Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH2:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:15]1(OC)[CH2:19][CH2:18][CH2:17]O1.O>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:19][CH:18]=[CH:17]2)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: COC1(OC)CCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(F)c(-n2cccc2)cc1F
Yield: 79.2 %

Procedure:
5.2 grams (0.03 mol) of 2,5-difluoro-4-aminobenzoic acid, melting at 250°-3°, are dissolved in 60 ml of glacial acetic acid, and 4 grams (0.03 mol) of dimethoxytetrahydrofuran are added. The mixture is heated at the boil for 10 minutes, 20 ml of water are added and the resulting mixture is left to cool. The precipitate formed is filtered off and washed with water to give 5.3 grams of a solid melting at 196°-8° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1>CN1C(=O)CCC1.O.C(OCC)(=O)C>[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(-n2cccn2)nn1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
To a solution of pyrazole (3.69 g, 25 mmol, 1.0 equiv) in NMP (25 mL) was added sodium hydride (60% dispersion in mineral oil, 1.5 g, 38 mmol, 1.5 equiv). The mixture was stirred for 15 min, followed by the addition of 3,6-dichloropyridazine (3.02 g, 25 mmol, 1.0 equiv). The reaction mixture was stirred for 1.5 h and then diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (3×50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give 3.89 g of 3-chloro-6-(1H-pyrazol-1-yl)pyridazine as a crude tan solid that was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Yield: 81.9 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.335 g; 0.85 mmol), LHMDS 1N in THF (1.27 mL; 1.27 mmol), 1-iodopropane (0.166 mL; 1.7 mmol) in DMF (4.2 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.302 g (82%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([CH2:42][CH2:43][C:44]#[N:45])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][N:36]([CH2:42][CH2:43][C:44]#[N:45])[CH2:37][CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Product: Cl

Procedure:
3-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionitrile hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 3-piperazin-1-yl-propionitrile (example 16f) in an analogous manner as described in example 25. LR-MS: 632.4 [(M+H)+]
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:44])[C:30]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)([CH3:35])[CH2:31][S:32]2)=[CH:27][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:29]1([OH:44])[C:28]2[C:33](=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[S:32][CH2:31][C:30]1([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH3:35])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Reactant: C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 9-(t-butyldimethylsilyloxy)-1-nonyne (12 g, 47.15 mmol) in dry tetrahydrofuran (150 ml) was added dropwise n-butyl lithium (25.5ml, 42.43 mmol, 1.66 mole/l in tetrahydrofuran) at −78° C., which was then stirred at −20° C. for 1 hour. Then, to this reaction mixture was added 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (3 g, 9.54 mmol) dissolved in tetrahydrofuran at the same temperature for 30 minutes, and the resulting mixture was stirred at −10° C. for 24 hours. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=9:1) to stoichiometrically give the title compound (5.40 g) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)Br.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31]([OH:33])=O.[NH2:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[N:36]=1>O1CCCC1>[CH3:41][C:39]1[CH:38]=[C:37]([CH3:42])[N:36]=[C:35]([NH:34][C:31](=[O:33])[CH2:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)[CH:40]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=O)Cc2cccs2)c1

Procedure:
9.22 g of triphenylphosphine, 6.93 ml of trichlorobromomethane, 5 g of 2-thienylacetic acid and 8.50 g of 2-amino-4,6-dimethylpyridine are dissolved in 120 ml of tetrahydrofuran. The mixture is brought to reflux and filtered, and the filtrate is concentrated; the residue is chromatographed on silica gel, eluting with dichloromethane, and the product obtained is recrystallized from isopropyl ether.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:7])[NH:5][NH2:6])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O>>[CH2:1]([NH:3][C:4](=[S:7])[NH:5][N:6]=[CH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[CH3:2]
Reactant: CCNC(=S)NN
Reactant: O=Cc1ccccn1
Product: CCNC(=S)NN=Cc1ccccn1

Procedure:
The title compound was prepared from 4-ethyl-3-thiosemicarbazide (100 mg, 0.838 mmol) and 2-pyridinecarboxaldehyde (80 μL, 0.838 mmol) similar to Example 3 and isolated as a white solid (137 mg, 78%). 1H NMR (DMSO-d6): 11.65 (s, 1H), 8.72 (t, J=5.4 Hz, 1H), 8.58-8.55 (m, 1H), 8.27 (dd, J=1.1, 8.1 Hz, 1H), 8.09 (s, 1H), 7.88-7.82 (m, 1H), 7.40-7.36 (m, 1H), 3.65-3.56 (m, 2H), 1.16 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[O-:2].[Li+].[C:4]([C:7]1[S:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][CH:11]=1)(=[O:6])C.[OH-].[K+]>>[CH2:13]([O:12][C:9]1[S:8][C:7]([C:4]([OH:6])=[O:2])=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: [O-]Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(C)=O)s1
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
When in Example 2, 1-bromooctadecane is substituted for 1-bromohexadecane, 2-octadecyloxythiophene is obtained. A mixture of 35.3 g (0.1 mole) of 2-octadecyloxythiophene and 12.3 g (0.12 mole) of acetic anhydride is cooled in an ice bath. While rapidly stirring this mixture, 1.4 g of boron trifluoride etherate is added, and the mixture is heated to 100° C with stirring for 1 hour after which it is cooled to room temperature. Ice water is added, and the mixture is extracted with chloroform. The chloroform solution is evaporated to dryness under reduce pressure to give 2-acetyl-5-octadecyloxythiophene. In 500 ml of 10% aqueous potassium hydroxide 2-acetyl-5-octadecyloxythiophene is combined with 35.0 g (0.6 mole) of lithium hypochlorite. The mixture is stirred vigorously on a steam bath overnight, then allowed to cool to room temperature and extracted with ether. The aqueous extract is acidified with hydrochloric acid to precipitate 5-octadecyloxy-2-thiophenecarboxylic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CS(C)=O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCn1ccc2ccccc21
Temperature: 60 °C

Procedure:
A solution of indole (1.0 g) in dry DMSO (1 ml) is dropped into a suspension of sodium hydride (60% suspension in mineral oil; 0.37 g) in dry DMSO (20 ml), heating to 60° C. for 1 h. After cooling at room temperature, the resulting solution is added dropwise with a solution of n-octyl bromide (2.82 ml) in dry DMSO (2.8 ml). After a night at room temperature, the reaction mixture is poured into water (200 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases are washed with a NaCl saturated solution, dried and evaporated to dryness. The resulting residue is purified by column chromatography (silica gel; eluent n-hexane) to obtain 1.86 g of 1-(n-octyl)indole as oil.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]1([NH:16][C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>O1CCOCC1.O>[C:17]([N:16]([C:2]1[N:4]=[C:5]([N:16]([C:17]#[N:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:8]([N:16]([C:17]#[N:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:1]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:18]
Reactant: N#CNc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: N#CN(c1ccccc1)c1nc(N(C#N)c2ccccc2)nc(N(C#N)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 9.20g (0.05 mole) of cyanuric chloride in 100 ml of dioxane was added to 100 ml of ice water. To this mixture at room temperature was added dropwise a solution of 0.15 mole of sodium phenylcyanamide in 70 ml of water over a 30 minute period. After stirring for 3 hours at room temperature, the reaction mixture was refluxed for 16 hours. After cooling to room temperature the reaction mixture was filtered. The residue was washed with water and dried to give 17.2g (80%) of of TNCT, m.p. 209°-215°. Recrystallization from toluene gave 10.8g with an m.p. of 215°-218°.
Reaction SMILES: Cl.[CH:2]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=1.C(N(CC)CC)C>C(#N)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:2]2[CH2:3][CH2:4]3)=[CH:11][C:12]=1[C:19]([F:20])([F:21])[F:22])([O-:18])=[O:17]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 80 °C
Yield: 88 %

Procedure:
To a flask containing 7-azabicyclo[2.2.1]heptane hydrochloride 7a (4.6 g, 34.43 mmol, obtained from Tyger Scientific Inc., 324 Stokes Avenue, Ewing, N.J., 08638 USA under a nitrogen atmosphere was added a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene 18 (6.0 g, 28.69 mmol) and triethylamine (8.7 g, 12.00 mL, 86.07 mmol) in acetonitrile (50 mL). The reaction flask was heated at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool and then was partitioned between water and dichloromethane. The organic layer was washed with 1 M HCl, dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel chromatography (0-10% ethyl acetate in hexanes) yielded 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane 19 (7.2 g, 88% yield) as a yellow solid. 1H NMR (400.0 MHz, DMSO-d6) δ 8.03 (d, J=9.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (dd, J=2.6, 9.1 Hz, 1H), 4.59 (s, 2H), 1.69-1.67 (m, 4H), 1.50 (d, J=7.0 Hz, 4H).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O)(=O)=O.O[CH2:15][CH2:16][N:17]([CH3:30])[S:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])(=[O:20])=[O:19].[OH:31][CH2:32][CH2:33][SH:34].[Na].N>CN(C)C=O>[OH:31][CH2:32][CH2:33][S:34][CH2:15][CH2:16][N:17]([CH3:30])[S:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])(=[O:20])=[O:19]
Reactant: Cc1cc(C)c(S(=O)(=O)N(C)CCO)c(C)c1
Reactant: OCCS
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Agent: N
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(C)CCSCCO)c(C)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
17.6 g (0.04 mole) N-(2-hydroxyethyl)-N-methylmesitylenesulphonamide mesitylenesulphonate were added to a mixture of 7.8 g (0.1 mole) 2-hydroxyethanethiol, 2.3 g (0.1 mole) sodium and 200 ml ammonia, and then 50 ml dimethylformamide were added, the reaction vessel being cooled in an acetone-CO2 bath. The cooling bath was removed and the mixture was stirred at about 20° C. overnight. Water and diethyl ether was added and the aqueous phase was extracted with diethyl ether. The combined ether phases were washed with brine and dried with Na2SO4. Removal of the solvent in vacuum gave 12.3 g of an oil, which was used as such without further purification. NMR showed that it was the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:18]([N:17]1[CH2:16][CH:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:5][C:1]1=[O:2])([CH3:20])[CH3:19]
Reactant: Cc1ccc(OCC(O)CNC(C)C)cn1
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 g of phosgene in 40 ml of toluene is added dropwise at 5°-10° C. to 15.6 g of 3-(2'-hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine, dissolved in 75 ml of dioxane, in the presence of 8 ml of 2,6-lutidine,whilst stirring. The reaction mixture is stirred overnight at room temperature and is then evaporated in vacuo. The evaporation residue is rendered alkaline with a little concentrated sodium hydroxide solution and is extracted with 200 ml of ethyl acetate. The organic phase is evaporated, initially at approx. 20 mm Hg and then at 0.1 mm Hg/60° C. bath temperature. Approx. 50 ml of ether are added to the residue which remains, giving crystalline 3-isopropyl-5-[(6-methylpyridin-3-yloxy)methyl]-oxazolidin-2-one of melting point 86°-88° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=O.O.[NH2:19][NH2:20]>C1(C)C=CC=CC=1.CN(C=O)C>[N+:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:20][N:19]=[C:11]2[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: O=C(c1ccc[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Temperature: 120 °C
Yield: 77 %

Procedure:
A mixture of (2-chloro-5-nitro-phenyl)-(1H-pyrrol-2-yl)-methanone (600 mg) and hydrazine hydrate (0.5 mL) in toluene (20 mL) and DMF (3 mL) was heated at 120° C. for 2 hours. The reaction was concentrated, the residue was washed with water and recrystallized to give 0.42 g (77%) of the titled compound as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17]2[C:12](=[C:13]([OH:28])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.[Na].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]1>C(O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([N:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])[C:17]2[C:12](=[C:13]([O:28][CH2:38][CH2:37][CH2:36][N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2cccc(O)c2n1
Reactant: ClCCCN1CCOCC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2cccc(OCCCN3CCOCC3)c2n1
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
2-(2-Methyl-4-fluorophenylamino)-4-(N-methylphenylamino)-8-hydroxyquinazoline (1.6 g, 4.3 mmol) was suspended in ethanol (25 ml) and to the stirred suspension was added a solution of sodium (0.1 g, 4.3 mmol) in ethanol (15 ml). Stirring was continued for 15 minutes and the mixture evaporated to dryness. The residue was dissolved in toluene (50 ml) and heated to reflux temperature. To this refluxing solution was added a freshly prepared solution of 3-morpholinopropyl chloride base (from 1.28 g, 6.4 mmol of hydrychloride salt) in toluene (20 ml). Refluxing was continued overnight and after cooling the mixture was washed with sodium carbonate solution and water, dried and evaporared. The residual oil was chromatographed on silica gel using CH2Cl2 as eluting solvent. After evaporation of the relevent fractions the residue was crystallised from diethyl ether/pentane to give the title compound (1.5 g, 71%) m.p. 133°-134°.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]1=O.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([CH:40]5[CH2:41][CH2:42][O:37][CH2:38][CH2:39]5)[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Reactant: O=C1CCCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 20 h
Yield: 81 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride from Example 746 (150 mg, 0.28 mmol), tetrahydropyran-2-one (39 μL, 0.42 mmol), NEt3 (78 μL, 0.56 mmol) and 4 Å powdered molecular sieves (300 mg) in DCE (3 mL) was stirred for 2 h before the addition of sodium triacetoxyborohydride (119 mg, 0.56 mmol). The resulting mixture was allowed to stir at r.t for 20 h then diluted with DCM and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting residue was dissolved in DCM and treated with 4M HCl in dioxane. The resulting solid was triturated with Et2O and dried in vacuo affording 772 (124 mg, 72%). LCMS (method I): RT 2.52 min, [M+H]+ 547.2. 1H NMR (DMSO, 400 MHz): δ 9.36 (1 H, s), 8.18-8.14 (1 H, m), 7.80-7.79 (1 H, m), 7.50-7.48 (2 H, m), 4.28 (4 H, brd s), 4.10-3.90 (6 H, m), 3.78-3.77 (5 H, m), 3.43-3.39 (7 H, m), 3.25-3.10 (1 H, m), 2.30-1.65 (7 H, m), 1.44-1.38 (3 H, m)
Reaction SMILES: [C:1]([NH:6][NH:7][C:8]([NH2:10])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2].[N:11]([O-])=[O:12].[Na+].Cl>O.CO>[C:1]([N:6]([N:11]=[O:12])[NH:7][C:8]([NH2:10])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)NNC(N)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C)(C)N(N=O)NC(N)=O

Procedure:
1-tert-Pentyl semicarbazide (12 g) in a mixture of 50 ml of water and 25 ml of methanol is cooled in an ice bath and 5.6 g of sodium nitrite are added. Conc. hydrochloric acid is added dropwise to this solution until a pH of 4 to 5 is established.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[CH3:16]>>[CH2:15]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[CH3:16]
Reactant: CCBr
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano [3,2-b]indol-4(5H)-one is alkylated with ethyl bromide to give 4.8 g of product, mp 103°-104° C, after recrystallization from methylene chloride-hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc2c(c1)OCO2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc2c(c1)OCO2

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(benzo[1,3]dioxol-5-yl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (189 mg, 0.46 mmol, see step (b) Example 6) and 4-trifluoromethylphenylboronic acid (129 mg, 0.68 mmol). Yield 175 mg, 68%.
Reaction SMILES: C([N:8]1[C:12]([SH:13])=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:10]=[N:9]1)C1C=CC=CC=1.N.[Na]>>[C:16]([CH2:15][CH2:14][C:11]1[N:10]=[N:9][NH:8][C:12]=1[SH:13])([OH:18])=[O:17]
Reactant: O=C(O)CCc1nnn(Cc2ccccc2)c1S
Agent: N
Agent: [Na]
Product: O=C(O)CCc1nn[nH]c1S
Reaction time: 0.67 h

Procedure:
1-Benzyl-4carboxyethyl-1,2,3-triazole-5-thiol (1.1 g., 4 mmol.) is suspended in 50 ml. of anhydrous liquid ammonia and sodium is added until a permanent blue color results. The reaction mixture is allowed to stir for 40 minutes then allowed to warm to ambient temperature while the ammonia evaporates. The residue is triturated with ether and the solid formed is collected and dissolved in water. The aqueous solution is acidified and extracted with ethyl acetate. The extract is dried (MgSO4) and evaporated to dryness to give 4-(2-carboxyethyl)-1,2,3-triazol-5-thiol.