Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[C:15](Br)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:52]=[O:53]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:14]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[C:52](=[O:53])[O:21]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2cccnc2Br)CCN(Cc2ccccc2)CC1
Reactant: CN(C)C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC2(CCN(Cc3ccccc3)CC2)c2cccnc21
Temperature: 80 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
A mixture of 3.4 g (9.7 mmol) 1′-benzyl-2-bromo-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-ol, 3.3 ml (1.9 mmol) N,N-diisopropylethylamine, 0.22 g (1.0 mmol) Pd(II) acetate and 0.25 g (1.0 mmol) triphenylphosphine in 100 ml N,N-dimethylformamide was purged with carbon monoxide and stirred under an atmosphere of carbon monoxide at 80° C. for 72 h. The reaction mixture was diluted with tert-butyl methyl ether and washed with water (pH adjusted to 8 with saturated aqueous sodium bicarbonate solution). The aqueous layer was extracted with two portions of tert-butyl methyl ether. The combined organic layers were washed with two portions of water and brine, dried over sodium sulfate and concentrated to dryness. Flash-chromatography gave the title compound (1.2 g, 43%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]1[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1>>[NH2:15][C:14]1[C:16]([C:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[O:5])=[CH:17][C:18]2[O:19][CH2:10][O:11][C:12]=2[CH:13]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=Cc1ccccc1Cl
Product: Nc1cc2c(cc1C(=O)c1ccccc1Cl)OCO2

Procedure:
(6-amino-1,3-benzodioxol-5-yl)-(2-chlorophenyl)-methanone (Xbb) was prepared by reacting 2-chlorobenzaldehyde with 0.020 moles of 3,4-methylendioxy aniline in a manner analogous to Example 1. MH+/Z=276.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][NH:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)#[CH:19].[OH-].[Na+].C(OCC)(=O)C.CCCCCC>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:19]=[CH:18]\[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C#Cc1ccccn1
Reactant: COc1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-c2ncn(/C=C\c3ccccn3)n2)cc(C(F)(F)F)c1
Temperature: 77.5 °C

Procedure:
In a 25 mL, 3 Neck round-bottomed flask equipped with nitrogen inlet and a rubber septum, 3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (0.25 g, 1.0 eq.), 2-ethynylpyridine (0.1 ml, 1.0 eq.) and sodium hydroxide (0.1028 g, 2.5 eq.) were dissolved in DMF (5.0 mL). The reaction mixture was stirred at 75-80° C. The progress of the reaction was followed by TLC analysis on silica gel with 50% ethyl acetate-hexane as mobile phase which shows that starting material was consumed after 15 h. Reaction mixture was diluted by water and extracted with ethyl acetate, combined organic layer was dried over sodium sulphate and distilled under reduce pressure (25° C., 20 mmHg) to obtain crude material. The crude compound was purified by column chromatography using 60/120 silica gel and ethyl acetate in hexane as mobile phase. The column was packed in Hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection. The compound started eluting from 18% ethyl acetate in hexane. Fractions containing such TLC profile were collected together to obtain pure compound 0.005 g; LCMS (%): Retention time 3.476 min (97.44%); (Z)-2-(2-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1H-1,2,4-triazole-1-yl)vinyl)pyridine: 1H NMR (400 MHz, DMSO) δ: 9.61 (s, 1H), 8.67-8.68 (d, 1H, J=4.8 Hz), 8.03 (S 1H), 7.86 (s, 1H), 7.71-7.76 (doublet of triplet, 1H), 7.30-7.732 (d, 1H, J=8 Hz), 7.20 (s, 1H), 7.14-7.16 (d, 1H, J=10.4 Hz), 6.40-6.42 (d, 1H, J=10.8 Hz), 3.94 (s, 1H). LCMS for C17H13F3N4O [M+H]+ 1345.3 found at 346.8 at 3.476 min (LCMS: 97.44%).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]
Reactant: NCCN1CCNC1=O
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(NCCN2CCNC2=O)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 78 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 1-(2-aminoethyl)imidazolidin-2-one instead of thiomorpholine to the title compound (203 mg, 78%) which was obtained as an off-white solid. MS: m/e 479.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:8]([C:10]2[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1ccc(Cl)nc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol was added an excess (ca. 2 eq.) of PDC in DCM. The suspension was shaken at room temperature overnight. The reaction was monitored by LC-MS, another 1-2 eq. of PDC was added and the reaction was shaken for another 6 hours. The crude product was filtered through Celite and purified by flash chromatography (silica gel, DCM). 1H NMR (CDCl3): δ (ppm): 7.50 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68 & 7.70 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.09-8.11 (m, 1 H), 8.24 (d, J=8.8 Hz, 1 H), 8.57 (d, J=2.0 Hz, 1H. MS: (M+H)/z=296.9
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[S:26](Cl)(=[O:28])=[O:27]>CN(C)C=O.[H-].[Na+]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:26]([C:20]4[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])(=[O:28])=[O:27])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CN1C=CC(c2c[nH]c3ccc(O)cc23)=CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4c(F)cccc4F)cc23)CC1
Yield: 51.1 %

Procedure:
By a method similar to Example 45, using 3-(1-methyl-pyridin-4-yl)-5-hydroxy-1H-indole (1.50 g, 6.5 mmol) in dimethylformamide (40 mL), sodium hydride (0.29 g of a 60% dispersion in oil, 7.2 mmol), 2,6-difluorobenzenesulfonyl chloride (1.52 g, 7.2 mmol) provided 1.35 g (51%) of 2,6-difluorobenzenesulfonic acid 3-(1-methylpiperidin-4-yl)-1H-indol-5-ylester as an off-white solid: mp 235-238° C.; MS(ES+): m/e 407.0 (M+1); 1H NMR (400 MHz, dmso-d6): 11.04 (br s, 1H), 7.92-7.82 (m, 1H), 7.42-7.33 (m, 2H), 7.29 (d, 1H, J=8.8 Hz), 7.15 (d, 1H, J=2.0 Hz), 7.06 (d, 1H, J=2.0 Hz), 6.79 (dd, 1H, J=8.8, 1.8 Hz), 2.78 (br d, 2H, J=11.2 Hz), 2.56-2.46 (m, 1H), 2.16 (s, 3H), 1.93 (br t, 2H, J=11.8 Hz), 1.74-1.64 (m, 2H), 1.60-1.46 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][N:24]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:4]1[CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=[C:2]([NH:22][C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(Cl)c2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(Nc3cc(C#N)ccn3)c2)CC1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(2,6-dichloro-4-pyridyl)piperidine-1-carboxylate (3.64 g, 11.0 mmol), 2-amino-4-cyanopyridine (1.35 g, 11.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (259 mg, 2.5 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (328 mg, 5 mol %) and potassium carbonate (2.13 g, 15.4 mmol). The flask was sealed with a septum and purged with nitrogen gas before injecting anhydrous 1,4-dioxane (22 mL, 0.5 M). The reaction mixture was stirred at 80° C. for 17 hr before cooling to rt and filtering through Celite, rinsing with CH2Cl2. After concentration, flash column chromatography (100:0-60:40 heptanes/EtOAc) afforded tert-butyl 4-[2-chloro-6-[(4-cyano-2-pyridyl)amino]-4-pyridyl]piperidine-1-carboxylate as a colorless film (1.745 g, 38%); 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=5.1 Hz, 1H), 7.94 (s, 1H), 7.42 (br s, 1H), 7.17 (s, 1H), 7.08 (d, J=5.1 Hz, 1H), 6.81 (s, 1H), 4.41-4.09 (m, 2H), 2.87-2.72 (m, 2H), 2.71-2.60 (m, 1H), 1.88-1.80 (m, 2H), 1.67-1.58 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: O.Cl.[C:3]12([CH2:13][CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=3[F:25])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>CO.[Fe]>[C:3]12([CH2:13][CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:25])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: O=[N+]([O-])c1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
To a mixture of water (50 mL) and iron powder (0.88 g, 15.8 mmol) at 65° C. was added concentrated hydrochloric acid (1 mL) dropwise and the mixture was stirred for 15 min. The aqueous layer of the mixture was poured out, and a solution of N-(2-(adamantan-1-yl)ethyl)-2-fluoro-4-nitroaniline (0.5 g, 1.57 mmol) in MeOH (50 mL) was added to the above processed iron powder. The mixture was further stirred at 65° C. for 30 min. The mixture was then cooled to rt and filtered. The filtrate was concentrated and the residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a white solid (382 mg, 84%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2cccnc2)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
Pyridin-3-ylboronic acid (307 mg, 2.50 mmol), 5-bromopyrazin-2-amine (391 mg, 2.25 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (88 mg, 0.13 mmol) were added to degassed dioxane (12 mL) and the mixture was stirred for 30 min. Then sodium carbonate (795 mg, 7.50 mmol) and degassed water (8 mL) were added and the reaction was heated in a closed reaction vial at 100° C. for 8 h. The reaction was allowed to stand at ambient temperature over the weekend. It was diluted into ethyl acetate (100 mL) and extracted with brine (3×25 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (0 to 5% methanol/ethyl acetate) to afford 5-(pyridin-3-yl)pyrazin-2-amine (235 mg, 1.37 mmol, 54.6% yield). 1H NMR (400 MHz, Acetone) δ ppm 9.13 (1 H, d, J=1.51 Hz), 8.54 (1 H, d, J=1.26 Hz), 8.50 (1 H, dd, J=4.78, 1.51 Hz), 8.22-8.28 (1 H, m), 8.07 (1 H, d, J=1.26 Hz), 7.39 (1 H, ddd, J=7.87, 4.72, 0.76 Hz), 6.05 (2 H, br. s.). MS (LC/MS) R.T.=0.58; [M+H]+=173.20.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>O>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][C:8]=1[C:13]([OH:15])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1O
Temperature: 200 °C

Procedure:
178 g (1 mol) of 4-trifluoromethoxyphenol and 345 g (2.5 mol) of potassium carbonate were initially introduced into an autoclave which was then pressurized to 60 bar with carbon dioxide and heated at 200° C. for 4 hours. After cooling and releasing the pressure, the residue was dissolved in 1.5 l of hot water, the solution was filtered hot, the cooled filtrate was extracted using methylene chloride and the extract was clarified using active carbon. The pH was then adjusted to 1 and the precipitated product was filtered off with suction. 192 g of product having a melting point of 129° C. were obtained, which corresponds to 86% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:12]3=[N:13][C:14]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:15][CH:16]=[C:11]3[C:10]([C:27](OC(C)(C)C)=[O:28])=[N:9]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][C:14]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:15][CH:16]=[C:11]3[C:10]([CH2:27][OH:28])=[N:9]2)=[CH:34][CH:35]=1
Reactant: COc1ccc(CNc2ccc3c(C(=O)OC(C)(C)C)nn(Cc4ccc(OC)cc4)c3n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2ccc3c(CO)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl 1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (2.65 g, 5.58 mmol) in 30 mL THF cooled in an ice bath was added a 2M solution of LiAlH4 in THF (3.49 mL, 6.98 mmol). The resulting mixture was stirred cold for 20 minutes and then warmed to room temperature and then left at room temperature for 2.5 hours. The mixture was then diluted with THF (50 mL) and then treated sequentially with water (265 μL), 15% NaOH (265 μL) and water (795 μL) and then stirred for 30 minutes. The resulting suspension was filtered through diatomaceous earth and the resulting cake was rinsed with THF (50 mL). The combined filtrates were preabsorbed onto silica gel (15) and the solvent removed in vacuo. This solid was purified on silica gel (80 g) column (0-20% MeOH/CH2Cl2) to give the title compound. LRMS (M+1)=404.9
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:28])[CH:9]=2)=[N:6][CH:7]=1.[C:29]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl>>[ClH:1].[ClH:41].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][N:26]([CH3:29])[CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:28])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CNCC2
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc3n2C)C1
Yield: 81 %

Procedure:
4-(5-Chloropyridin-2-yl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (57 mg, 0.14 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (54.5 mg, 81%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.72 (d, J=1.7 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.99 (dd, J=8.2, 2.2 Hz, 1H), 7.79 (d, J=7.1 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.56 (d, J=1.3 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.19 (dd, J=7.2, 1.8 Hz, 1H), 7.14 (dd, J=8.3, 1.8 Hz, 1H), 4.80-4.72 (br m, 1H), 4.46-4.34 (m, 1H), 3.96-3.86 (m, 1H), 3.75 (s, 3H), 3.65-3.55 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H); ESI MS m/z 405 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.0 min.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[C:8]([Cl:15])[N:7]=1>O1CCCC1>[Cl:5][C:6]1[CH:11]=[C:10]([O:2][CH3:1])[CH:9]=[C:8]([Cl:15])[N:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Cl)c1

Procedure:
To a tetrahydrofuran solution containing methanol (0.37 g, 0.0104×1.1 mol), sodium hydride (0.44 g (ca. 60% in mineral oil), 0.0104×1.05 mol) was added, then 2,6-dichloro-4-nitropyridine (2.00. g, 0.0104 mol) was added thereto and the resultant solution was stirred for about 2 hours at room temperature. After it was confirmed that there was no bubbling with the addition of methanol (1.0 g, 0.0355×0.9 mol), the resultant solution was stirred for about another 1 hour. After the reaction solution was partitioned between ethyl acetate and water, the obtained organic layer was washed successively with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter concentrated to obtain the substantially pure end product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=[O:26])C.C(C1C=C(C=CC=1)C(Cl)=O)#N>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Agent: N#Cc1cccc(C(=O)Cl)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (0.5 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester [CAS-No. 62088-13-5; prepared from 3-cyanobenzoyl chloride according to general procedure K, method a] (0.55 mmol) according to the general procedure M. Obtained as a white solid (160 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[CH2:10][Br:11].[OH-].[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][Br:11]
Reactant: BrCCBr
Reactant: Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1OCCBr
Temperature: 100 °C

Procedure:
22.4 ml (0.2 mole) of 2-methyiphenol and 34.6 ml (0.4 mole) of ethylene dibromide are mixed and heated at 100° C. The mixture is stirred vigourously with 125 ml 1.6N NaOH, continued heat and stirred till the pH value to 7. Upon cooling, after filtrating the extracted solids, the mixed solution's organic layer is extracted with chloroform and rinsing the extracted solids with NaCl and MgSO4. The generated product is filled into silica gel chromatography columns. The mixture solution of Hexane and Ethylacetate was used as the eluent solution. Upon purification, until white crystallization 2-methyphenoxy)ethylbromide are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C@H:11]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:16][C@H:15]2[N:25]([CH3:26])[C@@H:12]1[CH2:13][CH2:14]2)(OC)=[O:8]>C(OCC)C>[OH:8][CH2:7][C@H:11]1[C@@H:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:16][C@H:15]2[N:25]([CH3:26])[C@@H:12]1[CH2:13][CH2:14]2
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN1[C@H]2CC[C@@H]1[C@@H](CO)[C@@H](c1ccc(F)cc1)C2
Reaction time: 0.17 h

Procedure:
To a suspension of lithium aluminum hydride (0.8 g, 21 mmol) in diethyl ether (30 ml), at room temperature, was slowly added a solution of (1R, 2S, 3S)-2-carbomethoxy-3-(4-fluorophenyl)tropane (5 g, 18 mmol) in 100 ml diethyl ether. The reaction completed after stirring for 10 minutes and was quenched by addition of 0.8 ml water, 0.8 ml sodium hydroxide (15%) and 2 ml water. The aluminum salts were removed by filtration and the solvent was removed in vacuo leaving oil. The title compound precipitated upon trituration with pentane as white crystals, m.p. 79-80° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:14]>>[NH2:14][C@H:10]1[C@H:12]([OH:11])[CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: N
Reactant: c1ccc(CN2CC3OC3C2)cc1
Product: N[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
8.9 g (50 mmol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane are heated in 75 ml of ammonia solution (25% strength) at 120° C. in an autoclave for 8 hours. The solution is concentrated and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)=[N:4][N:3]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14](=[O:15])[CH2:13][N:10]1[N:9]=[N:8][C:7]([C:5]2[S:6][C:2]([Br:1])=[N:3][N:4]=2)=[N:11]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Brc1nnc(-c2nnn[nH]2)s1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1nnc(-c2nnc(Br)s2)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 5 from 5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazole and tert-butyl bromoacetate. The isolated title compound was contaminated with ˜20% of tert-butyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazol-1-yl]acetate. 1HNMR (CDCl3 300 MHz): δ 5.43 (s, 2H), 1.47 (s, 9H).