Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:32][CH:33]=2)=[O:28])=[CH:21][CH:20]=1>CS(C)=O>[N:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([C:34]([NH:36][N:37]=[C:15]([C:11]3[C:10]([OH:18])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:13]([CH3:14])[N:12]=3)[CH3:16])=[O:35])=[CH:32][CH:33]=2)=[O:28])=[CH:23][CH:24]=1
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 10.5 h
Yield: 52.6 %

Procedure:
1-[5-(3,4-Dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (40 mg, 0.14 mmol) in dimethyl sulfoxide (1.0 mL) was mixed with 5-hydrazinocarbonylthiophene-2-carboxylic acid 4-picolylamide (39 mg, 0.14 mmol) prepared in Reference Synthetic Example 4 and left at 100° C. for 10.5 hours. The solvent was evaporated, and the residue was dissolved in chloroform (1.0 mL). After addition of n-hexane (2.0 mL), the resulting crystals were recovered by filtration to give 40 mg of the desired product (yield 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[O:26]>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[NH:24][C:25]([NH:15][C:13]1[CH:14]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:10]=[CH:11][N:12]=1)=[O:26]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1cc(Nc2ccc(F)cc2)ncn1
Solvent: C1COCCO1
Product: O=C(Nc1cc(Nc2ccc(F)cc2)ncn1)Nc1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A suspension of N-(4-fluoro-phenyl)-pyrimidine-4,6-diamine (408.4 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 14 h at 80° C. After cooling to 5° C. the suspension is filtered, the residue washed with half-saturated K2CO3 solution, H2O and acetone and dried in vacuo.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.[C:11]([O:15][C:16]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][C@@H:20]1[NH2:26])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:30]([O:29][C:27]([N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[C@@H:19]1[CH2:24][CH2:23][CH:22]([NH:2][C:3]2([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]2)[CH2:21][C@@H:20]1[NH2:26])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C1(N)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CCC(=O)C[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)C1(NC2CC[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](N)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.63 g) was dissolved in dichloromethane (60 ml), and (1R*,2S*)-N,N-bis(tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine (3.0 g) and sodium triacetoxy-borohydride (2.51 g) were added to stir the mixture at room temperature for 3 hours. An aqueous solution of sodium hydrogencarbonate was added to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1→1:1) to obtain the title compounds (Stereoisomer A: 1.43 g and Stereoisomer B: 2.17 g) as colorless amorphous solids.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[CH2:16][CH2:15][CH2:14]4)[C:6]=2[N:7]=1.[CH2:20]([N:22]([CH2:35][CH3:36])[CH2:23][CH2:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)[CH3:21].FC(F)(F)C([O-])=O>CS(C)=O>[CH2:35]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:2]2[N:3]=[CH:4][C:5]3[N:10]=[N:9][N:8]([C:11]4[CH:12]=[C:13]5[C:17](=[CH:18][CH:19]=4)[CH2:16][CH2:15][CH2:14]5)[C:6]=3[N:7]=2)=[CH:31][CH:32]=1)[CH3:36]
Reactant: Clc1ncc2nnn(-c3ccc4c(c3)CCC4)c2n1
Reactant: CCN(CC)CCOC(=O)c1ccc(N)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Product: CCN(CC)CCOC(=O)c1ccc(Nc2ncc3nnn(-c4ccc5c(c4)CCC5)c3n2)cc1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of (3) (40 mg, 0.15 mmol) in DMSO (1.6 mL) was added 2-(diethylamino)ethyl-4-aminobenzoate (38 mg, 0.16 mmol). The mixture was irradiated at 140° C. for 10 min. After cooling to room temperature, the mixture was purified by reverse-phase chromatography to furnish the desired product (4) (32.2 mg, 0.046 mmol) as a trifluoroacetate salt. MS calcd. for C26H30N7O2 m/z calcd 472.24 (M+H),+ found 472.24.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:3])([CH3:4])[CH3:1])=[O:7])=[O:19]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)NCc1cccc(Cl)c1

Procedure:
N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Bachem) was coupled with 3-chlorobenzylamine using standard peptide coupling procedures to give the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][CH:23]1[CH2:28][N:27]([CH2:20][CH2:19][CH2:18][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:26][CH2:25][N:24]1[C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2C)c1

Procedure:
107 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (110 mg, 0.398 mmol), 2-methyl-1-m-tolylpiperazine (69 mg, 0.362 mmol), DIPEA (0.063 mL, 0.362 mmol) and NaBH(OAc)3 (269 mg, 1.267 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H+].[B-](F)(F)(F)F.[Si](C=[N+]=[N-])(C)(C)[CH3:26].O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH2:16][O:17][CH3:26])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(CO)CCCC1)OCc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COCC1(NC(=O)OCc2ccccc2)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold solution (0° C.) of (1-hydroxymethyl-cyclopentyl)-carbamic acid benzyl ester (250 mg, 1 mmol) and 48% aqueous HBF4 (0.13 ml, 1 mmol) in CH2Cl2 (4 mL) was added TMSCHN2 (2N in hexane, 2 mL, 4 mmol) via syringe. The resulting mixture was stirred, at 0° C., for ½ hour followed by the addition of water (10 mL). The aqueous mixture was extracted with CH2Cl2 (2×50 mL), and the combined organic layers were dried (sodium sulfate), filtered, concentrated and chromatographed with 30% ethyl acetate/hexane to provide the titled compound. MS (DCI) m/e 264 (M+H)+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])/[C:5]([NH:7][CH3:8])=[O:6].C1C(=O)N([Br:23])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1/[C:4](=[N:3]\[O:2][CH3:1])/[C:5]([NH:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)/C(=N/OC)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)/C(=N/OC)c1ccccc1CBr
Yield: 37.9 %

Procedure:
To (E)-2-methoxyimino-2-(2-methylphenyl)-N-methylacetamide (2.66 g, 0.01 mol), added were carbon tetrachloride (20 ml), NBS (1.96 g, 0.011 mol) and α,α'-azobis(isobutyronitrile) (0.16 g, 0.001 mol), and the reaction mixture was heated under reflux for 1 hour. After completion of the reaction, undissolved materials were removed and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/toluene) to give (E)-2-(2-bromomethylphenyl)-2-methoxyimino-N-methylacetamide (1.08 g; yield, 37.7%) as an oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[C:30]2[CH2:29][CH2:28][C@H:27]3[C@H:22]([CH2:23][CH2:24][CH2:25][NH:26]3)[C:21]=2[CH:20]=[CH:19][CH:18]=1.[C:31]1([C:37]2[CH:50]=[CH:49][C:40]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH:47]=O)=[O:42])=[CH:39][CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>ClC(Cl)C.C(OCC)(=O)C.CCCCC>[CH3:15][O:16][C:17]1[C:30]2[CH2:29][CH2:28][C@H:27]3[C@H:22]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:41](=[O:42])[C:40]3[CH:49]=[CH:50][C:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:38][CH:39]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc2c1CC[C@@H]1NCCC[C@H]21
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCCN1CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 12 h
Yield: 59.8 %

Procedure:
Sodium triacetoxyborohydride (1.5 g, 6.9 mmol) was added to a stirred mixture of cis-7-methoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (D6b, 1.0 g, 4.6 mmol) and 4-(4-phenylbenzoylamino)butyraldehyde (1.4 g, 5.1 mmol) in dichloroethane (50 ml) at room temperature. After stirring for 12 h, saturated aqueous K2CO3 (40 ml) was added and the mixture extracted into dichloromethane (3×20 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give a gum. Chromatography on silica, using 50-100% ethyl acetate/pentane as elution gradient, gave the title compound as a white solid (1.29 g, 60%).
Reaction SMILES: [BH4-].[Na+].[C:3]([CH:5]=[CH:6][C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=1)[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:4].Cl.N>C(O)C.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:4][CH2:3][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=[C:18]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=1
Reactant: CCOC(=O)C=Cc1cc(C=CC#N)cc(Cc2cccnc2)c1
Agent: Cl[Co]Cl
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1cc(CCCN)cc(Cc2cccnc2)c1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
Sodium borohydride (2.30 g) was added portionwise with vigorous stirring to a solution of ethyl 3-(2-cyanoethenyl)-5-(3-pyridylmethyl)cinnamate (Preparation 19; 2.0 g) and cobalt(II) chloride hexahydrate (4.48 g) in ethanol (150 ml) at 0° C. The mixture was stirred for 2 hours, carefully acidified to pH 2 with concentrated hydrochloric acid, stirred for a further 10 minutes, basified with concentrated aqueous ammonia solution (SG 0.880) and then filtered. The filtered material was washed with ethyl acetate, the combined filtrate and washings washed with water, and the combined aqueous washings then extracted three times with dichloromethane. The organic extracts were combined, dried (MgSO4) and evaporated under vacuum to give a gum, which was chromatographed on silica gel. The column was eluted with a methanol in dichloromethane elution gradient (1% to 5% methanol), followed by a dichloromethane: methanol:aqueous ammonia (SG 0.880) elution gradient (94:5:1 to 90:9:1). The product fractions were combined and evaporated under vacuum to give the title compound as a gum (0.825 g); Rf 0.25 (SS 2); δ (CDCl3): 1.20(3H,t,J=7.1 Hz), 1.70-1.77(4H,m), 2.54-2.60(4H,m), 2.70(2H,t,J=7.0 Hz), 2.87(2H,t,J=7.8 Hz), 3.90(2H,s), 4.09(2H,q,J=7.1 Hz), 6.83(2H,s), 6.88(1H,s), 7.18-7.22(1H,m), 7.43-7.46(1H,m), 8.43-8.48(2H,m).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[CH:13]=[CH:14][C:15]([F:19])=[C:16]([OH:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@H]1CCCC[C@@H]1NC>C1(C)C=CC=CC=1.CCOC(C)=O.O.[Cu]I>[NH2:10][C:8]1[N:7]([C:12]2[CH:13]=[CH:14][C:15]([F:19])=[C:16]([OH:18])[CH:17]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1
Reactant: Oc1cc(Br)ccc1F
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2ccc(F)c(O)c2)n1
Temperature: 150 °C
Yield: 69.6 %

Procedure:
To a solution of 3-(tert-butyl)-1H-pyrazol-5-amine (1.00 g, 7.20 mmol) in toluene (13 mL) was added 5-bromo-2-fluorophenol (1.51 g, 7.90 mmol), potassium carbonate (2.08 g, 15.1 mmol), (1S,2S)—N,N′-bis-methyl-1,2-cyclohexane-diamine (0.20 g, 1.40 mmol) then copper (I) iodide (0.07 g, 0.36 mmol). The mixture was degassed then heated at 150° C. for 1 h using microwave irradiation. Another portion of copper (I) iodide (0.07 g, 0.36 mmol) was added and the reaction mixture heated at 150° C. for a further 1 h using microwave irradiation. The mixture was diluted with EtOAc and water and the phases separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give an impure solid. The residue was partitioned between DCM and water and the phases separated. The organic layer was evaporated in vacuo and the residue was purified by FCC, using 0-5% MeOH in DCM. Further purification by FCC, using 0-25% EtOAc in DCM, gave the title compound as an orange gum (1.25 g, 70%). LCMS (Method 3): Rt 2.33 min, m/z 250.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>S(=O)(=O)(O)O.O>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1cccc(Cl)c1
Reaction time: 18 h

Procedure:
Concentrated sulphuric acid (5 drops) was added cautiously to a stirred mixture of 3-chlorophenol (74 g) and acetic anhydride (64.6 g) at ambient temperature. The mixture was left to stand for 18 hours and then added to water (300 ml). The mixture was extracted with dichloromethane and the combined extracts washed with sodium bicarbonate solution, dried and evaporated under reduced pressure. The oil obtained was distilled under vacuum to give 3-chlorophenyl acetate b.p. 116°-118° C. (2 mmHg).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[C:19]([O:23][C:24](=[O:33])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[C:19]([O:23][C:24](=[O:33])[NH:25][CH:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:2]2[C:3]3[N:4]([C:8]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)=[CH:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:30][CH2:31]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CSc1nccc(-c2cnc3c(Cl)nccn23)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Temperature: 95 °C
Reaction time: 15 h

Procedure:
To a solution of 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (from Example 44 supra) (0.9 g, 3.24 mmol) in DMF (25 mL) was added trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.04 g, 4.86 mmol) followed by diisopropylethylamine (0.63 g, 4.86 mmol). The reaction mixture was stirred at 95° C. for 15 hours and the mixture was poured into water. The precipitate formed was filtered, and. the obtained solid was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1) to afford {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 1.23 g, 83.4%). LC-MS: [M+H]+ 456.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:23][CH3:24])[C:9]=3[C:8]2=[O:25])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N+:12]([O-:36])[CH:11]=[C:10]([O:23][CH3:24])[C:9]=3[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cnc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Solvent: ClCCl
Solvent: CCO
Product: COc1c[n+]([O-])c(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of N-[6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide (0.35 g, 0.89 mmol) in CH2Cl2 (10 mL) was added mCPBA (1.08 g, 6.23 mmol) in portions. After stirring for 3.5 hours at reflux, the product mixture was cooled to room temperature, 1 mL of ethanol was added, and the solution was concentrated. The residue was partitioned between CHCl3 and saturated Na2SO3. The organic layer was extracted repeatedly with saturated sodium bicarbonate. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the crude title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cn1ccnc1S
Product: Cn1ccnc1SC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 2-mercapto-1-methylimidazole (0.68 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (1.04 g, 70%).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:17])[C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:14][OH:15])[CH:13]=1)([CH3:4])[CH3:3].[OH:18][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20]>C(O)C.C(OCC)(=O)C>[CH3:4][C:2]([NH:5][CH2:6][CH:7]([OH:17])[C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:14][OH:15])[CH:13]=1)([CH3:1])[CH3:3].[O-:20][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:18]
Reactant: CCCCCCCCCC(=O)O
Agent: CC(C)(C)NCC(O)c1ccc(O)c(CO)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCCCC(=O)[O-]
Reaction time: 36 h

Procedure:
Salbutamol base (13.91 g; 58.13 mmol) was dissolved in ethanol (600 mL, 96%) with magnetic stirring to give a pale yellow liquid. Capric acid (10.01 g; 58.11 mmol) was added with vigorous stirring which was continued until all solid material had dissolved. The solvent was removed by rotary-evaporation to give a pale yellow tacky semi-solid. This was dissolved in warm ethyl acetate (300 mL), then stored at 5° C. for 36 hours, resulting in the precipitation of a fine white solid. The mother liquor was removed by vacuum filtration, and the precipitate washed with cold ethyl acetate. Any remaining solvent was removed by storing the precipitate at 35° C. and 0 bar pressure for 6 hours. Salbutamol caprate was obtained as a white solid (18.93 g; 79.13%). Moisture content K.F. 0.32%; melting point 99.4° C. (onset of endotherm in DCS thermogram). The theoretical percentage of salbutamol base in salbutamol caprate is 58.14%. Experimentally the percentage salbutamol base in salbutamol caprate was found to be 56.42%. The pH of a saturated aqueous solution is 7.24. The aqueous solubility is 4.76 mg/mL.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([N:7]([CH3:9])[CH3:8])=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:3][CH:4]([CH:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)[CH2:5][N:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(C(=O)N(C)C)C1c2ccccc2CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(CN(C)C)C1c2ccccc2CCc2ccccc21
Temperature: 60 °C
Yield: 80.6 %

Procedure:
Dissolved 2-ethoxy-2-[10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]-N,N-dimethyl-acetamide (4.45 g, 13.8 mmol) in 100 mL of dry tetrahydrofuran, and added lithium aluminum hydride (0.6 g, 15.8 mmol) portionwise under a nitrogen atmosphere. Heated the reaction mixture at 60° C. for 2 hours. Cooled to 0° C., and carefully added 0.6 mL of water, 0.6 mL of 15 weight % NaOH, and then 1.8 mL of water in order to precipitate aluminum salts. Filtered precipitate, and washed with tetrahydrofuran. Evaporated filtrate, and purified the crude product by flash chromatography on silica gel eluting with 1:1 ethyl acetate:hexane. Combined appropriate fractions, and evaporated to give 3.44 g (81% yield) of β-ethoxy-10,11-dihydro-N, N-dimethyl-5 H-dibenzo[a,d]cycloheptene-5-ethanamine as a colorless oil. Dissolved free base in ethyl acetate, and added one equivalent of maleic acid dissolved in methanol. Evaporated, and added ether to precipitate maleate salt.
Reaction SMILES: [OH:1][CH2:2][C:3]([OH:5])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH:28]12[NH:35][CH:32]([CH2:33][CH2:34]1)[CH2:31][CH:30]([NH:36][C:37]1[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[CH:40]3)[CH2:29]2.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:42]1[C:43]2[C:39](=[CH:38][C:37]([NH:36][CH:30]3[CH2:31][CH:32]4[N:35]([C:3](=[O:5])[CH2:2][OH:1])[CH:28]([CH2:34][CH2:33]4)[CH2:29]3)=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC(C1)N2
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(CO)N1C2CCC1CC(Nc1ccc3[nH]ncc3c1)C2
Temperature: 25 °C
Reaction time: 23 h
Yield: 10.5 %

Procedure:
Hydroxyacetic acid (32 mg, 0.421 mmol), 1-hydroxybenzotriazole (76 mg, 0.496 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (95 mg, 0.496 mmol) were added in that order to a suspension of the N-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (100 mg, 0.413 mmol) obtained in Example 525 in dimethylformamide (1 ml), and the resulting mixture was stirred at room temperature for 23 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution to terminate the reaction, and was extracted twice with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was purified by a preparative thin-layer chromatography (200×200×0.5 mm, 4 plates, eluent: chloroform/methanol=15/1) to obtain 2-[3-(1H-indazol-5-ylamino)-8-azabicyclo[3.2.1]oct-8-yl]-2-oxoethanol (13 mg, 11%).