Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N-:66]=[N+:67]=[N-:68].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23][N:66]=[N+:67]=[N-:68])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
3,4,5-Tris(octadecyloxy)benzyl chloride (4.02 g, 4.31 mmol) was dissolved in a mixed solvent of chloroform (40 mL) and N,N-dimethylformamide (120 mL), sodium azide (418 mg, 6.42 mmol) was added, and the mixture was stirred at 80° C. for 3 hr. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with purified water (150 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, methanol was added thereto, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (3.92 g, 97.4%) as a white solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1O[CH2:9]1)(=[O:5])[C:2]([CH3:4])=C.[CH3:11]OC1C=CC(O)=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:11])(=[O:5])[CH:2]=[CH2:4]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: COc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C=CC(=O)OCCCC
Temperature: 25 °C

Procedure:
After the completion of the reaction, the solution was cooled to room temperature. To the solution, 10 g of glycidyl methacrylate, 0.33 g of p-methoxyphenol and 11.0 g of tetrabutylammonium bromide were added. The mixture was stirred until these added compounds dissolved completely. The solution thus obtained was heated to 80° C., and an addition reaction was allowed to take place for 16 hours between the carboxyl group in the copolymer and the epoxy group in the glycidyl methacrylate. Thereafter, the solution was cooled to room temperature to obtain an alkali soluble resin (A-2) in the form of resin solution.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:44](O)[CH2:45][CH2:46][OH:47]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:44][CH2:45][CH2:46][OH:47])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCCO
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide (41.8 mg, 0.100 mmol) was suspended in 2 mL of toluene containing 4-methylbenzenesulfonic acid hydrate (pTsOH, 23.8 mg, 0.125 mmol) and propane-1,3-diol (9.89 mg, 0.130 mmol). The reaction mixture was then heated to 140° C. for 5 minutes in a microwave reactor. The crude product was then filtered, evaporated to dryness, dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product (26.5 mg, 0.0556 mmol, 55.6%). ESI-MS m/z calc. 476.5, found 477.3 (M+1)+. Retention time 2.71 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[N:6]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=1
Reactant: O=c1[nH]cc(Br)cc1N1CCOCC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1cc(Br)cc(N2CCOCC2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 0.3 M solution of 5-bromo-3-morpholinopyridin-2(1H)-one (1.00 equiv.) in DMF was treated with sodium hydride (1.20 equiv.). The mixture was stirred for 15 min at ambient temperature. Tert-butyl (2-bromoethyl)carbamate (1.20 equiv.) was added. The mixture was stirred at 60° C. for 3 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated to give tert-butyl (2-(5-bromo-3-morpholino-2-oxopyridin-1(2H)-yl)ethyl)carbamate. LCMS (m/z) (M+H)=402.1/404.1, Rt=0.78 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[CH:27]=[N:26][CH:25]=2)[CH:6]=[N:7][CH:8]=1.Cl>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:24]2[CH:25]=[N:26][CH:27]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)[N:29]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(-c2ccc3c(c2)c(-c2cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n2)nn3C2CCCCO2)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cncc(-c2ccc3[nH]nc(-c4cncc(O[C@@H]5CCCNC5)n4)c3c2)c1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl (3R)-3-((6-(5-(5-methoxy-3-pyridinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.062 g, 0.106 mmol) and HCl (5 M in i-PrOH, 2.114 mL, 10.57 mmol, Acros) in 1 ml of MeOH and 1 mL of DCM was heated at reflux for 30 min. The crude reaction was cooled to RT and concentrated to a yellowish-green solid that was slurried with a 1/1 mixture of DCM/MeOH (2 mL) and applied to a pre-washed (5 mL MeOH) of Si-propylsulfonic acid (Silicycle, Cat# R51230B). The column was washed with MeOH (10 mL). The compound was released with 15 mL of 2 M NH3 in MeOH to afford 5-(5-methoxy-3-pyridinyl)-3-(6-((3R)-3-piperidinyloxy)-2-pyrazinyl)-1H-indazole as an off-white foam. MS (ESI, pos. ion) m/z: 403.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[C:15]#[N:16]
Reactant: Nc1ccccc1F
Reactant: N#CC1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccccc2F)CCC1

Procedure:
2-Fluoro-aniline (Aldrich Chemicals) (2.3 g, 21 mmol), cyanoketone (Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) and T.H.F. (30 ml) were heated under reflux for 24 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (125° C. 0.05 mm Hg) have the product as an off-white power.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:17]([NH:25][C:26]([NH:8][C:5]1[CH:4]=[C:3]([O:9][C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:2]([Br:1])=[CH:7][N:6]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ncccc1Oc1cc(N)ncc1Br
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: Cc1ncccc1Oc1cc(NC(=S)NC(=O)c2ccccc2)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
5-Bromo-4-(2-methylpyridin-3-yloxy)pyridin-2-amine (2.0 g, 7.14 mmol) and benzoyl isothiocyanate (1.0 ml, 7.5 mmol) were diluted in tetrahydrofuran (100 mL) and stirred at ambient temperature overnight. The solution was concentrated and charged with a mixture of ethyl acetate (10 mL) and hexanes (200 mL). The mixture was stirred for 10 minutes and filtered to give the title compound (2.8 g, 89% yield) as yellow solid.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19].N1C=CN=C1>CN(C)C=O.O>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc(F)c(F)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](Oc1ccc(F)c(F)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
Triisopropylsilyl chloride (166 mL, 961.5 mmol) was slowly added to a mixture of 3,4-difluorophenol (125 g, 961.5 mmol) and imidazole (65.4 g, 961.5 mmol) in N,N-dimethylformamide (500 mL), and the resulting solution stirred overnight at room temperature. The reaction mixture was diluted with water (1500 mL) and extracted with dichloromethane (3×300 mL). The combined organic layers washed with water (3×200 mL) and brine (2×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with petroleum ether) to afford (3,4-difluorophenoxy)triisopropylsilane (220 g, 80%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([NH:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=2[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])[C:26]([Cl:43])=[CH:25][N:24]=1>>[Cl:43][C:26]1[C:27]([NH:29][C:30]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=2[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])=[N:28][C:23]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([NH:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:24][CH:25]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCC(=O)NC1CC(C)(C)c2ccc(N)cc2NC1=O
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)COC)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2-methoxy-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (60 mg, 54%) HPLC 99% purity, LCMS 596 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.69 (s, 1H), 9.39 (s, 1H), 9.16 (s, 1H), 8.94 (t, 1H), 8.18 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.48-7.44 (m, 2H), 7.34-7.29 (m, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J=8.7 Hz, 1H), 4.22-4.17 (m, 1H), 4.00 (s, 2H), 3.82 (s, 2H), 3.33 (s, 3H), 3.10 (s, 1H), 2.19-2.15 (m, 1H), 1.91 (t, J=12.2 Hz, 1H), 1.33 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(F)c2)c1C(=O)OC
Yield: 112.5 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.4 g, 6.7 mmol) in acetone (30 mL) and potassium carbonate (2.8 g, 20 mmol) was added 3-fluorobenzyl bromide (0.89 mL, 7.0 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (50 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-fluoro-benzyloxy)-phthalic acid dimethyl ester (2.4 g, 113% crude yield). The product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13](Cl)([Cl:15])[Cl:14].[OH-].[Na+].O>CN1CCCC1=O>[Cl:8][C:7]1[C:2]([CH:13]([Cl:15])[Cl:14])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1cnc(C(Cl)Cl)c(Cl)c1

Procedure:
2,3-Dichloro-5-(trifluoromethyl)pyridine (43.2 g, 0.20 mole) was dissolved in 140 g (1.17 mole) of chloroform and 105 g of N-methylpyrrolidone. Sodium hydroxide (40 g of 50 percent aqueous solution, 0.5 mole) was added with stirring and the mixture was allowed to stir for 20 hours at room temperature. Another 10 g of 50 percent aqueous sodium hydroxide was added and stirring was continued. After 27 total hours a large excess of water was added. The resulting aqueous layer was removed and the organic layer was concentrated on a rotary evaporator under reduced pressure to obtain an oil containing the title compound. The oil was distilled in a fractionating column and the product fractions washed with dilute aqueous sodium carbonate to obtain 18.8 g of the title compound (35.5 percent of theory) having 97 percent purity by gas chromatography. The product, which was identified by its mass spectrum (parent peak at 263 mass units) and gas chromatographic parameters (compared with an authentic standard), had a boiling point of 108°-114° C. at 19 mm Hg pressure. Approximately 17.5 g of unreacted 2,3-dichloro-5-(trifluoromethyl)pyridine was also recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=O)[CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:34][NH2:35]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:35][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)n[nH]1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-(2,4-dibenzyloxyphenyl)-2,4-dioxobutanoate (3.23 g) in ethanol (10 mL) is treated with hydrazine hydrate (0.4 mL), refluxed for 2 hours and then cooled to room temperature. The mixture is filtered to yield ethyl 3-(2,4-dibenzyloxyphenyl)-pyrazole-5-carboxylate as a solid (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure G′ above and using 3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure I′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[OH:8].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:23][N:22]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Oc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1F

Procedure:
Synthesized using 3-fluoro-4-hydroxyphenylboronic acid (196 mg, 2.00 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 40 mg, 0.15 mmol, 24%. 1H NMR (500 MHz, DMSO-d6): δH (ppm): 5.25 (s, 2H), 6.92 (brs, 1H), 7.03 (t, J=8.8 Hz, 1H), 7.25 (t, J=1.2 Hz, 1H), 7.69 (dd, J=8.2, 2.2 Hz, 1H), 7.74 (ddd, J=8.5, 2.2, 0.6 Hz, 1H), 7.80 (brs, 1H), 7.83 (dd, J=13.0 Hz, 2.2 Hz, 1H), 7.87 (dd, J=8.2, 0.6 Hz, 1H), 8.57 (dd, J=2.2, 0.6 Hz, 1H), 10.2 (s, 1H); MS (ESI): m/z=270.12 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([OH:23])=O)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:21]([C:16]1[C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:23]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)NCCO

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 from (R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 33 Step 2) using ethanolamine instead of ammonium chloride.
Reaction SMILES: Cl.Cl[CH:3]1[CH2:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[N:5]([CH3:22])[CH2:4]1.O.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]([CH3:22])[CH:3]([CH2:4][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[CH:17]=1
Reactant: CN1CC(Cl)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: C1CCNCC1
Agent: Cl
Solvent: O
Product: CN1c2ccc(Cl)cc2C(c2ccccc2)=NCC1CN1CCCCC1

Procedure:
100 mg of 3,8-dichloro-1-methyl-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine hydrochloride is heated in 10 ml piperidine under reflux for 24 hours. For processing the mass was poured into water, extracted with chloroform and the chloroform was subsequently distilled off in a vacuum. The product was recrystallized from ether and there was obtained 7-chloro-1-methyl-2-piperidinomethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine which also was identical with the same material obtained in Examples 4 and 6 of application Ser. No. 355 986 directly by heating acyldiamines with phosphoroxychloride and subsequent reaction with piperidine; m.p. 143°-145° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:44]([Si:48]([CH3:51])([CH3:50])Cl)([CH3:47])([CH3:46])[CH3:45].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:48]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:51])[CH3:50])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.85 g (6.48 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)-phenyl]-2(R)-[(p-benzyloxyphenyl)methyl]hexanoic acid in 11 ml of DMF are silylated, at RT for 16 h and under a protective gas, with 4.49 g (29.8 mmol) of tert-butyldimethylchlorosilane and 3.6 g (53.1 mmol) of imidazole. The reaction mixture is poured onto ice-water and the whole is extracted 3 times with ethyl acetate. The organic phases are washed with 10% citric acid solution, 2 times with water and with saline, dried with Na2SO4 and evaporated. The residue is dissolved in 79 ml of methanol and 30 ml of THF, and this solution is treated with 5.37 g of potassium carbonate and 30 ml of water and stirred at RT for 3 h. The reaction mixture is subsequently poured onto an ice-cold 10% citric acid solution, and this mixture is extracted 3 times with ethyl acetate. The organic phases are washed with 2 portions of H2O and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 1:1) affords the title compound: TLC Rf (C)=0.28; tRet (II)=20.9 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]2[O:22][CH2:21]2)=[CH:18][CH:17]=1.[H-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:21][CH:20]([C:19]3[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=3)[OH:22])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: Cc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(O)Cn2c3c(c4ccccc42)CN(C)CC3)cc1
Yield: 11.1 %

Procedure:
2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (400 mg, 2.1 mmol), 4-methylstyrene oxide (2.1 g, 15.7 mmol) and NaH (252 mg, 6.3 mmol) were heated in DMF (5 mL) at 120° C. for 16 h to obtain 75 mg of racemic-2-(1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., inject ion vol. 5 mL). 1H NMR (CDCl3, TFA salt) δ (ppm): 13.45-13.20 (bs, 1H), 7.40-7.05 (m, 8H), 5.0-4.9 (t, 1H), 4.8-4.6 (t, 1H), 4.25-4.05 (m, 3H), 3.70-3.60 (m, 1H), 3.40-3.30 (m, 2H), 3.05 (m, 1H), 3.00-2.91 (m, 3H), 2.3 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[CH:12]1([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([NH:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:16]3[N:15]([CH:12]4[CH2:14][CH2:13]4)[CH:19]=[N:18][N:17]=3)[N:25]=2)=[O:11])[CH:3]=1
Reactant: Cc1cnc(C(=O)O)cc1Cl
Reactant: Nc1cccc(-c2nncn2C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)Nc2cccc(-c3nncn3C3CC3)n2)cc1Cl
Yield: 47 %

Procedure:
A solution of 4-chloro-5-methylpicolinic acid (159 mg, 0.924 mmol), 6-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ylamine (169 mg, 0.840 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (383 mg, 1.01 mmol), and N-methylmorpholine (11 μL, 1.01 mmol) in N,N-dimethylformamide was stirred at 65° C. for 1.2 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile, and the solid product was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL), diethyl ether (80 mL), and dried under vacuum to afford 4-chloro-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methylpicolinamide as a white powder (140 mg, 47% yield).