Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.B(O)(O)[C:16]1[CH:21]=[CH:20][C:19]([N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C>[C:4]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:32]3[CH:33]=[CH:34][C:29]([N:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]4[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=4)=[CH:30][CH:31]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccc(Nc2ccccc2)cc1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(Nc2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)cc1
Temperature: 100 °C

Procedure:
4.3 g (17 mmol) of 4-bromodiphenylamine, 5 g (17 mmol) of triphenylamine-4-boronic acid, and 532 mg of tri(o-tolyl)phosphine were put into a 500 mL three-neck flask, and the atmosphere in the flask was substituted by nitrogen. 60 mL of toluene, 40 mL of ethanol, and 14 ml of a potassium carbonate aqueous solution (0.2 mol/L) were added into this mixture. The mixture was deaerated while being stirred under reduced pressure, and after deaeration, 75 mg (0.35 mmol) of palladium(II) acetate was added. This mixture was refluxed at 100° C. for 10.5 hours. An aqueous layer of the mixture was extracted with toluene. The extracted solution and an organic layer were washed together with saturated brine, and magnesium sulfate was added thereto for drying. This mixture was filtrated and the filtrate was concentrated to obtain an oily light-brown substance. The oily substance was dissolved in about 50 mL of toluene, and was subjected to suction filtration through Celite (manufactured by Celite Co., Ltd.), alumina, and Florisil (manufactured by Floridin Company). A solid substance obtained by concentrating the filtrate was purified by a silica gel column chromatography (developing solvent was a mixed solvent of hexane:toluene=4:6) to obtain a white solid substance. The obtained white solid substance was recrystallized with chloroform/hexane, so that 3.5 g of an white substance was obtained in yield 49%.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])[C:4](=[O:30])[CH2:3]1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[O:22][C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])[C:4](=[O:30])[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Solvent: c1ccncc1
Product: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-α-D-glucopyranoside (100 mg, 0.23 mmol) was dissolved in dry pyridine (2 ml), cooled to 0° C. and t-butyldimethylsilylchloride (39 mg, 0.26 mmol) added. The reaction mixture was stirred at room temperature overnight. The solution was evaporated, the residue was taken up in CHCl3 (10 ml), washed with water (3 ml), dried over MgSO4 and concentrated. The residue was purified by chromatography using CHCl3/MeOH 10:1 as the mobile phase to give Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-6-O-t-butyldimethylsilyl-α-D-glucopyranoside (15) (77 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCCC(NS(=O)(=O)c1ccc(Br)cc1)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCC(NS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 9.4 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)hexanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (554.2 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.6 ml) and 1-methyl-2-chloropyridinium iodide (875.4 mg) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (123.8 mg).
Reaction SMILES: C([N:9]1[CH2:21][C:20]2[C:19](=[O:22])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH3:23])[C:11]=2[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)C>CCOCC.O>[CH3:23][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:19](=[O:22])[C:20]2[CH2:21][NH:9][CH2:10][C:11]1=2
Reactant: Cn1c2c(c(=O)c3ccccc31)CN(C(=O)c1ccccc1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Cn1c2c(c(=O)c3ccccc31)CNC2

Procedure:
A mixture of 10 g of 2-benzoyl-1,2,3,4-tetrahydro-4-methyl-9H-pyrrolo[3,4-b]quinolin-9-one, 10 g of potassium hydroxide, 10 ml of water and 100 ml of ethanol is heated at reflux for 17 hours, cooled, diluted with 50 ml each of ether and water and filtered. The recrystallisation of the residue from methanol and ether yields 1,2,3,4-tetrahydro-4-methyl-9H-pyrrolo[3,4-b]quinolin-9-one. M.P. 209°-213° (decomposition).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]3[N:23]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:22]=[N:21][N:20]=3)[C:10](=[O:43])[CH:9]([N:44]3C(=O)C4=CC=CC=C4C3=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>O1CCCC1>[NH2:44][CH:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[N:23]([C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:22]=[N:21][N:20]=2)[C:10]1=[O:43]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: NC1N=C(c2ccccc2)c2ccccc2N(Cc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 51.3 %

Procedure:
To a solution of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1-trityl-1H-tetrazol -5-yl)methyl]-2H-1,4-benzodiazepin-2-one (128 g) in tetrahydrofuran (2.56 l) was added hydrazine monohydrate (10.43 ml ) at room temperature. The mixture was stirred at 60° C. for 4 hours and the resultant precipitate was filtered off. The filtrate and the washings were evaporated in vacuo and the residue was dissolved in dichloromethane. After the insoluble material was filtered off, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with 1N-sodium hydroxide solution and subsequently with water. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuo to about 300 ml. The residue was stirred at room temperature. The resulting precipitates were collected by filtration to give (3RS)-3-amino-1,3-dihydro-5-phenyl-1-[(1-trityl-1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (53.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCO)c1

Procedure:
3-Nitrophenethyl alcohol (1.50 g) is added to a suspension of Pd/C (10%, 500 mg) in ethanol (15 mL). The mixture is placed under hydrogen gas pressure (35 psi) in a Parr hydrogenator for 1 h. The catalyst is removed by filtration through Celite and the solution is concentrated to afford 3-aminophenethyl alcohol. Condensation with the resulting crude aniline according to the general procedure at room temperature for 36 followed by purification by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 33/1; 20/1) affords 2.94 g (78%) of the title compound as an orange amorphous solid. Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ 12.26, 10.82, 8.53, 8.41, 7.46-7.26, 7.19-7.06, 4.68, 3.99-3.92, 3.67-3.61, 3.58, 3.48, 2.77, 2.36, 0.93, 0.82; IR (liq.) 1696, 1672, 1627 (s), 1610 (s), 1591 (s), 1571 (s), 1494, 1428 (s), 1301 (s), 1281 (s), 1259 (s), 1233, 1208, 1117 (s), 1104 cm-; MS (ESI+) m/z 457 (100, (M+H)+), 458 (25). HRMS calcd for C25H29FN2O5+H m/z 457.2138, found 457.2143.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]CC.[Na+].Cl>C(O)C>[F:19][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:9][N:8]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CCOC(=O)c1c(-c2ccc(F)c(F)c2)noc1C
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(F)c(F)c2)noc1/C=C/c1ccccc1
Yield: 87.4 %

Procedure:
To a stirred solution of 3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (50 g, 187 mmol) and benzaldehyde (19.1 mL, 187 mmol) in ethanol (280 mL) was added sodium ethoxide (2.71 M, 75.8 mL, 206 mmol) and the reaction was stirred at reflux for 1 h. Hydrochloric acid (1 N, 225 mL) was added and the resulting mixture was then triturated with dichloromethane and filtered to afford the title compound (53.5 g, 87%) as a light yellow solid. MS: m/e=328.3 [M+H]+.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@@H:12]2[O:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O>C1COCC1.[Cu](Cl)(Cl)(Cl)Cl.[Li]>[C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@H:12]([OH:14])[CH2:13][CH2:3][CH2:2][C@@H:1]([CH3:15])[CH2:6][CH3:5])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: Cl[Cu](Cl)(Cl)Cl
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)CCC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 206.9 %

Procedure:
Separately, 0.42 g of lithium copper tetrachloride was dissolved in 80 ml of THF in a flask, and the solution was cooled to -50° C. The above prepared Grignard reagent was added dropwise to the solution at that temperature, followed by stirring for 15 minutes. After cooling the reaction mixture to -55° C., a mixture of 2.0 g of (R)-glycidyl p-toluenesulfonate and 20 ml of THF was added thereto dropwise to conduct reaction at that temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated to obtain 2.85 g (25.64%) of the titled compound.
Reaction SMILES: I[C:2]1[O:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C(C)(C)OB([C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:12]1([C:3]2[C:4]3[C:9](=[O:10])[NH:8][CH:7]=[N:6][C:5]=3[O:11][C:2]=2[C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:38][CH:39]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1[nH]cnc2oc(I)c(-c3ccccc3)c12
Reactant: CC1(C)OB(c2ccc(OCCN3CCCC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: O=c1[nH]cnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Temperature: 80 °C

Procedure:
Compound 11 (242 mg, 0.716 mmol), 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)pyrrolidine 25 [prepared by Specific Method A2] (500 mg, 1.58 mmol), K2CO3 (247 mg, 1.79 mmol), and Pd(dppf)2Cl2 (524 mg, 0.072 mmol) were combined in a pyrex tube. After purging with N2, DMF (7.3 mL) and H2O (1.45 mL) were added and the tube was sealed. The mixture was heated at 80° C. for 5 h. After cooling to RT, CH2Cl2 was added and the organic layers were washed with H2O, followed by brine. The organic layers were then dried over Na2SO4 and concentrated to a brown oil. Flash chromatography (SiO2, gradient eluent: 0-15% MeOH in CH2Cl2), followed by trituration with EtOAc and filtration afforded compound 26.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COCCOCOc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C1COCCN1
Product: COCCOCOc1ccc(C#Cc2ccc(C(=O)N3CCOCC3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 76.3 %

Procedure:
In a manner analogous to Example 25(b), by reaction of 1.1 g (2.3 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzoyl chloride with 600 μl (6.8 mmol) of morpholine, 930 mg (44%) of the expected amide were obtained, which amide had the melting point 142°-3° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17]>ClCCl.CCOCC>[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]
Reactant: OCc1cccc(I)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
A suspension of pyridinium chlorochromate (2.45 g, 11.4 mmol) and dry celite (˜2.00 g) in dry dichloromethane (20 ml) was stirred at room temperature for 15 min. 3-Iodobenzyl alcohol (11) (1.02 g, 4.35 mmol) in dry dichloromethane (5 ml) was added. The suspension was shielded from light and stirred at room temperature for 2 h after which it was diluted with ether, and filtered through celite. The cloudy brown filtrate was concentrated to a red-brown gummy paste which was re-dissolved in dichloromethane and passed through a short silica column, eluting with dichloromethane. This gave a clear, colourless solution which was concentrated to give 3-iodobenzaldehyde (12) as a white solid (0.953 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)C(OC)=O.[Cl-].[Li+].O.[CH3:21]S(C)=O>>[CH2:1]([O:2][C:3](=[O:17])[CH2:4][C:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:21]
Reactant: COC(=O)C(C(=O)OC)C1(C#N)CCCCC1
Reactant: CS(C)=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CCOC(=O)CC1(C#N)CCCCC1
Yield: 74 %

Procedure:
26.9 g (100 mmol) of (1-cyanocyclohexyl)malonic acid dimethyl ester, 4.3 g (100 mmol) or lithium chloride and 3.6 g (200 mmol) of water were heated in 300 ml of dimethyl sulfoxide for 22 hours to 150° C. Then it was cooled mixed with 700 ml of water and extracted with 1000 ml of pentane. 14.4 g of (1-cyanocyclohexyl)acetic acid ethyl ester was obtained by distillation of the organic phase, corresponding to a yield of 74 percent (relative to the (1-cyanocyclohexyl)malonic acid dimethyl ester used). Data for the product was:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: NNc1ccccc1
Reactant: COc1ccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)cc1
Product: COc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 81 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methoxyl-phenyl)-1H-pyridazin-4-one (A-2) and phenylhydrazine according to the method described for Example 1 in 81% yield. MS: M=345.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH3:18].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:20]([Cl:19])(=[O:22])=[O:21])[S:17][C:11]=2[N:10]=[C:9]1[CH3:18]
Reactant: Cc1nc2sccc2c(=O)n1-c1ccccc1Cl
Reactant: O=S(=O)(O)Cl
Product: Cc1nc2sc(S(=O)(=O)Cl)cc2c(=O)n1-c1ccccc1Cl
Reaction time: 1.5 h

Procedure:
To 140 ml of chlorosulfonic acid was added little by little 54.8 g of 3,4-dihydro-3-(2-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidine. After the mixture was heated at 70°-75° C. on the oil bath and stirred for 1.5 hours, the reaction mixture was cooled and then poured onto 2 l of icewater carefully. The precipitated crystals were collected by suction-filtration to afford 65 g of the title compound, m.p. 172°-174° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([CH3:15])=[N:6][C:7]([CH3:14])=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].N.CN(C)C1C=CC=CC=1.[Br:26][CH2:27][C:28](Br)=[O:29]>CO.ClCCl>[Br:26][CH2:27][C:28]([NH:3][C:4]1[C:5]([CH3:15])=[N:6][C:7]([CH3:14])=[CH:8][C:9]=1[C:10]([F:13])([F:11])[F:12])=[O:29]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(C(F)(F)F)c(N)c(C)n1
Agent: Cl
Agent: N
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(F)(F)F)c(NC(=O)CBr)c(C)n1
Yield: 95.8 %

Procedure:
3-Amino-2,6-dimethyl-4-trifluoromethylpyridine dihydrochloride (15.60 g, 59.30 mmol) was dissolved in methanol (100 mL). In an ice bath, an ammonia-saturated methanol solution (300 mL) was added, and the mixture was rendered uniform. The reaction mixture was extracted from chloroform-water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL), and subsequent to the addition of N,N-dimethylaniline (10.80 g, 89.12 mmol), a solution of bromoacetyl bromide (15.52 g, 76.90 mmol) in dichloromethane (40 mL) was added dropwise while stirring the mixture in an ice bath. The mixture was stirred at room temperature for two hours, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (silica gel: 400 g; developer: hexane:acetone=10:1→4:1→3:1). Recrystallization from ethyl acetate and hexane afforded the title compound (17.68 g, 96%) as colorless needles.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:18]([O:20]CC)=O)[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[N:9]=1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:18]([NH:23][CH2:24][C:25]2[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])=[O:20])[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
Aqueous NaOH (0.308 g, 7.72 mmol) was added to a solution of ethyl 6-bromo-1-cyclopentyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1.3 g, 3.8 mmol) in EtOH (10 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The crude acid (1 g, 3.23 mmol) was then dissolved in DMSO (10 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.98 g, 6.47 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (2.52 g, 4.85 mmol) was added to it and stirring was continued overnight. After completion of the reaction, reaction mass was poured into ice to obtain solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (1 g, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]2[CH:7]=[C:8]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 60 °C

Procedure:
94.0 g (0.5 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene were stirred into 100 ml of chlorosulfonic acid at 20° C. within 30 min. The reaction solution was maintained at 60° C. for 1 hour, cooled to room temperature and then poured into 1.5 l of ice and extracted with ether. The organic phase was washed to neutrality with brine and water, dried over magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from methanol yielded 55.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-sulfonyl chloride of melting point 71°-74° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])(=[O:9])=[O:8])[N:3]=1.[C:19](OCC)(OCC)([O:21][CH2:22][CH3:23])[CH3:20]>C(#N)C.C(O)(=O)C>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][S:7]([C:4]1[N:3]=[C:2]([N:1]=[C:19]([O:21][CH2:22][CH3:23])[CH3:20])[NH:6][N:5]=1)(=[O:9])=[O:8]
Reactant: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(C)=Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1

Procedure:
6.16 g (20.0 mmol) 5-amino-N-(2,6-dichlorophenyl)-1H-1,2,4-triazole-3-sulphonamide was heated in 50 ml acetonitrile with 4.2 ml (23.0 mmol) triethyl orthoacetate and 3 drops glacial acetic acid for 5 hours under reflux. The mixture was cooled and evaporated to dryness. The residue was recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[S-:12][C:13]#[N:14].[K+].O>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:12][C:13]#[N:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: N#C[S-]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (16.7 g, 85.8 mmol) in acetic acid (100 mL) was added at room temperature potassium thiocyanate (8.82 g, 90.8 mmol) over 1.5 hr or longer, and the mixture was stirred for 3 hr. The reaction mixture was poured into vigorously stirred water (500 mL), and the mixture was stirred for 30 min. The resulting solid was collected by filtration, and dried to give the title compound (16.5 g, 89%) as pale-yellow crystals.