Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)=O.[CH3:5][C:6](=O)[CH2:7][C:8](=O)[CH3:9].C([O-])(=O)CO.[NH2:17][C:18]1[NH:22][N:21]=[C:20]([CH2:23][OH:24])[N:19]=1>CC(OC)(C)C>[CH3:5][C:6]1[CH:7]=[C:8]([CH3:9])[N:22]2[N:21]=[C:20]([CH2:23][OH:24])[N:19]=[C:18]2[N:17]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])CO
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 100 °C
Reaction time: 0.38 h
Yield: 58.6 %

Procedure:
To a 10L reactor was charged HOAc (4.7 L), 2,4-Pentanedione (543 mL, 5.29 mol), and the glycolate salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol (944 g, 4.96 mol). The mixture was heated to 100° C. until the solution was homogeneous. After reaching 100° C., the solution should be nearly homogeneous. The time at 100° C. should be ˜15-30 min. After this time, if the solution remains cloudy heating should be discontinued. The resulting solution was cooled to ambient temperature, and MTBE (16 L) was added and the mixture stirred for 30 min. The mixture was filtered through a 14″ Buchner, rinsed with MTBE (7 L), and dried in a vacuum oven overnight at 50° C. to provide 518 g (59%) of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol as a white solid. The filtrate contained significant product, so a second crop was isolated by charging the MTBE filtrates to a 22L reactor and cooling to 0° C. MTBE (8 L) was added and stirred for 2 hours. The resulting slurry was filtered and dried to yield an additional 173.7 g (20%) of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol as a grey solid. Both crops were carried forward. 1H NMR (300 MHz, d6-DMSO): 2.57 (s, 3), 2.71 (d, 3, J=0.8), 4.63 (uneven d, 2, J=5.7), 5.49 (t, 1, J=6.2), 7.13 (d, 1, J=0.8).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:40][CH3:41])[C:35]([NH:37][CH2:38][CH3:39])=[O:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:40][CH3:41])[C:35]([NH:37][CH2:38][CH3:39])=[O:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCNC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1,3-diethylureido)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (165 mg) is dissolved in ethanol (3 ml) and thereto is added 2N-aqueous sodium hydroxide solution (342 μl) and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→17:3) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1,3-diethylureido)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (68 mg). MS (m/z): 696 [M+H]+
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=O)[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].O>N1C=CC=CC=1>[C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[S:17])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1ccn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: O
Product: O=c1[nH]c(=S)ccn1[C@H]1CC[C@@H](CO)O1
Yield: 95 %

Procedure:
When the 2',3'-dideoxy-uridine derivatives being raw materials in the invention are allowed to react with phosphorus pentasulfide in pyridine solvent, the amount of phosphorus pentasulfide is desirable to be not less than 0.5 times mol, preferably 1 to 2 times mol to 2',3'-dideoxy-uridine derivatives. In order to raise the yield of reaction further, it is preferable to add water to the reaction system and the amount of water to be added therefor is preferable to be 0.5 times mol to equivalent mol to phosphorus pentasulfide. Although the reaction proceeds without the addition of water, the reaction liquor becomes blackish brown and tarry substances are produced at this time resulting in the lowering in yield by several steps. The reaction completes by refluxing for 2 to 5 hours. After the completion of reaction, the pyridine solution is concentrated to distill off pyridine and the residue is extracted with chloroform. Thus, aimed 2',3'-dideoxy-4-thiouridine derivatives can be obtained easily in a yield of not less than 95 %. Following this, by eliminating the protecting groups with alkali or acid according to usual method, 2',3'-dideoxy-4-thio-uridine being the compound of the invention can be prepared in high yield and yet with ease.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Br:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Br:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]#N>ICC.CO>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Br:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Br:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][CH3:22]
Reactant: N#CSc1c(C#N)nn(-c2c(Br)cc(C(F)(F)F)cc2Br)c1N
Solvent: CO
Solvent: CCI
Product: CSc1c(C#N)nn(-c2c(Br)cc(C(F)(F)F)cc2Br)c1N

Procedure:
5-amino-1-[2,6-dibromo-4-(trifluoromethyl)phenyl]-4-thiocyanato-1H-pyrazole-3-carbonitrile, which was used directly in step 2 with iodoethane and methanol as solvent to give the 5-amino-1-[2,6-dibromo-4-(trifluoromethyl)phenyl]-4-methylthio-1H-pyrazole-3-carbonitrile, m.p. 211-214° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1cnccc1Br
Product: OC(CCCc1ccccc1)c1cnccc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 4-bromo-pyridine-3-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [Li+].[BH4-].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH2:29][CH2:30][C:31](OC)=[O:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH2:29][CH2:30][CH2:31][OH:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=3)[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)CCn1nc(-c2ccc(C(F)(F)F)cc2)c2c1CCN(C(=O)OC(C)(C)C)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCO)C1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A solution of LiBH4 (26 mg, 1.2 mmol) in THF (0.5 mL) was added to a 0° C. solution of 1-(2-methoxycarbonyl-ethyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (317 mg, 0.70 mmol) in THF (4.0 mL). The mixture was stirred for 5 min then additional LiBH4 (15 mg) was added and stirring continued for 17 h. The mixture was partitioned between EtOAc (80 mL) and saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 0-8% MeOH/CH2Cl2) afforded 268 mg (95%) of the title compound. HPLC (reverse phase conditions), tR=6.82 min. MS (electrospray): m/z calculated for C21H26F3N3O3 [M++Na] 448.18, found 448.10. 1H NMR (CDCl3, 400 MHz): 7.73 (br d, J=8.2 Hz, 2H), 7.65 (br s, 2H), 4.64 (br s, 2H), 4.21 (t, J=6.4 Hz, 2H), 3.76 (br s, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.73 (br t, J=5.4 Hz, 2H), 2.04 (q, J=6.1, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[C:7]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[CH:7]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:6]1)=[O:4]
Reactant: COC(=O)C1Cc2ccc(O)cc2C(CC2CCCC2)=N1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1Cc2ccc(O)cc2C(CC2CCCC2)N1
Reaction time: 8 h
Yield: 1382.3 %

Procedure:
400 mg (0.1 mmol) of 1-cyclopentylmethyl-7-hydroxy-3,4-dihydro-isoquinoline-3-carboxylic acid methyl ester (Example 419, Step 2) was dissolved in 20 ml of methanol with a catalytic amount of Pd/C and stirred overnight under H2 atmosphere (60 psi). Filtaration followed by evaporation of the solvent under vacuo gave 0.4 g of 1-cyclopentylmethyl-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester as a thick liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:15]([F:16])[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[F:16][CH:15]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][CH:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CCC1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCNCCC1F

Procedure:
A solution of benzyl 4-(tert-butoxycarbonylamino)-5-fluoroazepane-1-carboxylate (0.55 g, 1.50 mmol) in MeOH (75 mL) was passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford tert-butyl 5-fluoroazepan-4-ylcarbamate as a mixture of syn and anti isomers as a colourless oil (317 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC1C=CC(O)=CC=1)CCC>>[C:1]1([NH:7][C:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Agent: CCCCNc1ccc(O)cc1
Product: c1ccc(Nc2cccc3ccccc23)cc1

Procedure:
N-phenyl-2-naphthylamine; octylated diphenylamine; 4-n-butylaminophenol;
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:18]=[C:17]([Br:31])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.O1CCOCC1.[ClH:39]>>[ClH:39].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:18]=[C:17]([Br:31])[CH:16]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cc(NC(=O)c3ncc(Br)cn3)c2)COC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)cc(NC(=O)c3ncc(Br)cn3)c2)COCC(N)=N1

Procedure:
A solution of ((R)-5-{3-bromo-5-[(5-bromo-pyrimidine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (22 mg, 0.039 mmol) in 4 M HCl in dioxane (0.8 ml, 80 eq.) was warmed to 40° C. for 24 hrs in a closed reaction vial. After completion volatiles were removed under reduced pressure to yield the title compound (hydrochloride salt) in the form of a colourless solid. 1H-NMR (500 MHz, DMSO-d6): 11.05 (s, 1H), 10.61 (s, 1H, NH), 9.25 (s, 2H), 9.19 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.44 (s, 1H), 4.59 (m, 2H), 3.91 (m, 2H), 1.63 (s, 3H); MS: 470 [(M+H)+].
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:3][CH2:4][N:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCCC1
Temperature: 100 °C
Yield: 10 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (200 mg, 1.2 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (403 mg, 1.26 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (650 mg, 4.7 mmol) in DMF (4 ml). The mixture was heated to 100° C. and further portions of 1-(2-chloroethyl)pyrrolidine hydrochloride (800 mg in total) were added periodically over 4 hours while the reaction mixture was maintained at 100° C. The reaction was then allowed to cool and volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water, separated and the organic phase passed through phase separating paper. Column chromatography eluting with methylene chloride/methanol (95/5) gave 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl) ethoxy)quinazoline (50 mg, 10%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]([CH3:19])([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[CH2:10][C:11]([CH3:18])([CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)(C)Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)(C)Cc1nc2ccccc2n1Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
9 g of ethyl 4-(benzimidazol-2-yl)-3,3-dimethylbutanoate, prepared in Example 40, are added to a suspension of 21.5 g of 60% sodium hydride in 50 ml of anhydrous dimethylformamide. The mixture is stirred for 1 hour at 50° C., 5.6 g of 4-chlorobenzyl chloride are then added and the solution obtained is heated for 5 hours at 90° C. The solvents are concentrated under vacuum and the residue is taken up with water and then extracted with ether. The ether phase is washed with water and then dried over magnesium sulfate and the ether is evaporated off to dryness to give 12.9 g of ethyl 4-[1-(4-chlorobenzyl)benzimidazol-2-yl]-3,3-dimethylbutanoate in the form of an oil, which is used as such for the next step.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].C(OCC)(=O)C.[CH3:33][CH:34]([CH2:38][CH3:39])[C:35]([OH:37])=[O:36]>CC(C)=O.[OH-].[Na+].O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:37][C:35](=[O:36])[CH:34]([CH3:33])[CH2:38][CH3:39])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCC(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCC(C)C(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 30 ml of acetone is dissolved 0.4 ml of 2-methylbutyric acid, and 2.0 ml of 2N-NaOH and 3 ml of water is added, followed by addition of 0.88 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 6 hours and allowed to stand at room temperature (15°-25° C.) for 2 days, followed by addition of 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 100 ml of diisopropyl ether-n-hexane (2:8), elution is carried out with 400 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.8 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[C:26]1([CH:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:36]1([CH:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[O:34])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 540.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[CH:7][CH:6]=2.[N-:13]=[N+:14]=[N-:15].[Na+].Cl>C(O)C>[CH3:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]1[N:13]=[N:14][N:15]=[C:2]1[CH:3]=[N:4]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2ncc(Cl)nc12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2ncc3nnnn3c12
Reaction time: 3 h

Procedure:
The crude 3-chloro-5-methylquinoxaline obtained in the step above was stirred for 3 hours at reflux temperature in 75 ml. of ethanol containing 1.8 g. of sodium azide and 20 ml. of 1N HCl. When the reaction mixture was cooled, the product precipitated as needles. Recrystallization of the product from ethanol produced highly purified 9-methyltetrazolo[1,5-a]quinoxaline, m.p. 166°-68° C. The product was identified by NMR analysis and by elemental microanalysis.______________________________________ Theoretical FoundC 58.37% 58.11%H 3.81 3.98N 37.82 37.60______________________________________
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([CH2:29]OS(C)(=O)=O)[C:12]2[O:21][C:20]3[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][C:15]=3[C:13]=2[CH:14]=1>O1CCCC1>[N:1]1([CH2:29][C:11]2[C:12]3[O:21][C:20]4[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:16][C:15]=4[C:13]=3[CH:14]=[C:9]([Br:8])[CH:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(COS(C)(=O)=O)cc(Br)cc3c2C1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cn4cccn4)cc(Br)cc3c2C1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of 1H-pyrazole (20 mg, 0.52 mmol) in tetrahydrofuran (3 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 26 mg, 0.39 mmol). After stirring the mixture for 1 h the product of step A (120 mg, 0.26 mmol) was added and the reaction warmed to ambient temperature over 2 h. The reaction mixture was quenched with 5% sodium bicarbonate solution and then extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (95:5 hexanes/ethyl acetate) to give tert-butyl 6-((1H-pyrazol-1-yl)methyl)-8-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (40 mg, 35%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.55 (d, J=1.5 Hz, 1H), 7.48 (d, J=1.8 Hz, 2H), 7.14 (d, J=1.5 Hz, 1H), 6.28 (t, J=2.1 Hz, 1H), 5.55 (s, 2H), 4.50 (s, 2H), 3.82 (t, J=5.4 Hz, 2H), 2.87 (t, J=5.4 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7]>[Rh].C(O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(c1ccco1)N1CCCNCC1
Agent: [Rh]
Solvent: CCO
Product: O=C(C1CCCO1)N1CCCNCC1

Procedure:
N-(2-Furoyl)homopiperazine (33.0 g.) in 200 ml. of ethanol was hydrogenated over 5% rhodium-on-carbon catalyst at three atmospheres pressure. The catalyst was removed by filtration and the product distilled to give the desired product, B.P. 135° at 1 mm.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=O)(C)(C)C.[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]([NH2:35])=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21]>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][NH:8][C@H:9]([C:17]([NH:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH2:20][CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:19])[CH2:10]1)[CH3:16]
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCON=C1CN[C@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 91% purity by LC/MS. MS(ESI+): m/z=365.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.Br[CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH2:10][CH2:9][CH2:8][N:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1
Reactant: O[C@@H]1CCNC1
Reactant: BrCCCc1cccs1
Product: O[C@@H]1CCN(CCCc2cccs2)C1
Yield: 85 %

Procedure:
Prepared as in Intermediate I-15 from (3R)pyrrolidin-3-ol (commercially available) and 2-(3-bromopropyl)thiophene. The yield was 1.02 g (85%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3C(C)=NC(C)=C[CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.[CH3:40][N:41]1C(C=O)=C[N:43]=[CH:42]1.C(=O)=O>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:41]([CH3:40])[CH:42]=[N:43][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=1
Reactant: Cn1cncc1C=O
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (Intermediate 12: step d, 3.0 g, 6.97 mmol) was added THF (40 ml) and the solution was cooled to −70° C. n-BuLi (2.5 M in hexanes, 2.8 mL, 7 mmol) was added dropwise. After 2 minutes, 1-methyl-1H-imidazole-5-carbaldehyde (1.2 g, 9 mmol, in 10 mL THF) was introduced. After 15 minutes, the dry-ice bath was replaced with a 0° C. bath. After 35 minutes the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc:THF (10:2) 5×50 mL. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give the title compound.