Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C@@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C@@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Yield: 80 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and (S)-methyl 2-aminopropanoate hydrochloride. Yield 80%, colorless liquid. MS 324 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=3[F:22])=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Brc1ccc2ncc(I)n2c1
Product: Fc1cc(Cl)ccc1-c1cnc2ccc(Br)cn12

Procedure:
The title compound, light brown solid (0.54 g, 76%), MS (ISP) m/z=327.3 [(M+H)+], mp 159° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (0.42 g, 2.38 mmol).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH2:39][C:40]([OH:42])=O)[N:31]=1.Cl.Cl.[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1.CCN(C(C)C)C(C)C>>[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][N:58]([C:40](=[O:42])[CH2:39][N:32]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:38]4[C:30]([C:26]4[NH:25][CH:29]=[CH:28][N:27]=4)=[N:31]3)[CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: CCOc1cc(N2CCNCC2)c(F)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Protocol A—the HBTU coupling procedure) A solution of [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]acetic acid (0.30 M, 0.40 mL, 0.12 mmol) was transferred to a vial. 1-(4-Chloro-5-ethoxy-2-fluorophenyl)piperazine dihydrochloride (48 mg, 0.14 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (55 mg, 0.14 mmol) and i-Pr2NEt (0.30 mL) were added to the vial and the mixture was stirred at ambient temperature. After 30 minutes, LC/MS analysis indicated formation of desired product and complete consumption of the carboxylic acid starting material. The mixture was diluted with EtOAc, washed with water (1×) and brine (1×), dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (1% to 8% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ □8.79 (dd, 0.6; H, J=8.4, 1.6 Hz), 8.66 (dd, 0.4; H, J=8.0, 1.6 Hz), 8.57-8.55 (m, 1H), 7.29-7.26 (m, 1H), 7.22-7.16 (m, 1H), 7.09-7.05 (m, 2H), 6.50-6.45 (m, 2H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 4.07-4.01 (m, 2H), 3.81-3.69 (m, 4H), 3.17-3.13 (m, 1.6H), 3.08-3.02 (m, 2.4H), 1.50-1.42 (m, 3H); LC/MS m/z (M+H)+ 484.4.
Reaction SMILES: [C:1]([S-:4])(=[S:3])[CH3:2].[Na+].Cl[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[C:1]([S:4][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[S:3])[CH3:2]
Reactant: CC(=S)[S-]
Reactant: CCOC(=O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(SC(C)=S)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 0.2 moles of sodium dithioacetate and 38 g. (0.12 moles) of ethyl α, 2'-dichloro-4-biphenylylacetate in 300 ml. of absolute ethanol is stirred at room temperature for 15 hours. The reaction mixture is filtered, washed with absolute ethanol and evaporated to dryness in vacuo. The residue is treated with ether, filtered and evaporated to dryness to obtain ethyl α-thioacetylthio-2'-chloro-4-biphenylylacetate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][NH2:15].C[Si]([N:30]=[C:31]=[O:32])(C)C>C(O)(C)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][NH:15][C:31]([NH2:30])=[O:32]
Reactant: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: NC(=O)NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reaction time: 20 h

Procedure:
A solution of N-(1H-benzimidazol-2-ylmethyl)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-propane-1,3-diamine (0.14 g, 0.42 mmol—see preparation of N-{3-[(1H-benzimidazol-2-ylmethyl)-(S)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-propyl}-guanidine) in isopropanol (2.8 mL) was treated with trimethylsilylisocyanate (80 μL, 0.58 mmol) at room temperature. The reaction was stirred 20 hours and concentrated under reduced pressure. This afforded, after column chromatography with silica gel (5:1:94 MeOH:NH4OH:CH2Cl2), the desired urea (37 mg, 23%). 1H NMR (CDCl3) δ 1.57 (m, 1H), 1.70-1.85 (m, 3H), 2.06 (br, 1H), 2.26 (br, 1H), 2.62 (m, 1H), 2.70-3.00 (m, 4H), 3.38 (br, 1H), 3.87 (m, 2H), 4.18 (m, 1H), 4.50 (br, 2H, NH2), 6.95 (br, 1H, NH), 7.18 (m, 3H), 7.46 (d, 1H, J=7.0 Hz), 7.45-7.70 (br, 2H), 8.55 (d, 1H, J=4.0 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[C:42]1([CH:48]2[CH2:52][CH2:51][NH:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[H-].[Na+]>CN(C)C=O.COC(C)(C)C>[CH3:40][O:39][CH2:38][CH2:37][CH2:36][N:32]1[C:31]2[CH:41]=[C:27]([CH2:26][O:25][CH:10]3[CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:50]5[CH2:51][CH2:52][CH:48]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH2:49]5)=[CH:4][CH:5]=4)[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11]3)[CH:28]=[CH:29][C:30]=2[O:35][CH2:34][CH2:33]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Reactant: c1ccc(C2CCNC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CN4CCC(c5ccccc5)C4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The stirred solution of 0.0435 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.0155 g of 3-phenylpyrrolidine in 0.5 ml of N,N-dimethylformamide is admixed at 0° C. with 0.0076 g of sodium hydride dispersion (60% in oil). The reaction mixture is stirred at 0° C. over 15 minutes, then at room temperature for 1 hour, and subsequently diluted with 80 ml of tert-butyl methyl ether. The mixture is washed with 20 ml of water, then 10 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rt=4.72.
Reaction SMILES: [CH:1]1([C:8]2[N:13]3[N:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10](O)[C:9]=2[C:18]2[C:36]([F:37])=[CH:35][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:20][C:19]=2[F:38])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:41])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:41][C:10]1[C:9]([C:18]2[C:19]([F:38])=[CH:20][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:35][C:36]=2[F:37])=[C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]2[N:14]=[CH:15][N:16]=[C:12]2[N:11]=1
Reactant: CN(CCCOc1cc(F)c(-c2c(O)nc3ncnn3c2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CN(CCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To tert-butyl 3-[4-(7-cycloheptyl-5-hydroxy[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]propyl(methyl)carbamate (876 mg, 1.64 mmol) is added 5.8 mL of phosphorous oxychloride and 2.9 mL of N,N-diethylaniline, and the mixture is heated at 90° C. for 3 h. The excess phosphorous oxychloride is removed in vaccuo, and the resulting residue is diluted with ethyl acetate. The organic layer is washed with ice water and saturated sodium chloride (x2), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 40% ethyl acetate in hexanes. Concentration provides tert-butyl 3-[4-(5-chloro-7-cycloheptyl [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]propyl(methyl)carbamate as a light yellow oil (452 mg). MS: m/z 550.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:26])[C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:11][CH:10]=1)#[N:2].Cl.[H][H]>[Pd].[C].C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:26])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccc(C(O)C(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1ccc(C(O)C(=O)O)cc1

Procedure:
A solution of 0.01 moles of benzyl 2'-cyano-4-biphenylylglycolate dissolved in 100 ml. of acetic acid and containing 0.01 mole of hydrogen chloride is shaken with hydrogen over a 5% Pd carbon catalyst until 0.01 moles of hydrogen is absorbed. The catalyst is then filtered and the solution is evaporated to dryness and crystallized to obtain 2'-cyano-4-biphenylylglycolic acid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([F:7])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(Cc2ccccc2)CC1
Temperature: -71 °C
Reaction time: 0.83 h
Yield: 51.1 %

Procedure:
To a cooled (-71° C.) and stirred solution of diethylaminosulfur trifluoride (634 μl, 4.80 mmol) in anhydrous dichloromethane (15 ml) was added dropwise, via cannula, a solution of 1-tert-butyloxycarbonyl-4-benzyl-4-hydroxypiperidine (700 mg, 2.40 mmol) in anhydrous dichloromethane (15 ml) over 20 minutes, under nitrogen. After a further 50 minutes at -75° C., the mixture was warmed to -10° C. and stirred for a further 2 hours. Water (20 ml) and saturated aqueous potassium carbonate (7 ml) were added and products were extracted with diethyl ether (1×70 ml). The organic solution was washed with brine (1×25 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, hexane-diethyl ether, 86:14) gave 190 mg of 1-tert-butyloxycarbonyl-3,4-dehydro-4-benzylpiperidine and 360 mg (51%) of the title compound as pale yellow oils; δH (360 MHz, CDCl3) 1.44 (9H, s), 1.46-1.78 (4H, m), 2.90 (2H, d, J=22 Hz), 2.98-3.08 (2H, m), 3.86-3.94 (2H, m), 7.16-7.34 (5H, m); m/z (ES) 294 (M+ 1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([S:11][CH3:12])[CH:5]=2.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>CC#N.CN(C1C=CN=CC=1)C>[C:17]([O:16][C:14]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:11][CH3:12])[CH:5]=2)[CH:10]=[C:2]1[CH3:1])=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: CSc1ccc2cc(C)[nH]c2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CSc1ccc2cc(C)n(C(=O)OC(C)(C)C)c2c1

Procedure:
2-Methyl-6-methylthioindole (13.9 g) prepared according to Allais A. et al. Eur. J. Med. Chem.—Chim. Ther. (1975), 10(2), 187–99, was dissolved in CH3CN (150 mL) followed by the addition of (BOC)2O (18 g) with 480 mg DMAP. After 5 h the mixture was evaporated to dryness and the resulting 2-methyl-6-methylsulfanyl-indole-1-carboxylic acid tert-butyl ester was purified by chromatography over silica gel.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>O1CCOCC1.CCO>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:13]2[N:12]=[C:11]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([I:1])[C:10]=4[N:9]=[N:8]3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CS(=O)c1nccc(-n2nnc3c(I)cccc32)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Temperature: 110 °C
Reaction time: 4 h
Yield: 139.3 %

Procedure:
A mixture of 4-iodo-1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-benzotriazole (2.0 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (1.8 g) in 1,4-dioxane (25 mL) was stirred at 110° C. for 4 h. The solvent was removed in vacuo to provide an oil, which was taken up in EtOH and heated in a water bath until a light orange solid formed. The solid was filtered, washed with Et2O, and dried to provide 4-[4-(4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexane-carboxylic acid ethyl ester (3.56 g, 93%) as a light orange powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Product: COc1ccc(S(=O)(=O)n2cc(C3=CCN(C)CC3)c3cccnc32)cc1

Procedure:
(24.1 mg, 54%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.9 mg, 0.12 mmol) and 4-methoxybenzenesulfonyl chloride (48.2 mg, 0.23 mmol); HRMS-FAB+ for C20H21N3O3S: calculated MH+:384.13818; found:384.13811.
Reaction SMILES: CS[C:3]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=1.[N+:14]([CH3:17])([O-:16])=[O:15]>>[N+:14](/[CH:17]=[C:3]1\[NH:4][C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8][CH2:9]\1)([O-:16])=[O:15]
Reactant: CSC1=Nc2ccccc2CCC1
Reactant: C[N+](=O)[O-]
Product: O=[N+]([O-])/C=C1/CCCc2ccccc2N1

Procedure:
A mixture of Example 182C (2.481 g, 12.97 mmol) and nitromethane (13.99 mL, 259 mmol) was heated with an oil bath at 120° C. for 48 hours. The nitromethane was evaporated and the crude mixture was purified by silica gel chromatography (Analogix IntelliFlash™ 280, SF25-80) eluting with 15-30% ethyl acetate/hexanes to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.15 (s, 1H), 7.34-7.25 (m, 3H), 7.25-7.15 (m, 1H), 6.87 (s, 1H), 2.77-2.64 (m, 2H), 2.22 (m, 2H), 2.14 (m, 2H); MS (ESI+) m/z 205.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.O.[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>O1CCOCC1>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([O:17][CH:24]([F:26])[F:25])[C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(Cl)cc1Cl
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1cc(-n2nc3c(c2Cl)CCCC3)c(Cl)cc1Cl
Reaction time: 0.25 h

Procedure:
To a solution of 6.4 g of 3-chloro-2-(2,4-dichloro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole II-1 in 12.5 ml of dioxane were added 12.5 ml of water and 6.4 g of 50% sodium hydroxide. The mixture was heated at 50°~60° C., mixed with excessive amount of chlorodifluoromethane, and heated at 50°~60° C. To the mixture was dropwise added 6.4 g of 50% sodium hydroxide respectively 2.5 hours later and 4 hours later within 15 minutes. The resulting mixture was allowed to react for 2.5 hours, cooled, neutralized, and extracted with ether. The extract was washed with saturated aqueous sodium chloride, dried and concentrated. The residue was purified by silica-gel chromatography to give 4.0 g of the titled compound I-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][C:4]=1[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:13])[CH:5]=1
Reactant: COc1ccc(CCCO)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)cc1C
Reaction time: 2 h
Yield: 69 %

Procedure:
Compound 42-3 (860 mg) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.39 g) and N-bromosuccinimide (0.934 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (800 mg) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>CCO>[NH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ncc(C(=O)O)c(N)c2c1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
To a stirred solution of ethyl-4-amino-6-methoxyquinoline-3-carboxylate (Example 1a, 1.23 g, 5.0 mmol) in EtOH (20.0 mL) was added aqueous NaOH (2.0 N, 5.0 mL) at room temperature. The reaction mixture was then refluxed for 3 hr. The solution was then filtered and washed with water. The filtrate was cooled to 0° C. and neutralized carefully with 1 N HCl to pH 7. Most of the EtOH was removed under reduced pressure, and the precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as an off-white solid (1.01 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.40 (dd, J=2.8, 9.4 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 8.77 (s, 1H). MS 219 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:10][CH:9]=1.[OH-].[K+]>C(O)C.O>[OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1ccc(OCCSCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1ccc(OCCSCCO)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]propanoic acid, methyl ester (37.64 g, 0.132 mol) in 80% aqueous ethanol (300 ml) was treated with a solution of potassium hydroxide (17.0 g, 0.257 mol) in water (25 ml) and the resulting mixture was stirred at 22° C. for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (200 ml) and dichloromethane (200 ml). The aqueous phase was then adjusted to pH 2 with 6N hydrochloric acid and extracted several times with dichloromethane. The combined organic extracts were washed with brine, dried (magnesium sulfate) and evaporated to give 35.67 g (100%) of the title material as a white solid: mp 64-65° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[CH2:24]([NH:28][C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Solvent: Cc1ccccc1
Product: CCCCNc1cccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12

Procedure:
A mixture of of 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine in toluene (2 mL) and excess of butylamine (1 mL) in sealed tube was heated at 110° C. for overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give N-butyl-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-α]pyridin-7-amine. 1H NMR (CDCl3): δ 8.53 (d, 2H, J=5.1 Hz), 7.54–7.57 (m, 2H), 7.20–7.24 (m, 3H), 7.06 (t, 2H, J=8.6 Hz), 7.02–7.00 (m, 1H), 6.04 (bs, 1H), 5.95 (d, 1H, J=7.7 Hz), 3.39 (q, 2H, J=6.4 Hz), 1.74–1.78 (m, 2H), 1.47–1.56 (m, 2H), 0.99 (t, 3H, J=7.4 Hz); MS m/z 361 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:25](=[O:26])[N:24]([CH:27]([CH3:29])[CH3:28])[C:23]2[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=2[N:21]([CH:34]([CH3:36])[CH3:35])[C:20]1=[O:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:25](=[O:26])[N:24]([CH:27]([CH3:29])[CH3:28])[C:23]3[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=3[N:21]([CH:34]([CH3:36])[CH3:35])[C:20]2=[O:37])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)N1C(=O)C(N)C(=O)N(C(C)C)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CC(C)N1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N(C(C)C)c2ccccc21

Procedure:
Following General Procedure I above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (Example 8-P), the title compound was prepared as a white solid (melting point=232-233° C.). Purification was by flash chromatography eluting with EtOAc/hexanes (4:1 gradient to 6:1). Rf=0.31 (4:1 EtOAc/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(OCC)(=O)C>[CH2:16]([O:15][C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(CCO)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
4-Aminophenethyl alcohol (3.5 g) was dissolved in ethyl acetate (60 ml), to which was added 1N sodium hydroxide (50 ml). To the mixture was added, while stirring at room temperature, carbobenzoxy chloride (4.5 g). The mixture was stirred for 30 minutes. The organic layer was then separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 4-benzyloxycarbonylaminophenethyl alcohol (4.5 g) as a liver brown crystalline product (4.5 g),