Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:36](O)(=O)C(O)=O>>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][N:28]([CH3:36])[CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNC[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Reactant: O=C(O)C(=O)O
Agent: C=O
Product: CN(CC(=O)O)C[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 0.13 g of ethyl ester of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]glycine obtained in Example 40 were added 2 ml of formalin and 2 ml of oxalic acid: The mixture was heated at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was subjected to 5 extraction with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, then with water, followed by drying. The solvent was distilled off under reduced pressure. The residue was dissolved in 6 ml of methanol. To the solution were added 0.2 g of potassium carbonate and 2 ml of water. The mixture was stirred for 2 hours at 60° C. The reaction mixture was concentrated under reduced pressure, to which was added water, followed-by extraction with ether. The aqueous layer was acidified to pH 4 with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. From the residue was obtained 0.1 g of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]-N-methylglycine as crystals, m.p. 195°-197° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[N:18]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:20][NH:19]1>C(#N)C>[N:19]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:20][CH2:21][CH:22]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[N:18]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)C1CCNN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 74.4 %

Procedure:
Sat. aq. K2CO3 (210 mL) was added into a solution of benzyl chloroformate (12.0 ml, 84 mmol) and crude di-tert-butyl pyrazolidine-1,5-dicarboxylate (12.74 g, assumed 46.8 mmol) in acetonitrile (137 ml) at 0° C. The reaction was allowed to warm to room temperature and was stirred for 4.5 hrs. The aqueous phase was extracted with EtOAc (3×100 mL), and the organic layers were dried over Na2SO4. The solvents were removed in vacuo, and the crude product was purified by silica gel chromatography (CombiFlash, Column: 220 g; 0-35% ethyl acetate in hexane; 60 min) to provide the desired product 1-benzyl 2,3-di-tert-butyl pyrazolidine-1,2,3-tricarboxylate (14.15 g, 74% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: ClCc1ccccn1
Reactant: N#Cc1ccc(O)cc1F
Agent: Cl
Product: N#Cc1ccc(OCc2ccccn2)cc1F
Yield: 72.1 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (1.0 g) and 2-chloromethylpyridine hydrochloride (1.2 g) were processed in the same manner as in Production Example 1-1 to obtain the entitled compound (1.2 g).
Reaction SMILES: O1C2(CCC(N3CCN([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)CC3)CC2)OCC1.[OH-:24].[Na+]>Cl.O1CCOCC1>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH:17]2[CH2:22][CH2:21][C:20](=[O:24])[CH2:19][CH2:18]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(N2CCN(C3CCC4(CC3)OCCO4)CC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-(4-fluoro-phenyl)-piperazine (3.13 gm) (C18H25FN2O2) in 100 ml 3N hydrochloric acid and 100 ml dioxane was stirred at ambient temperature for 2 hours. The mixture is cooled to 0° C., neutralized with 2N sodium hydroxide and extracted with 2×100 ml ethyl acetate. The ethyl acetate layer was washed with water and brine (each 2×40 ml), dried over sodium sulfate and concentrated to a solid. This material, which was recrystallized from ethyl ether (1.5 gm), has a melting point of 104-106° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:13][CH2:14][CH2:15][NH:16][C:17]2[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.[C:24](Cl)(=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(Cl)(Cl)Cl>[CH2:40]([C:41]1[N:16]([CH2:15][CH2:14][CH2:13][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=1)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccccc1NCCCn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCCn1ccnc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Triethylamine (0.72 ml) was added to a solution containing N-[3-(1H-imidazol-1-yl)propyl]-1,2-benzenediamine (1.000 g) in chloroform (10.0 ml), and then stearoyl chloride (1.58 ml) was added thereto while being cooled with ice. After being stirred for 4.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (3.85 ml) was added to a solution containing the residue (2.149 g) in ethanol (22 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.273 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1), thereby yielding the entitled compound (1.657 g) as yellow solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].C([OH:18])C#CC.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1>[Cl:13][C:8]1[CH:7]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:11]=[CH:10][C:9]=1[OH:18]
Reactant: CC#CCO
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1ccc(O)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The product from example 4 step (i) (1.0 g) in dry NMP (20 ml) was treated with 2-butyn-1-ol (0.63 ml) and sodium tert-butoxide (0.864 g) and the mixture stirred at 80° C. for 2 h. The mixture was partitioned between water/ethyl acetate, the organics separated, dried and evaporated under reduced pressure, yield 1.06 g.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:8]=2[O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([S:17]([N:20](COC)[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)(=[O:19])=[O:18])=[C:12]([F:30])[CH:11]=2)=[CH:5][N:4](C2CCCCO2)[N:3]=1.CO.O>Cl>[NH2:1][C:2]1[C:6]([C:7]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:8]=2[O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([S:17]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)(=[O:19])=[O:18])=[C:12]([F:30])[CH:11]=2)=[CH:5][NH:4][N:3]=1
Reactant: COCN(c1ccncn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2cn(C3CCCCO3)nc2N)cc1F
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1n[nH]cc1-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 108.5 %

Procedure:
4-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamide (Preparation 887, 58 mg, 0.093 mmol) in methanol (1 mL, 20 mmol) and 2 M of hydrogen chloride in water (1 mL, 2 mmol) was heated at 60° C. for 2 hours then concentrated. The residue was liophilized from acetonitrile-water to give 50 mg of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11](N3CCC4C=CNC=4C3C)=[O:12])[CH:10]=2)[CH:7]=1.[Cl:23][C:24]1[O:25][C:26]2[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[C:27]=2[N:33]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:29]3[CH2:30][CH2:31][C:26]4[O:25][C:24]([Cl:23])=[N:33][C:27]=4[CH:28]3[CH3:32])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2oc(Cl)nc21
Product: CC1c2nc(Cl)oc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 2-chloro-4-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH3:28])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+]>O.CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH3:28])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Lipase from Rhizopus delemar (300 mg, ex. Biocatalysts Ltd.) was stirred in deionised water (125 ml) and the pH of the mixture adjusted to 7.0. To this mixture, at ambient temperature (23° C.), was added a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoate (690 mg) (enantiomer ratio 8:92 as prepared in example 1) in acetone (5 ml). The resulting reaction mixture was stirred at ambient temperature and pH 7.0 was maintained by autotitration with 0.1M sodium hydroxide solution until hydrolysis was complete. 0.1M Sodium hydroxide solution was added to bring the reaction mixture to pH 9.5 after which it was washed with dichloromethane. The aqueous phase was acidified with hydrochloric acid to pH1 and the acid extracted into dichloromethane, washed, dried (magnesium sulphate), and evaporated. The resulting solid was triturated with hexane to yield 490 mg of (+)3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid as a white solid; m.p. 121°-123° C.; enantiomer ratio 92.8 (by HPLC assay); [a]D25 +13°, MeOH, c 0.5. Enantiomer ratios of 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid were determined by HPLC on a chiral AGP column eluting with 4.8% acetonitrile in 0.01M sodium dihyrogen phosphate solution at pH 7.0 and detecting products by UV monitoring at 245 nm. Enantiomer ratios are quoted in the order of elution.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccn1C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)n1C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.5 g. (0.03 mole) of p-nitrobenzoyl chloride in 60 ml. methylene chloride is added to a suspension of 3.9 g. (0.03 mole) aluminum chloride in 20 ml. methylene chloride. The resulting suspension is added dropwise to a chilled (−15° C.) solution of ethyl 1-methylpyrrole-2-acetate in 50 ml. methylene chloride. The solution is stirred for 15 minutes at −10° C. and at room temperature for 15 minutes. The reaction mixture is poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo. A solid, ethyl 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetate, crystallizes from the remaining oily residue which is isolated by recrystallization from methanol, m.p. 103-106° C.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16]OC.C(OCC)(=O)C.Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[Cl:15][CH2:16][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: N#Cc1ccccc1-c1ccccc1
Reactant: COCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(CCl)cc1
Yield: 48.3 %

Procedure:
To vigorously stirred 2-phenylbenzonitrile (68.1 g) under ice-cooling was added titanium tetrachloride (432 g) dropwise for 30 minutes. The precipitated crystals were pulverized and then chloromethyl-methyl ether (61 g) was added dropwise for 20 minutes with stirring under ice-cooling. After stirring at 60° C. for 2 hours, additional chloromethyl-methyl ether (15.3 g) was added and the mixture was stirred for an additional hour. To the reaction mixture was added ethyl acetate (200 ml) dropwise with stirring under ice-cooling. Then ice was added until hydrogen chloride gas development ceased and iced water (400 ml) was added before stirring for a while. The precipitated crystals were filtered and dried. The filtrate was extracted with ethyl acetate, washed with water, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography on silica gel to give crystals which were combined with the previously obtained crystal and recrystallized from methanol to yield pale yellow prisms (41.8 g, 48%).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(C)C.[OH-].[K+]>C(O)C>[CH2:15]([S:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)ccc2ccncc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: O=[N+]([O-])c1c(SCc2ccccc2)ccc2ccncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.52 g. (2.5 mmole) of 7-chloro-8-nitroisoquinoline and 0.317 g. (2.56 mmole) of benzyl mercaptan in 5 ml. of degassed isopropanol under argon at 0° C. was treated with 0.16 g. (2.5 mmole) of 86% KOH in 2 ml. of ethanol dropwise over fifteen minutes. The mixture was stirred for one hour at 25° C. and filtered. The collected product was washed with water and ethanol and then dried to yield 7-benzylthio-8-nitroisoquinoline having a melting point of 151°-153° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: S=C(NN=Cc1ccc(Cl)cc1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 4-chlorobenzaldehyde (79 mg, 0.56 mmol) similar to Example 3 and isolated as a white solid (68 mg, 40%). 1H NMR (CDCl3): 9.15 (s, 1H), 7.73 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.39 (d, J=8.7 Hz, 2H), 6.24-6.14 (m, 2H), 4.30-4.25 (m, 1H), 3.06 (s, 1H), 2.97 (s, 1H), 1.95-1.87 (m, 1H), 1.68 (d, J=9.0 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.45-1.39(m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCCNCC1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: O=Cc1c(N2CCCCCC2)n(-c2ccccc2)c2ccccc12
Yield: 42 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with azepane as described in Example 2 to give the title compound (42% yield). NMR (CDCl3) 10.25 (1H, s), 8.23 (1H, d), 7.58 (2H, m), 7.51 (1H, m), 7.39 (2H, d), 7.25 (1H, m), 7.15 (1H, t), 6.98 (1H, d), 3.50 (4H, m), 2.55 (4H, m), 2.33 (3H, s), 1.78 (2H, m).
Reaction SMILES: Cl[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([CH2:41][OH:42])[S:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:42][CH2:41][C:38]1[S:39][CH:40]=[C:36]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:8])[CH:37]=1
Reactant: CC1(C)OB(c2csc(CO)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2csc(CO)c2)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1, 50 mg, 0.124 mmol), (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methanol (45 mg, 0.187 mmol), 2 M Na2CO3 (0.124 mL, 0.249 mmol) and DME (2.5 mL) were added to a MW vial, which was sealed and evacuated/purged with argon. PdCl2(dppf)-(CH2Cl2) was added (10 mg, 0.012 mmol) and the mixture was stirred at 140° C. for 30 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 5) tR 1.55 min, m/z=479.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CC(C)=O>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:21]
Reactant: COc1cccc(S)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(CSc1cccc(OC)c1)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-methoxybenzenethiol (15.0 mL, 120 mmol) and potassium carbonate (16.6 gm, 120 mmol) in 150 mL of acetone at room temperature was added dropwise 2-bromo-1,1-diethoxy-ethane (16.5 mL, 110 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solids in the reaction mixture were removed by filtration and were washed well with acetone. The filtrate was concentrated. The residue was diluted with water and extracted several times with ether. The ether layers were combined and washed with 0.5 M KOH, water, brine, and were then dried over anhydrous sodium sulfate, filtered, and concentrated to yield 28.2 gm of the title compound.
Reaction SMILES: [N:1]([C:4]1([CH3:11])[CH:9]([OH:10])[CH2:8][CH:7]=[CH:6][CH2:5]1)=[N+:2]=[N-:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH3-]C#N.[Na+]>CO.C(Cl)Cl.CO>[N:1]([C:4]1([CH3:11])[CH2:5][CH2:6][N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:8][CH:9]1[OH:10])=[N+:2]=[N-:3]
Reactant: CC1(N=[N+]=[N-])CC=CCC1O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1(N=[N+]=[N-])CCN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A solution of 6-azido-6-methylcyclohex-3-enol (3.9 g, 25 mmol) in MeOH/DCM (100 mL/20 mL) cooled to −78° C. was degassed by bubbling nitrogen through it for 5 min. Ozone was then bubbled through the reaction mixture until a greyish-blue colour persisted. Nitrogen was again bubbled through the cold reaction mixture until only a pale colour persisted. A solution of benzylamine (2.7 g, 25 mmol) dissolved in MeOH (5 mL) was added followed by NaCNBH3 (6.4 g, 101.5 mmol) in MeOH (10 mL). The mixture was allowed to warm to room temperature and stirred for 16 hr. The solvents were removed under reduced pressure and the residue partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was further extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (40 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (1-10% 7 M NH3 in MeOH/DCM) gave 5-azido-1-benzyl-5-methylazepan-4-ol as a viscous yellow oil (4.8 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.25-7.34 (m, 5H), 3.69-3.62 (m, 2H), 3.51-3.47 (m, 2H), 2.96-2.89 (m, 1H), 2.69-2.62 (m, 3H), 2.19-2.11 (m, 1H), 1.99-1.85 (m, 1H), 1.78-1.68 (m, 1H), 1.61-1.57 (m, 1H), 1.43 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[N:7][C:6]=1[C:14]([O:16]C)=[O:15])=[O:4].[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[H-].[Na+].Cl>CN(C=O)C.CO>[CH2:10]([C:8]1[N:7]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([I:18])=[CH:20][CH:21]=2)[C:6]([C:14]([OH:16])=[O:15])=[C:5]([C:3]([OH:2])=[O:4])[N:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: BrCc1ccc(I)cc1
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nc(C(=O)O)c(C(=O)O)n1Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Dimethyl 2-butylimidazol-4,5-dicarboxylic acid (7.12 g, 29.6 mmol) and 4-iodobenzyl bromide (10.56 g, 35.5 mmol) were dissolved in DMF (50 ml), and 60% oily sodium hydride (1.3 g, 32.5 mmol) was added in small portions while stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours and methanol was added to treat excess sodium hydride. Then the reaction solution was neutralized with 2N HCl and the product was extracted with dichloromethane. The extracted solution was dried over sodium sulfate and concentrated in reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the titled compound (11.1 g, 82%) as a tan solid (mp:98-99° C., Rf:0.60 silica gel-ethyl acetate/hexane/=1/1). This has the following NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20]
Reactant: CC1(C)CC(n2ncc(Cl)c(Cl)c2=O)CC(C)(C)C1
Reactant: CN(C)CCN
Product: CN(C)CCNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Cl

Procedure:
4-Chloro-5-(2-dimethylaminoethyl)amino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one was prepared from 4,5-Dichloro-2-(3,3,5,5-tetramethyl cyclohexyl)pyridazin-3-one in a similar manner using 2-Dimethylaminoethyl amine (4 equivalents). 1H NMR (300 MHz CDCl3) 7.60 (s, 1H), 5.44 (m, 1H), 5.33 (m, 1H), 3.33 (m, 2H), 2.59 (m, 2H), 2.29 (s, 6H), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).