Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Cl[C:14]1[N:15]=[C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:17]2[S:22][C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O>[CH3:31][N:30]([CH3:32])[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:21]2[S:22][C:17]3[C:16]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:15][C:14]([N:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[C:2]4[CH3:1])=[N:19][C:18]=3[CH:20]=2)[CH2:25][CH2:26]1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Temperature: 150 °C
Yield: 12.1 %

Procedure:
A solution of 2-methylindole (0.131 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 15 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 1 h the reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish the title compound (0.059 g, 12%) as a light brown solid. MS m/e 491 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33-1.57 (m, 2H) 1.74 (d, J=12.43 Hz, 2H) 2.08 (t, J=10.55 Hz, 3H) 2.18 (s, 6H) 2.64 (s, 3H) 2.95 (d, J=11.30 Hz, 2H) 3.74-3.87 (m, 6H) 3.89-4.04 (m, 4H) 6.42 (s, 1H) 6.98-7.20 (m, 2H) 7.37 (s, 1H) 7.43-7.56 (m, 1H) 8.03 (d, J=7.54 Hz, 1H)
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:10]([O-])=[O:11].[Na+].[Cl-].[K+]>C(O)(=O)C.O>[OH:11]/[N:10]=[C:2](/[C:3](=[O:4])[CH3:5])\[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C(=N\O)C(C)=O
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred and ice-cooled solution of ethyl acetoacetate (292 g) in glacial acetic acid (296 ml) was added a solution of sodium nitrite (180 g) in water (400 ml) at such a rate that the reaction temperature was maintained below 10° C. Stirring and cooling were continued for about 30 min., when a solution of potassium chloride (160 g) in water (800 ml) was added. The resulting mixture was stirred for one hour. The lower oily phase was separated and the aqueous phase was extracted with diethyl ether. The extract was combined with the oil, washed successively with water and saturated brine, dried, and evaporated. The residual oil, which solidified on standing, was washed with petrol and dried in vacuo over potassium hydroxide, giving ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (309 g).
Reaction SMILES: [F-].[Cs+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=3)=[C:18](I)[C:12]=2[C:11]1=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+:29]([C:32]1[CH:33]=[C:34]([CH:49]=[CH:50][CH:51]=1)[CH2:35][Sn](CCCC)(CCCC)CCCC)([O-:31])=[O:30]>CN(C=O)C.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu]I>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=3)=[C:18]([CH2:35][C:34]3[CH:49]=[CH:50][CH:51]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=3)[C:12]=2[C:11]1=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cn1c2c(c(I)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1cccc([N+](=O)[O-])c1
Agent: [Cu]I
Agent: [Pd]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c(Cc3cccc([N+](=O)[O-])c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
Cesium fluoride (0.048 g, 0.320 mmol), palladium tetrakis(triphenylphosphine) (0.018 g, 0.016 mmol) and CuI (0.0060 g, 0.032 mmol) were added to a solution of 2-(2-amino-pyrimidin-4-yl)-3-iodo-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (prepared as described in Example 1) (0.075 g, 0.160 mmol) and 3-nitro-benzyl tributyl stannane (0.102 g, 0.240 mmol) in dry DMF (1.5 ml) under an argon atmosphere. The reaction mixture was stirred at 120° C. under microwave irradiation for 1 h. The reaction mixture was diluted with purite water (2.0 ml) and the precipitate was filtered, dissolved into DCM and purified on silica gel (DCM/MeOH from 100:0 up to 85:15), affording 2-(2-Amino-pyrimidin-4-yl)-1-methyl-3-(3-nitro-benzyl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.0558 g, 0.116 mmol, 73%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH3:19])=[N:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.O[C:28]1[CH:42]=[CH:41][C:31]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH3:19])[O:13][C:9]=2[CH2:8][CH2:7][CH2:6][O:5][C:28]2[CH:42]=[CH:41][C:31]([CH2:32][P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: CCOP(=O)(Cc1ccc(O)cc1)OCC
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOS(C)(=O)=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)cc1)OCC

Procedure:
3-[4-(4-Chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl methanesulfonate (400 mg), diethyl 4-hydroxybenzylphosphonate (365 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and diethyl 4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]benzylphosphonate was obtained as a yellow oil (526 mg, 97%) from an ethyl acetate-eluted fraction.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].ClCCl.C(N(S(F)(F)[F:39])CC)C>O>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:39])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(OCc2ccc(C(F)c3cccc(C#N)c3)cc2)c(C)c1O
Temperature: -78 °C
Yield: 79.6 %

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (0.5 g, 1.29 mmol) and dichloromethane (15 mL) is stirred at −78° C. Diethylaminosulfur trifluoride (0.2 mL, 1.48 mmol) is added and the reaction is warmed to room temperature and stirred 30 min. The mixture is cooled to 0° C. and diluted with water (50 mL). The layers are separated, and the aqueous layer is extracted with dichloromethane (3×50 mL). The organic layers are combined, dried on magnesium sulfate, filtered, and concentrated. The residue is purified via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to give the title compound (400 mg, 80%) as a white solid. LCMS M+1 390.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.Cl[CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.CCOC(C)=O.O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][C:12]([N:13]3[CH2:25][CH2:26][CH2:27][S:28]3(=[O:30])=[O:29])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)CCCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(N3CCCS3(=O)=O)cc2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5 g, 22.8 mmol) was dissolved in DCM (100 mL, 0.2M), triethylamine (15 mL, 5.0 molar equivalent) was added to the mixture. The reaction was stirred at 0° C. for 5 min. 3-chloropropane-1-sulfonyl chloride (4.2 g, 23.0 mmol) was added portion wise. The reaction was stirred at 0° C. for 1 hr and brought gradually to room temperature, heated to reflux at 70° C. for 2 hr. The mixture was cooled to room temperature, diluted with EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified through a silica column to afford 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]isothiazolidine 1,1-dioxide as off-white solid (5.2 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, 2H), 7.18 (d, 2H), 3.76 (t, 2H), 3.53 (t, 2H), 2.41 (t, 2H), 1.28 (s, 12H).
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:18]C)=[C:14]([CH:17]=1)[CH:15]=[O:16])([CH3:9])[CH:7]=[CH2:8].O>C(Cl)Cl>[CH3:9][C:6]([C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH:17]=1)[CH:15]=[O:16])([CH3:5])[CH:7]=[CH2:8]
Reactant: C=CC(C)(C)c1ccc(OC)c(C=O)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C=CC(C)(C)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A solution of boron trichloride (1M in CH2Cl2, 39.7 mmol) was added dropwise under argon at −78° C. to a stirred solution of 5-(1,1-Dimethyl-allyl)-2-methoxy-benzaldehyde (13.2 mmol) in dry CH2Cl2 (120 ml). The dry ice—acetone bath was removed and reaction allowed warming to RT. Stirred at RT for 18 hours, before the reaction mixture was cooled to 0° C. and iced water (125 ml) slowly added. Extracted with CH2Cl2 (2×100 ml). The organic phases were washed with brine, dried (Na2SO4), filtered, and evaporated to black oil. Purified by flash chromatography (heptane:EtOAc) to give the title product as yellow oil in 56% yield. 1H-NMR (CDCl3) δ 10.82 (s, 1H), 9.81 (s, 1H), 7.43 (d, 1H), 7.41 (s, 1H), 6.86 (d, 1H), 5.92 (dd, 1H), 5.02-4.96 (m, 2H), 1.34 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.P(OC)(OC)OC.[F:15][C:16]([F:22])([F:21])[S:17](Cl)(=[O:19])=[O:18].[F:23][C:24]([F:58])([F:57])[C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]2[O:34][CH:35]=[C:36]([CH2:38][O:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH2:48][CH2:49][N:50]4[CH:54]=[CH:53][N:52]=[C:51]4[CH2:55]O)=[CH:42][CH:41]=3)[N:37]=2)=[CH:27][CH:26]=1>C1COCC1.O>[F:57][C:24]([F:23])([F:58])[C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]2[O:34][CH:35]=[C:36]([CH2:38][O:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH2:48][CH2:49][N:50]4[CH:54]=[CH:53][N:52]=[C:51]4[CH2:55][S:17]([C:16]([F:22])([F:21])[F:15])(=[O:19])=[O:18])=[CH:42][CH:41]=3)[N:37]=2)=[CH:27][CH:26]=1
Reactant: OCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: COP(OC)OC
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (91.0 μl), trimethyl phosphite (77.0 μl) and trifluoromethanesulfonyl chloride (69.5 μl) were added to a solution of [1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]methanol (250 mg, 0.503 mmol) in THF (5 ml) at −30° C., and the mixture was stirred at the same temperature for 20 min and at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give the titled compound (38 mg) as a colorless crystal powder.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].S(Cl)(C)(=O)=O.[I].[Na].[C:25]([O:29][C:30]([NH:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C.[Cl-].[Na+].O.C(N(CC)CC)C>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:35]1[CH2:36][CH2:37][C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CC(C)C(C#N)(CCCO)c1ccc(C#N)s1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [I]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C(C#N)(CCCN1CC[C@@H](NC(=O)OC(C)(C)C)C1)c1ccc(C#N)s1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
867 mg (3.49 mmol) of 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexanol was dissolved in 20 ml of acetonitrile. 0.58 ml (1.20 eq).of triethylamine and 0.30 ml (1.10 eq) of mesyl chloride were added thereto. After 10 minutes, brine was added, and the objective product was extracted with ethylacetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The product was dissolved in 30 ml of acetonitrile, 1.57 g (3.00 eq) of sodium iodine, 0.54 ml (1.10 eq) of triethylamine and 845 mg (4.54 mmol) of (3R)-3-tert-butoxycarbonylaminopyrrolidine were added, and the mixture was heated at 60° C. After completion of the reaction, brine was added, and the objective product was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to 100 g of Cromatorex NH silica gel (ethyl acetate:hexane=25 to 35% of ethyl acetate), to give 1.34 g (3.21 mmol, 92.0%) of the title compound as a yellow oil. The physico-chemical data of the compound was as below.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:34][CH:33](O)[CH2:32]3)[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].C(N(S(F)(F)[F:42])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:42][CH:33]1[CH2:34][N:31]([C@H:28]2[CH2:27][CH2:26][C@H:25]([CH2:24][NH:23][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[O:18][C:19]([F:20])([F:21])[F:22])[N:6]=3)[CH2:30][CH2:29]2)[CH2:32]1
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CC(O)C2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CC(F)C2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidin-3-ol (100 mg, 0.20 mmol) in CH2Cl2 (25 mL) was added dropwise a solution of diethylaminosulfur trifluoride (32 μL, 0.24 mmol) in CH2Cl2 (0.5 mL) at room temperature over a period of 15 min. When the reaction was complete, the mixture was treated with saturated NaHCO3 and stirred for 5 min. The organic phase was separated and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as eluent to afford 26 mg of the title compound as a pale yellow solid (26%), m/z 499.1 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.NC1C(COCCOC)=NNC=1NC>>[NH2:13][C:12]1[C:3]([NH:2][CH3:1])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CNc1nc2ccccc2cc1[N+](=O)[O-]
Agent: CNc1[nH]nc(COCCOC)c1N
Product: CNc1nc2ccccc2cc1N
Yield: 97.3 %

Procedure:
2-Methylamino-3-nitroquinoline (711 mg, 3.5 mmol) was reduced according to the procedure of Preparation 11 (d) to give the title compound, (590 mg, 97%), m.p. 133°-136° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][CH:12]1[CH2:21][CH2:20][CH2:19][C:18]2[N:17]=[C:16](C#N)[CH:15]=[CH:14][C:13]1=2.[C:24](=[O:27])(O)[O-:25].[Na+]>Br.O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][CH:12]1[CH2:21][CH2:20][CH2:19][C:18]2[N:17]=[C:16]([C:24]([OH:25])=[O:27])[CH:15]=[CH:14][C:13]1=2
Reactant: O=C([O-])O
Reactant: COc1ccccc1CCNC1CCCc2nc(C#N)ccc21
Agent: Br
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(n1)CCCC2NCCc1ccccc1O
Temperature: 25 °C

Procedure:
14.6 g (47.5 mmol) of 5-{[2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile were taken up in 100 ml of hydrobromic acid (48% in water) and stirred at boiling point for 5 hours. The reaction solution was then cooled to room temperature, diluted with water and adjusted to pH 6 with saturated sodium bicarbonate solution. The crystals formed were filtered off with suction, washed with water and air-dried. This gave 14.6 g (46.76 mmol, 98% of theory) of the target compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1004 %

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (0.30 g, 0.16 mmol) and triethylamine (0.34 ml, 2.42 mmol) in dichloromethane (8 ml) was added p-chlorophenoxyacetyl chloride (0.36 mg, 1.77 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 80:1) to yield the title compound as a white solid (0.57 g, 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH3:21]
Reactant: CNC
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Product: CN(C)c1ncnc2ccc(-c3ccc(F)cc3)cc12
Yield: 76 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and dimethylamine in 76% yield, using the procedure described for example 37 and was characterized by its mass spectrum as follows: MS (m/z): 268 ([M+H]+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[CH2:11][C:5]=2[CH:4]=1)#[N:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[NH4+].[OH-]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)c1ccccc1S2
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Cc3cc(C#N)ccc3Sc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyano-10-oxo-dibenzo[b,f]thiepine (0.10 g, 0.40 mmol) in dry toluene (10.00 mL), was added methyl piperazine (0.21 mL, 1.80 mol) followed by the dropwise addition of TiCl4 (1M in toluene, 1.60 mL, 1.6 mol) via syringe. The mixture was stirred at room temperature for 30 min then refluxed for 5 h. The reaction mixture was cooled, dumped into conc NH4OH and extracted with CHCl3. The combined organic phases were dried (MgSO4) and concentrated in vacuo to dryness. The crude material was chromatographed (20%MeOH/EtOAc) to give 2-cyano-10-(4-methyl-piperazinyl)-dibenzo [b,f]thiepine; yield 0.05 g, (5%).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:20]1[C:24]([C:25]2[N:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=2)=[CH:23][N:22]=[CH:21]1>>[C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]([CH:17]3[CH2:19][CH2:18]3)[C:31]([C:28]3[CH:27]=[N:26][C:25]([C:24]4[O:20][CH:21]=[N:22][CH:23]=4)=[CH:30][N:29]=3)=[O:32])[CH2:14][CH2:15]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cnc(-c2cnco2)cn1
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3cnc(-c4cnco4)cn3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine and 5-oxazol-5-yl-pyrazine-2-carboxylic acid following a procedure analogous to that described in Example 1. LC (method 8): tR=1.57 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(CCCCCC(O)C(OC)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([CH2:8][CH2:9][CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(=O)CCC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COC(=O)C(O)CCCCCC(=O)OC(C)(C)C
Agent: [Na+]
Product: COC(=O)C(O)CCC(=O)OC(C)(C)C
Yield: 27.7 %

Procedure:
Crude methyl 4-tert-butoxycarbonyl-2-oxobutanoate (1.65 g, 7.6 mmol) and sodium triacetoxyborohydride (1.6 g, 7.6 mmol) were reacted by the same procedure as described in Example 1 for the preparation of methyl 7-tert-butoxycarbonyl-2-hydroxyheptanoate to give the title compound (460 mg, 28% 2 steps) as a colorless liquid.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:24].CO>C(Cl)Cl>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][Br:24])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Solvent: CO
Solvent: ClCCl
Product: BrCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a suspension of 2-phenyl-4-(4-hydroxymethylphenoxy)ethyloxazole (30 g, 102 mmol) in 300 mL of methylene chloride at 5° C under a nitrogen atmosphere was added phosphorous tribromide (10.02 mL, 107 mmol) dropwise keeping the temperature of the reaction below 20° C. The resulting solution was allowed to stir for about 2 hours at room temperature. The reaction was cooled to about 10° C and 20 mL of methanol was added. After about 5 minutes, the solvent was removed and the solid remaining was partitioned between 1.35 L of ethyl acetate and 1.05 L of cold 5% aqueous sodium bicarbonate. The organics were washed with another 1.05 L of 5% aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and removed to give 33.3 g of the title compound.
Reaction SMILES: NC1N(C2C=CC=CC=2[O:13]C)N=CC=1C(N)=O.[NH2:18][C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:22]=[C:21]([CH3:30])[C:20]=1[C:31]#[N:32]>>[NH2:18][C:19]1[N:23]([CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:22]=[C:21]([CH3:30])[C:20]=1[C:31]([NH2:32])=[O:13]
Reactant: Cc1nn(C2CCOCC2)c(N)c1C#N
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Product: Cc1nn(C2CCOCC2)c(N)c1C(N)=O

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbonitrile provided the title compound. 400 MHz 1H NMR (CD3OD) δ 4.20 (m, 1H), 4.05 (m, 2H), 3.50 (m, 2H), 2.18 (s, 3H), 2.09 (m, 2H), 1.77 (m, 2H). MS: (M+H m/z 225.0).