:33])=[C:28]([Cl:34])[CH:27]=1)[OH:25]>C(OCC)(=O)C.C(N(CC)CC)C>[S:6]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:22][CH2:23][CH:24]([C:26]2[CH:27]=[C:28]([Cl:34])[C:29]([NH2:33])=[C:30]([Cl:32])[CH:31]=2)[OH:25])=[CH:7]1
Reactant: O=C(CCCCCBr)OCCc1ccsc1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(C(O)CNCCCCCC(=O)OCCc2ccsc2)cc1Cl

Procedure:
According to method I (tetrahydrofuran, reflux 4 days) from {2-(3-thienyl)ethyl}6-bromohexanoate and 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol. Working up by means of chromatography (ethyl acetate/triethylamine 8:1). Recrystallized as the base from diethyl ether. Melting point: 71°-73° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][CH:55]([NH2:63])[CH2:54]1>ClCCl.O>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:63][CH:55]3[CH2:56][C:57]4[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=4)[NH:53][CH2:54]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: NC1CNc2ccccc2C1
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
70 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.22 mmol), 54 mg of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.26 mmol) and 133 mg of 4-methylmorpholine (1.32 mmol) were initially charged in 1.5 ml of dichloromethane. After 10 min at RT, 53 mg of 1,2,3,4-tetrahydroquinoline-3-amine (0.24 mmol) were added, and the mixture was stirred at RT overnight. About 5 ml of water were added, the reaction solution was stirred for another 30 min and the resulting precipitate was filtered off, washed thoroughly with water and dried under high vacuum. The crude product was purified by preparative thin-layer chromatography (dichloromethane/methanol 20:1). This gave 52 mg of the title compound (52% of theory).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([N:5]2[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1n[nH]cc1C
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCOC(=O)c1nn(-c2cccc(OC)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
Ethyl 4-methyl-1H-pyrazole-3-carboxylate (2.58 g) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.9 g, 46%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:14](=[O:25])[N:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[C:17]([Cl:19])[N:18]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:14](=[O:25])[N:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[C:17]([Cl:19])[N:18]=1
Reactant: Nc1ccc(Br)cc1Br
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(CC)n1cc(Cl)nc(Nc2ccc(Br)cc2Br)c1=O
Yield: 44.7 %

Procedure:
2,4-Dibromoaniline (500 mg), toluene (8 mL), and sodium hydride (60% in oil, 398 mg) were stirred for 10 minutes at room temperature and then 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone (468 mg, Example 1, part B) was added. The reaction was heated at reflux 3 hours, cooled, and quenched with water (50 mL). The mixture was extracted with ethyl acetate (100 mL), which was washed with brine, then dried and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:19) affording 400 mg of material, which was crystallized from ether/hexane to give the title compound (240 mg). Elemental analysis: calcd. for C15H16N3OClBr2: C, 40.07; H, 3.597; N, 9.356; Cl, 7.895; Br, 35.55. Found: C, 40.41; H, 3.49; N, 9.34; Cl, 8.27; Br, 35.71.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C([O-])(O)=O.[Na+]>CCO>[C:11]1([N:17]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 90.6 %

Procedure:
A mixture of 4,4,4-trifluoro-3-oxobutanenitrile (2.056 g, 15 mmol) and phenylhydrazine hydrochloride (2.169 g, 15 mmol) in EtOH was heated at 90° C. for 8 hours. The reaction was quchened with water, basified with saturated NaHCO3 solution, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as yellow solid (3.089 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 5H), 5.85 (s, 1H), 3.95 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[S-:5][C:6]#[N:7].[K+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[NH:14][CH2:15][C:16]#[CH:17]>C(#N)C>[F:9][C:10]([F:21])([F:22])[C:11]1[CH:12]=[C:13]([N:14]([CH2:15][C:16]#[CH:17])[C:6]([NH:7][C:1](=[O:3])[CH3:2])=[S:5])[CH:18]=[CH:19][CH:20]=1
Reactant: N#C[S-]
Reactant: C#CCNc1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: [K+]
Solvent: CC#N
Product: C#CCN(C(=S)NC(C)=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Acetyl chloride (2.75 g) was mixed with acetonitrile (70 ml), and the mixture was cooled to 0° C. Then, potassium thiocyanate (3.75 g) was added thereto, and the mixture was stirred at room temperature for 6 hours. After cooling to 0° C. again, 3-trifluoromethyl-N-propargyl-aniline (7 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate (300 ml), and the extract was washed with water. The solvent was distilled off to give N-[3-(trifluoromethyl)phenyl]-N-propargyl-N'-acetylthiourea as crystallines (8 g). This identification was achieved by proton nuclear magnetic resonance (1H-NMR).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)#[N:2].[NH3:12].[H][H]>[O-2].[O-2].[Ti+4]>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH2:12].[NH:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:1]1
Reactant: N
Reactant: [H][H]
Reactant: N#CCCC1CCCCC1=O
Agent: [Ti+4]
Agent: [O-2]
Product: C1CCC2NCCCC2C1
Product: NCCCC1CCCCC1N
Yield: 4.5 %
Yield: 92.5 %

Procedure:
Through a tubular reactor (diameter 16 mm, packing height 50 cm, oil-heated double jacket), installed upstream of the hydrogenation reactor and packed with 63.5 g (100 ml) of titanium dioxide (anatase) in the form of 1.5 mm extrudates, there were passed upwardly, per hour, 16.0 g of 2-(2-cyanoethyl)-cyclohexanone (purity 97.5%, 0.103 mole) and 51 g of liquid ammonia (87 ml, 3.0 moles) at a pressure of 250 bar and a temperature of 80° C. Hydrogen was then added to the stream at ar ate of 60 standard liters per hour, and the effluent from the in-line imination reactor was passed upwardly through the hydrogenation reactor at a pressure of 250 bar and a temperature of 130° C. The effluent was depressurized to standard pressure, and the ammonia was distilled off. Gas-chromatographic analysis of the hydrogenation product gave 92.5% of 2-(3-aminopropyl)-cyclohexylamine and 4.5% of decahydroquinoline. The effluent was collected over a period of 46 hours and fractionated by distillation in a 30 cm packed column containing 3 mm glass rings. There were obtained 674 g of 2-(3-aminopropyl)-cyclohexylamine, corresponding to a yield of 91.0% of theory.
Reaction SMILES: [O-]CC.[Na+].[H-].[Na+].[NH2:7][C:8]([NH2:10])=[S:9].C([O:13][C:14](=O)[CH:15]([C:24]#[N:25])[CH2:16][C:17]1([CH2:22][CH3:23])[O:21][CH2:20][CH2:19][O:18]1)C>C(O)C>[NH2:25][C:24]1[NH:10][C:8](=[S:9])[NH:7][C:14](=[O:13])[C:15]=1[CH2:16][C:17]1([CH2:22][CH3:23])[O:18][CH2:19][CH2:20][O:21]1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C#N)CC1(CC)OCCO1
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(Cc2c(N)[nH]c(=S)[nH]c2=O)OCCO1
Temperature: 75 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
To a 60° C. solution of sodium ethoxide, prepared from 1.92 g (80 mmol) of sodium hydride and 60 of ethanol, was added 6.09 g (80 mmol) of thiourea and 18.2 g (80mmol) of α-cyano-2-ethyl-1,3-dioxolane-2-propanoic acid ethyl ester. The mixture was heated to 75° C. for 4 hours then allowed to cool to ambient temperature and stirred for 18 hours. The reaction was then concentrated to a solid. The solid was dissolved in 100 mL of water and the solution adjusted to pH 6.9 with glacial acetic acid which caused a solid to precipitate. The solid was collected by filtration and washed with 100 mL of water. The wet cake was combined with 60 mL of ethanol and stirred for 15 minutes. The remaining solids were collected by filtration, washed with 40 mL of ethanol, and dried in vacuo (40° C., 10 torr) to provide 11.0 g (53.4%) of 6-amino-5-(2-ethyl-1,3-dioxolan-2-ylmethyl)-2-thiouracil as a cream colored solid. nmr (500 MHz, dmso-d6) δ0.80 (t, J=7.4 Hz, 3H), 1.51 (q, J=7.4 Hz, 2 H), 2.51 (s, 2H), 3.81 (m, 2H), 3.92 (m, 2H), 5.95 (s, 2H), 11.43 (s, 1H), 11.69 (s, 1H)