Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>>[C:1]1([C@H:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:9][NH2:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1c[nH]cn1
Reactant: c1ccc([C@@H]2CN2)cc1
Product: NC[C@H](c1ccccc1)n1ccnc1

Procedure:
1 g of (R)(-)-2-phenyl-aziridine and 1.14 g of imidazole are heated at 120° for 24 hours. After cooling the reaction mixture can be used for the acylating step without further purification. An analytical sample can be obtained by chromatography over silica gel;
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][NH2:32])[CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:32][CH2:31][C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][CH:22]=[N:21]5)=[CH:26][CH:27]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: NCc1ccc2cccnc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5cccnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (480 mg, 1.69 mmol) and quinolin-7-ylmethanamine (400 mg, 2.53 mmol) in acetonitrile (5 mL) and N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-prep HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM diethylamine]) to yield an off white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[N:6][N:5]2[CH:17]=[N:18][N:19]=[C:4]2[CH:3]=1>[Pt]=O.C(O)C>[NH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([CH3:1])=[CH:3][C:4]3[N:5]([CH:17]=[N:18][N:19]=3)[N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc2nncn2nc1-c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cc2nncn2nc1-c1cccc(N)c1

Procedure:
A mixture comprising 2.28 g. of 7-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as described in Example 4), 100 ml. of ethyl alcohol and a catalytic amount of platinum oxide is shaken in a Parr shaker under 40 pounds of hydrogen pressure for 11/2 hours. The reaction mixture is filtered free of catalyst and the filtrate is concentrated to afford the product of the example as a yellow solid, m.p. 182°-186° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:37][CH2:36][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:28]=[C:27]5[C:22]([CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26]5)=[CH:21][CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO>[N:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:37][CH2:36][C:11]3([CH2:12][CH2:13][N:14]([C:17]([C:19]4[CH:28]=[C:27]5[C:22]([CH2:23][CH2:24][NH:25][CH2:26]5)=[CH:21][CH:20]=4)=[O:18])[CH2:15][CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)cc2C1
Agent: Cl
Solvent: CO
Product: O=C(c1ccc2c(c1)CNCC2)N1CCC2(CC1)CCN(c1ccncc1)CC2

Procedure:
1.25 M hydrogen chloride in methanol (15.5 ml, 19.36 mmol) was added at RT to a solution of tert-butyl 7-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.9 g, 3.87 mmol) in methanol (4 ml), and the reaction mixture was refluxed for 1.5 h. The solvent was removed in vacuo, the residue was taken up in a small amount of ethanol (3 ml), and diethyl ether (50 ml) was added. The mixture was then cooled for 30 min in an ice bath, and the resulting solid was filtered out, washed with diethyl ether and dried in vacuo. Yield: 1.56 g (94%).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[NH:2][N:3]=[C:10]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:9]=1)=[O:22])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)C(C)Oc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C(C)Oc2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 448.5 %

Procedure:
Hydrazine hydrate (41.7 μL, 0.4 mmol) was added to a stirred solution of 2,4-dioxo-5-phenoxy-hexanoic acid ethyl ester (566 mg, 2.14 mmol) in EtOH (4.5 mL). The mixture was stirred at 80° C. for 1 hour. Then, the mixture was stirred at room temperature for 16 hours. Hydrazine hydrate (20 μL, 0.2 mmol) was added and the mixture was stirred at 80° C. for 2 hours. More hydrazine hydrate (41.7 μL, 0.4 mmol) was added and the mixture was stirred at 80° C. for 2 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and solvents evaporated in vacuo to yield (rac)-5-(1-phenoxy-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (467 mg, 78% yield) as a colourless oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>>[N:15]1([CH2:14][CH2:13][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][C:2]2=[NH:10])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: ClCCN1CCOCC1
Reactant: Nc1nc2ccccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Product: N=c1sc2ccccc2n1CCN1CCOCC1
Yield: 25.9 %

Procedure:
Benzothiazol-2-ylamine (1.0 g, 6.6 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (1.2 g, 6.6 mmol) and triethylamine (2.8 mL, 20 mmol) were heated at 80° C. for 16 hours. The solid was recrystallized from ethyl acetate, collected by filtration, dried under vacuum to provide 0.45 g (26%) of the title compound. MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 494 (0.039 g, 0.1 mmol) was suspended in dry CH2Cl2 (1 mL) under an argon atmosphere. K2CO3 (0.029 g, 0.21 mmol) was added followed by ethyl chloroformate (0.02 mL, 0.021 mmol). The suspension was stirred for 48 h at room temperature. Work up as described in the preparation of compound 277. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.0, 159.1 (dd), 155.6 (dd), 153.7, 147.9, 139.5, 135.6, 135.1, 133.6, 132.6, 131.9, 129.1, 124.4 (dd), 124.3 (dd), 121.3, 119.8, 116.2, 112.7, 111.6 (dd), 104.9 (dd), 61.3, 19.7, 14.5
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH2:8][OH:9])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:9][CH2:8][C:7]2[O:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:27][C:26]=1[CH3:32]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1COc1ccc(CCC(=O)OC)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of [4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (0.108 g, 0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.078 g, 0.400 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.8 mmole) in toluene (2 mL). The reaction is stirred overnight, then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as a white solid. Mass [EI+] 448 (M++H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]2[CH2:19][N:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21][CH2:22][S:23][C:17]=2[CH:16]=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[C:18]2[CH2:19][N:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21][CH2:22][S:23](=[O:9])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)N1CCSc2cccc(Cl)c2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCS(=O)c2cccc(Cl)c2C1
Reaction time: 0.25 h

Procedure:
A solution of 3-chloroperbenzoic acid (2.26 g) in dichloromethane (150 ml) was added dropwise with cooling from 0° C. to -2° C. to a stirred solution of 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.05 g, prepared as Example 19 above) in dichloromethane (100 ml). The reaction mixture was stirred for 15 minutes, washed with water and dried, and the solvent was removed by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethyl acetate. Yield 2.86 g (m.p. 167°-169° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]([Cl:25])=[CH:18][C:17]=3[Cl:26])=O)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[Cl:25][C:19]1[CH:18]=[C:17]([Cl:26])[C:16]2[N:15]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:27]([F:29])([F:28])[F:30])[CH:11]=3)[O:23][C:22](=[O:24])[C:21]=2[CH:20]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)cc(Cl)cc12
Temperature: 55 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
To a solution of 2-(3-chloro-2-pyridyl)-N-[2,4-dichloro-6-hydroxycarbonyl-phenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide (18.4 g, 38.3 mmol) in methylene chloride (130 mL) was added acetic anhydride (39.4 mL, 417 mmol). The reaction was then heated to 55° C. for 2 h and then stirred for a further 16 h at room temperature. The resulting solid was filtered and washed with cold methylene chloride. Trituration with diethyl ether afforded the title compound (10.1 g, 57%).
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]([CH3:12])[CH2:7][C:8]([CH3:11])=[CH:9][CH3:10])[CH:3]=O.NC1C=CC=CC=1.S([O-])([O-])(=O)=[O:21].[Na+].[Na+].[OH-].[K+]>CCOCC>[CH3:12][CH:6]1[CH2:5][C:2]([CH3:3])([CH3:1])[C:9]([CH:10]=[O:21])=[C:8]([CH3:11])[CH2:7]1
Reactant: CC=C(C)CC(C)C=C(C)C=O
Reactant: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: CCOCC
Product: CC1=C(C=O)C(C)(C)CC(C)C1
Reaction time: 1 h

Procedure:
A mixture of the two isomeric aldehydes obtained according to paragraph (d) (36.5 g.), aniline (21.4 g.) and anhydrous sodium sulphate (20 g.) in 55 ml. of ether was left at 20° under stirring during one night. After having filtered washed and concentrated to the initial volume the solution was poured with vigorous stirring into 221 ml. of conc. H2SO4 and 22.1 g. of ice. The temperature was kept between -20 and -25° during 1 h., and the mixture was then added to 300 g. of ice and immediately distilled by means of steam distillation. The distillate was saturated with NaCl, extracted with ether and treated as usual. 36 g. of a mixture of crude α- and β-cyclocitral were thus obtained. The subsequent isomerisation was carried out at -10° in 120 ml. of a 8.5% Chanolic KOH solution (80% ethanol). The mixture was allowed to react during 3 h. in an atmosphere of argon, diluted then with pet.-ether (30°-50°), poured into 400 ml. of a NaCl saturated aqueous solution and finally extracted with pet.-ether. By distillation 4-methyl-β-cyclocitral was obtained:
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]N>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:19]=1[NH:24][C:2]([CH3:15])=[C:3]2[S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: NNc1ccccc1Cl
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Agent: Cl
Product: Cc1[nH]c2c(Cl)cccc2c1Sc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 2-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([C:23]([OH:25])=O)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[CH:15]=2)[N:8]=[CH:7][N:6]=1)[CH3:4].[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH:32]([NH2:34])[CH3:33]>>[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH:32]([NH:34][C:23]([C:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:15]=[C:10]([N:9]2[C:5]([CH:3]([O:2][CH3:1])[CH3:4])=[N:6][CH:7]=[N:8]2)[CH:11]=1)=[O:25])[CH3:33]
Reactant: COC(C)c1ncnn1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: CC(N)c1cnccn1
Product: COC(C)c1ncnn1-c1cc(C(=O)NC(C)c2cnccn2)cc(-c2ccc(C)cc2)c1

Procedure:
5-[5-(1-Methoxy-ethyl)-[1,2,4]triazol-1-yl]-4′-methyl-biphenyl-3-carboxylic acid was subject to the amide coupling reaction described in step 4 of Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-yl-ethylamine, to give 5-[5-(1-methoxy-ethyl)-[1,2,4]triazol-1-yl]-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=443.
Reaction SMILES: [S-2:1].[Na+].[Na+].[O-]CC.[Na+].[C:8]1([C:14]#[C:15][C:16](=[O:30])[C:17]#[C:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[C:8]1([C:14]2[S:1][C:18]([C:19]3[N:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:22]=[CH:21][CH:20]=3)=[CH:17][C:16](=[O:30])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [S-2]
Reactant: O=C(C#Cc1ccccc1)C#Cc1ccnn1-c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cc(-c2ccccc2)sc(-c2ccnn2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
To sodium sulfide (0.079 g) was added 0.25 M sodium ethoxide in ethanol solution (20.0 mL), and the mixture was stirred at room temperature for 10 min. To a solution of 1-phenyl-5-(1-phenyl-1H-pyrazol-5-yl)penta-1,4-diyn-3-one (0.25 g) in ethanol (10.0 mL) was added the above-mentioned solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (80.0 mg).
Reaction SMILES: [CH2:1]([Br:4])[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9](CCCO)[CH:10]=[CH:11][CH:12]=1>CC#N>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH2:3][CH2:2][CH2:1][Br:4])[CH:10]=[CH:9][CH:8]=1
Reactant: C=CCBr
Reactant: COc1cccc(CCCO)c1
Solvent: CC#N
Product: COc1cccc(CCCBr)c1
Reaction time: 1.5 h

Procedure:
Allyl bromide (25 mL, 0.28 mmol) was added to a solution of 3-(3-methoxyphenyl)propanol (8.8 g, 0.053 mol), N,N′-carbonyldiimidazole (9.6 g, 0.0605 mol) and CH3CN (45 mL) at room temperature. After 1.5 hr at rt and 1.5 hr at reflux, the reaction mixture was cooled, partitioned between EtOAc (250 mL) and H2O (300 mL), the organic layer washed with H2O (300mL), 5% HCl (200 mL), dilute NaHCO3 solution (200 mL), brine (300 mL), and dried (Na2SO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[C:9](C#CC3C=CC(C(O)=O)=CC=3)[CH:8]=[CH:7][C:6]=2[C:5]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:4][CH2:3]1.CC1(C)C2C=CC([C:40]#[C:41][C:42]3[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=3)=CC=2C(SCC)=CC1>>[CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:40]#[C:41][C:42]3[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=3)=[CH:7][C:6]=2[C:5]([S:23]([CH2:26][CH3:27])(=[O:24])=[O:25])=[CH:4][CH2:3]1
Reactant: CCS(=O)(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: CCSC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CCS(=O)(=O)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4- (7,8-dihydro-8,8-dimethyl-5-ethylsulfonylnaphth-2-ylethynyl)benzoic acid (Compound 150), 25 mg (0.07 mmol) of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 152) was converted to the title compound (white solid, recrystallized from ethyl alcohol) using 95 mg (0.28 mmol) of 50% 3-chloroperoxybenzoic acid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[CH:16](=[O:18])[CH3:17]>>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[O:10][C:11]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CC=O
Reactant: CCc1cc(-c2ccco2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(C)O)o2)c(C)[nH]c1=O

Procedure:
Example 267 is substantially repeated except for utilizing 3-ethyl-6-methyl-5-furan-2-yl-1H-pyridin-2-one prepared in accordance with the procedures of Example 44, Step 2 and acetaldehyde to afford the title compound. MS: m/e=248 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[OH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: NC1CCc2[nH]c3ccc(O)cc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
To a solution of 0.871 gm (2.98 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 200 mL ethanol were added about 2.0 gm Raney Nickel and hydrogen introduced to the reaction mixture under balloon pressure. After stirring for 18 hours at room temperature the balloon was refilled with hydrogen and the reaction stirred an additional 3 days at room temperature. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a colorless solid. The residual solid was subjected to silica gel chromatography, eluting with 80:15:5 dichloromethane: methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.335 gm (56%) of the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Cl:9][C:10]1[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[C:14]([Cl:21])=[CH:13][C:11]=1[NH2:12].[OH-].[Na+]>O>[CH3:8][C:2]1[CH:1]=[C:6]([O:7][S:17]([C:15]2[CH:16]=[C:10]([Cl:9])[C:11]([NH2:12])=[CH:13][C:14]=2[Cl:21])(=[O:19])=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)c(S(=O)(=O)Cl)cc1Cl
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(OS(=O)(=O)c2cc(Cl)c(N)cc2Cl)c1
Reaction time: 0.5 h

Procedure:
110 g of m-cresol are dissolved in 1.5 liters of water at 60° C. and pH 10.5. 497 g of a 52.4% strength moist paste of 2,5-dichloro-aniline-4-sulphonic acid chloride are added in portions, over the course of 45 minutes, to this solution at 60° C. At the same time, the pH value is kept constant at between 10.0 and 10.5 by simultaneous dropwise addition of a total of 100 ml of a 45% strength sodium hydroxide solution. The mixture is then stirred for a further 30 minutes, after which the precipitate obtained is filtered off, washed until neutral and dried at 60° C. in a vacuum drying cabinet. 275 g of 4-amino-2,5-dichlorobenzenesulphonic acid 3-methyl-phenyl ester are obtained. ##STR7##
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH:4]=[CH:3][NH:2]1.S(=O)(=O)(O)O.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>>[N+:12]([C:3]1[NH:2][O:1][CH:6]=[CH:5][CH:4]=1)([O-:14])=[O:13]
Reactant: C1=CNOC=C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C1=CC=CON1

Procedure:
Oxazine XXIV (1.27 mmol) was dissolved in sulfuric acid (10.2 g, 5.57 ml, 102 mmol, Eq: 80). The light yellow solution was cooled in an ethanol/ice bath. Nitric acid fuming (1.78 mmol) was added dropwise over a period of 1 minute. The mixture was stirred under ice-bath cooling for 30 minutes and poured carefully onto ice-water (30 ml). The mixture was basified with a 5N NaOH solution and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on silica gel [Eluent: Heptane/ethyl acetate (0% to 50%)] to afford the pure nitro-oxazine XXV.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.O.[NH3:12]>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:12])=[O:9])[CH2:3][CH2:2]1
Reactant: N
Reactant: COC(=O)C1CCOCC1
Solvent: O
Product: NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 43.5 h
Yield: 74.6 %

Procedure:
To methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) was added concentrated ammonia water (50 mL), and the reaction mixture was stirred at room temperature for 43.5 hours. Thereafter, the reaction mixture was cooled in an ice water bath, and the precipitate was filtrated. Then, the precipitate was dried at 40° C. under reduced pressure, to obtain 33.4 g of a title compound (yield: 74.6%).
Reaction SMILES: I[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:3][CH2:4][OH:5].[O:12]1CCC[CH2:13]1>>[C:6]1([C:2]2[C:13](=[O:12])[O:5][CH2:4][CH:3]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: OCC=C(I)c1ccccc1
Product: O=C1OCC=C1c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
3-Iodo-3-phenyl-prop-2-en-1-ol (Description 1; 1 g, 3.8 mM) was dissolved in tetrahydrofuran (20 ml) and Hunig's base (2.67 ml, 15.4 mM) and degassed using a Firestone valve (×3). Carbon monoxide was bubbled through the solution for 10 minutes after which tris(dibenzylideneacetone)dipalladium (141 mg; 4 mol %) and 1,4 bis(diphenylphosphino) butane (65 mg; 4 mol %) were added. The reaction was heated at 50° C. under an atmosphere of carbon monoxide. After 2 hours, when the reaction was 50% complete, an extra addition of the palladium source and phosphine ligand were made. After a further 2 hours the reaction was cooled, filtered, the solvent removed in vacuo and the residue was dispersed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×40 ml), the combined organic layers were washed with brine, dried over MgSO4 and the solvent removed in vacuo. Purification was carried out by silica chromatography eluting in increasing concentrations of ethyl acetate in hexane (0-15%) to afford the title compound as a tan-coloured solid (0.56 g, yield 91%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:20]([CH2:24][C:25](Cl)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:24][C:25]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:3]3=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]3[N:1]=[C:25]2[CH2:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:12][CH:13]=1)=[O:26]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCO)cc2)n1
Product: Cc1cc(C)c2nc(CC(C)(C)C)n(-c3ccc(CCOC(=O)CC(C)(C)C)cc3)c2n1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and tert-butylacetyl chloride.