Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].[C:20]1([C:26]2[O:27][C:28]([CH3:34])=[C:29]([CH2:31][CH2:32]O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][CH2:31][C:29]2[N:30]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:27][C:28]=2[CH3:34])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OCC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester was reacted with 2-(2-phenyl-5-methyl-oxazol-4yl)-ethanol in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O>>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][N:25]1[CH:26]=[C:22]([C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:14][CH:13]=3)[N:21]=2)[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:24]1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Reactant: CN(C)CCO
Product: Cc1ccc(-c2nn(CCN(C)C)cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 55 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and 2-dimethylamino-ethanol.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([C:20]([NH2:22])=[O:21])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: N#Cc1cccc(C(N)=O)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 71.7 %

Procedure:
A mixture of methyl thiosalicylate (1.1 g, 6.4 mmol), 6-cyano-2-pyridinecarboxamide (0.47 g, 3.1 mmol), triethylamine (1.0 ml, 7.1 mmol) and toluene (3 ml) was refluxed for 6 hrs as described in Example. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (0.63 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([O:24][CH3:25])=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: COc1ccc2c(=O)n(S(=O)(=O)c3ccc(Cl)cc3)c(=O)[nH]c2c1
Yield: 57.3 %

Procedure:
313 mg (1.44 mmol) of 4-chlorobenzenesulfonylisocyanate and 200 mg (1.20 mmol) of 2-amino-4-methoxybenzoic acid were treated in the same way as in Example 1 to obtain 252 mg of the above-identified compound (yield 62.8%). Properties: colorless crystal, Melting point: 205°-206° C., PMR (δppm, DMSO-d6):3.79 (3H,s), 7.08 (1H,d), 7.28-7.30 (2H,m), 7.75 (2H,d), 8.16 (2H,d), 11.42 (1H,br).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)#[N:32]>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:36]3[CH2:37][CH2:38][CH:33]([C:31]#[N:32])[CH2:34][CH2:35]3)[CH:30]=[CH:29][CH:28]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: N#CC1CCNCC1
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(C#N)CC2)c1

Procedure:
Analogously to the process described in Example 8, 150 mg (0.313 mmol) of the compound from Example 1A and 69 mg (0.626 mmol) of 4-cyanopiperidine were used to obtain 68 mg (43% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].CO[C:5]([C:7]1[S:8][CH:9]=[C:10](C)[C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:6].C([CH:25]([C:29](Cl)=[O:30])[C:26](Cl)=[O:27])C.[O-:32][CH2:33][CH3:34].[Na+]>CN(C=O)C>[CH2:33]([O:32][C:29]([C:25]1[C:26](=[O:27])[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:5]=1[OH:6])=[O:30])[CH3:34]
Reactant: COC(=O)c1scc(C)c1NCc1ccc(OC)cc1
Reactant: CC[O-]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Solid NaH (60% in min. oil, 4.62 g, 135 mmol) was added in portions to a stirred solution of 3-(4-methoxybenzylamino)-thiophene-2-carboxylic acid methyl ester (53) (26.69 g, 96 mmol) in dry DMF. The solution was stirred for 10 min. at room temperature and cooled to 0° C. Ethyl malonyl chloride was added slowly and the solution was further stirred at room temperature for 15 min. Sodium ethoxide (13.1 g, 192 mmol) was added to the solution and the solution was heated to 110° C. for 2 h. The solution was cooled and excess solvent was distilled off The residue was dissolved in a mixture of water (350 mL) and 4 M NaOH (50 mL), and the insoluble impurities were filtered off The filtrate was washed by diisopropyl ether and then acidified to pH 4 by cold diluted HCl solution. The solids formed were filtered, washed by water, and dried under vacuum at room temperature to yield 27 g (79%) of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as off-white solids. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 3.70 (s, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.27 (s, 2H), 6.86 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.34 (d, J=5.6 Hz, 1H), 8.14 (d, J=5.6 Hz, 1H), 13.31 (br, 1H) ppm; MS m/z=360 amu (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a mixture of piperazinyl compound 2 (146 mg, 0.43 mmol) and triethylamine in dichloromethane (5 ml) was added p-toluenesulphonyl chloride (51 mg, 0.45 mmol) in dichloromethane (1 ml) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and 2 h at room temperature. Then the reaction mixture was diluted with chloroform (15 ml), washed with water, brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (CHCl3 /MeOH; 98:2 ) to give the title compound as a colorless solid (75 mg, 16%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:15]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH2:16][CH3:17])[CH3:14].C([N-]C(C)C)(C)C.[Li+].C[O:35][C:36](=O)[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[N:39][CH:38]=1>O1CCCC1>[CH2:13]([N:15]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[C:36]([OH:35])[C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH3:43])[CH:42]=2)[C:20]1=[O:25])[CH2:16][CH3:17])[CH3:14]
Reactant: COC(=O)c1cncc(C)c1
Reactant: CCN(CC)CN1CCCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCN(CC)CN1CCCC(=C(O)c2cncc(C)c2)C1=O
Temperature: 25 °C
Yield: 13.2 %

Procedure:
To a solution of diisopropylamine (4.4 mL, 31.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (12 mL, 30 mmol). The solution was allowed to warm to rt over 30 min and was re-cooled to −78° C. A solution of 1-diethylaminomethyl-piperidin-2-one (3.87 g, 21.0 mmol) in tetrahydrofuran (10 mL) was added to the lithium diisopropylamide via syringe. The reaction mixture was maintained at −78° C. for 1 h and was treated with a solution of 5-methylnicotinic acid methyl ester (2.12 g, 14.0 mmol) in tetrahydrofuran (20 mL) via syringe. The reaction mixture was allowed to warm to rt and was maintained overnight. The reaction mixture was quenched with water (30 mL) and was extracted with ether (2×). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography [1/0 to 1/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to provide 560 mg (13%) of 1-diethylaminomethyl-3-[hydroxy-(5-methylpyridin-3-yl)methylene]piperidin-2-one. To a solution of the piperidin-2-one (550 mg, 1.8 mmol) in acetone (10 mL) was added conc. hydrochloric acid (2 L) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was allowed to cool to rt, diluted with isopropyl alcohol, and allowed to stand at 0° C. The product was isolated by filtration, thus providing 400 mg (85%) of 5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl dihydrochloride.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C([NH:29][CH:30]([C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:62][CH:61]=1)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:33][CH:32]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl>ClCCl>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([CH:30]([NH2:29])[C:60]2[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:62][CH:61]=2)=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC2c3ccccc3-c3ccccc32)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(N)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To dichloromethane (10 ml) was added DBU (1,8-diazabicyclo[5,4,0]-7-undecene, 200 μl), and N—Fmoc-di(4-docosoxyphenyl)methylamine (500 mg, 474 μmol) obtained in Example 4 was added, and the mixture was stirred at room temperature for 5 hours. 1N Hydrochloric acid (1.3 ml) was added dropwise and, after stirring, the solvent was evaporated and the residue was washed with acetonitrile (10 ml) to give di(4-docosoxyphenyl)methylamine (340 mg, 408 μmol, yield 86%).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:25][CH2:26][C:27]1[C:28]([OH:35])=[N:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33]>ClCCl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:25][CH2:26][C:27]2[C:28]([OH:35])=[N:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Cc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A mixture of 4-benzoylbenzoic acid (106 mg, 0.5 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylluroniumhexafluorophosphate (285 mg, 0.75 mmol), triethylamine (152 mg, 1.5 mmol) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (20 mL). The organic phase was separated, dried over sodium, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-benzyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (50 mg, 29%). LRMS (M+H+) m/z: 346.17. found 346. HPLC purity (214 nm): 97%. 1H NMR (300 MHz, d6-DMSO): δ 11.50 (s, 1H), 8.29 (t, J=4.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.28-7.13 (m, 7H), 5.85 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 3.96 (s, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:27](Cl)(=[O:29])=[O:28])=[CH:15][CH:14]=1)[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:11][CH3:12])=[CH:32][CH:31]=1)(=[O:28])=[O:29]
Reactant: Cc1noc(N)c1Br
Reactant: CCc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-ethylbenzyl)benzo[b]-thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-(4-ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.42 g) and THF (6 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexanes provided 0.21 g (43%) of a tan solid, m.p. 128-130° C.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[O:5].[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])=[O:5])[CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Cl)cc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2Cl)CC1
Yield: 74.4 %

Procedure:
Proceeding as indicated in example 2, with 0.053 mole (17.5 g) of 2,2',4'-trichloro-5-nitro-benzophenone, 0.088 mole (8.8 g) of 4-methylpiperidine and 0.0712 mole (9.8 g) of calcium carbonate in 50 cm3 of ethanol, 15.5 g (Yield: 75%) of the expected product are obtained after re-crystallization in a mixture of isopropyl ether and toluene (70 v./30 v.) M.P.: 103° C.
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][N:11]([CH2:13][C:14]1[O:18][C:17]([CH2:19][S:20][CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1)[CH3:12].CC(C)CC(=O)C>O>[CH3:12][N:11]([CH2:13][C:14]1[O:18][C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:3]([NH:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=1)[CH3:10]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1

Procedure:
N-Methyl-1-(methylthio)-2-nitroetheneamine (230 g) in water (400 ml) was stirred and heated at 45°-50°. 2-[[[5-(Dimethylamino) methyl-2-furanyl]methyl]thio]ethanamine (321 g) was added dropwise over 4 hr and the resultant solution stirred for a further 31/2 hr. The solution was then heated at reflux for 1/2 hr., cooled to 70° and 4-methylpentan-2-one (2 liters) added. The water was removed by azeotropic distillation under reduced pressure (260 torr) and the resultant solution treated with charcoal (10 g) at 50°. The solution was filtered and cooled to 10°. N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (380 g) was filtered off and dried m.p. 69°-70°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](Cl)=[O:12].[C:14]1([CH2:20][NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11](=[O:12])[CH2:10][N:21]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: c1ccc(CCNCc2ccccc2)cc1
Reactant: Nc1ccc(F)cc1
Product: O=C(CN(CCc1ccccc1)Cc1ccccc1)Nc1ccc(F)cc1

Procedure:
In a manner similar to Preparation 1 react 4-fluorobenzenamine with chloroacetyl chloride followed by N-(phenylmethyl)benzeneethanamine to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17].S(Cl)(Cl)=O.Cl.[CH2:24]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[CH3:25].C(N(CC)CC)C>ClCCl>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][NH:29][C:7]([C:5]1[S:6][C:2]([NH2:1])=[C:3]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:4]=1)=[O:9])[CH3:25]
Reactant: CCOC(=O)CN
Reactant: Nc1sc(C(=O)O)cc1C(=O)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CNC(=O)c1cc(C(=O)c2ccccc2Cl)c(N)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
14.0 g (50 mmol) of 5-amino-4-(2-chlorobenzoyl)-thiophene-2-carboxylic acid [the synthesis is carried out analogously to Hromatka et al., Monatsh. Chem. 104, 973 (1973)] are suspended in 250 ml of anhydrous dichloromethane, 8 ml of thionyl chloride are added dropwise, and the mixture is stirred at room temperature for 2.5 hours. It is then evaporated in vacuo, the residue is taken up in dichloromethane, and the solution is added dropwise to a mixture of 7 g (50 mmol) of glycine ethyl ester hydrochloride and 16 ml of triethylamine in 100 ml of anhydrous dichloromethane. After 1 our at room temperature the mixture is extracted with water. The residue from the concentrated organic phase is worked up by chromatography on silica gel. 8.1 g (44% of theory) of the title compound of melting point 216°-218° C. are obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-:9].[K+].S([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)([O-])(=O)=O.Cl>O.C(O)C.CO>[CH2:4]([O:9][CH:18]([CH3:19])[CH2:20][CH2:21][CH2:15][CH2:16][CH2:17][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:3][CH2:1][CH2:8][CH3:7]
Reactant: Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CCCCCOC(C)CCCCCOc1ccc(O)cc1
Reaction time: 5 h
Yield: 66.7 %

Procedure:
2.3 g of hydroquinone, 0.94 g of 85% KOH, 4 ml of methanol and 20 ml of ethanol were stirred at 50°-53° C., and 4.36 g of the above tosylate was dropped in 1 hour. After the addition, the mixture was stirred for 2 hours at 60°-65° C. and for 5 hours at 76°-78° C. After the reaction, the mixture was poured into cold water, acidified to pH 1 with 6N-hydrochloric acid and extracted with hexane. After being washed with water, the extract was dried with anhydrous MgSO4, and the solvent was distilled off. The product was further purified by silica gel column chromatography (hexane/ethyl acetate=10/3) to obtain 2.05 g of 4-(6-pentyloxyheptyloxy)phenol.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[I-].C[CH:28]=[N+:29]=[CH:30]C.[C:32]([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:28][N:29]([CH3:30])[CH3:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reactant: O=C([O-])[O-]
Reactant: CC=[N+]=CC
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(CN(C)C)c2cc(Sc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 16.6 %

Procedure:
A mixture of 4-Hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (177 mg, 0.5 mmol; see example D-1f), N,N-dimethylmethyleneammonium iodide (94 mg, 0.5 mmol), K2CO3 (104 mg, 0.75 mmol), and anhydrous CH2Cl2 (3 ml) was stirred at ambient temperature for 2.5 d before the mixture was concentrated in vacuo. To the residue was added water (15 ml), the mixture was acidified by addition of 6 N HCl and then washed with Et2O (3×30 ml). Subsequently, the mixture was neutralized by the addition of concentrated aqueous NaHCO3 and extracted with EtOAc (20 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a dark oil (34 mg); MS-(+)-ion M+1=411.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH:4]=2
Reactant: Clc1cccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Clc1cccc2nn(C3CCCCO3)cc12
Temperature: 45 °C
Yield: 94.6 %

Procedure:
To a 1 L flask with mechanical stirrer was added 4-chloro-1H-indazole 12 (75.0 g, 0.492 mol), pyridinium p-toluenesulfonate (1.24 g, 4.92 mmol), CH2Cl2 (500 ml) and 3,4-dihydro-2H-pyran (98.6 ml, 1.08 mol). With stirring, this mixture was heated to 45° C. for 16 hours. Analysis of reaction mixture shows production of both isomers of product. Cooled reaction to 25° C. and added CH2Cl2 (200 ml). Washed the solution with water (300 ml) and saturated NaHCO3 (250 ml). Dried the organics with MgSO4 and concentrated to dryness. Purified the crude product by dissolving in EtOAc/Hexanes (4:6, 1 L) and adding SiO2 (1.2 L). The mixture was filtered and the cake was washed with EtOAc/Hexanes (4:6, 2 L). The organics were concentrated to yield 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole 13 as an orange solid (110.2 g, 95%) and a minor amount (about 10%) of the THP regioisomer, 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. Isomer 1: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1 Hz, 1H), 7.50 (dd, J=9 Hz, 1 Hz 1H), 7.29 (dd, J=9 Hz, 8 Hz 1H), 7.15 (dd, J=8 Hz, 1 Hz 1H) 5.71 (dd, J=9 Hz, 3 Hz 1H) 4.02 (m, 1H) 3.55 (m, 1H) 2.51 (m, 1H) 2.02 (m, 2H) 1.55 (m, 3H). LCMS (ESI pos) m/e 237 (M+1); Isomer 2: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=1 Hz, 1H), 7.62 (dd, J=9 Hz, 1 Hz 1H), 7.20 (dd, J=9 Hz, 8 Hz 1H), 7.06 (dd, J=8 Hz, 1 Hz 1H) 5.69 (dd, J=9 Hz, 3 Hz 1H) 4.15 (m, 1H) 3.80 (m, 1H) 2.22 (m, 2H) 2.05 (m, 1H) 1.75 (m, 3H). LCMS (ESI pos) m/e 237 (M+1).