Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[C:19]3[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])=[N:4][N:3]=1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[C:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][C:19]2[C:9]([CH2:8][S:7][C:5]3[S:6][C:2]([NH:1][CH2:31][CH:28]4[CH2:30][CH2:29]4)=[N:3][N:4]=3)=[C:10]([Cl:27])[CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15]1)=[O:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: O=CC1CC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(N)s3)c2CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(NCC4CC4)s3)c2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 6-(5-amino-[1,3,4]thiadiazol-2-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.252 g, 0.59 mmol) in anhydrous DCE (1 mL), add a solution of cyclopropane carboxaldehyde (0.083 g, 1.2 mmol) in anhydrous DCE (1 mL) at room temperature. Add sodium tris(acetoxy)borohydride (0.38 g, 1.8 mmol) and a solution of glacial acetic acid (0.20 mL, 3.5 mmol) in anhydrous DCE (1 mL) to the reaction mixture at room temperature. Heat at reflux overnight, cool the reaction mixture to room temperature and add saturated aqueous NaHCO3 (25 mL) to the mixture. After stirring at room temperature for 1 h, extract the two-phase mixture with DCM (2×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 hexane/EtOAc over 33 min; 95:5 to 50:50 hexane/EtOAc over 33 min; 50:50 to 0:100 hexane/EtOAc over 30 min; 35 mL/min) to afford the desired intermediate (0.087 g, 31%). MS (ES+) m/z: 481.2 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]#[CH:21])[CH:19]=1)[C:15]#[N:16].N>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:21]=2)[CH:19]=1)[C:15]#[N:16]
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1cc(Cl)cc(C#N)c1
Agent: N
Product: N#Cc1cc(Cl)cc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and the product of Example 66A (82 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ7.66 (s, 1H), 7.97 (t, J=1.6 Hz, 1H), 8.30 (d, J=1.6 Hz, 2H), 8.71 (d, J=2.4 Hz, 1H), 8.77 (dd, J=2.8, 1.6 Hz, 1H), 9.31 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 283 (M+H)+, 285 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:47][CH2:48][CH2:49][CH3:50])[C:6]([C:8]1[N:9]=[C:10]([C:19]2[CH:34]=[CH:33][C:22]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])=[CH:21][C:20]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[N:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:47]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:19]2[CH:34]=[CH:33][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[N:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)=[O:7])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCN(CCCC)C(=O)c1cn(CC(=O)OCC)c(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: [Pd]
Solvent: CO
Product: CCCCN(CCCC)C(=O)c1cn(CC(=O)OCC)c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of benzyl 4-(4-(dibutylcarbamoyl)-1-(2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (250 mg, 0.36 mmol) in MeOH (5.0 mL) was added Pd/C (10%). The resulting reaction mixture was stirred under H2 atmosphere for 2 h. The reaction mixture was filtered through a small pad of CELITE®, washed thoroughly with MeOH and concentrated in vacuo to provide the title compound (190 mg, 88%). 1H NMR (DMSO-d6, 1:1 mixture of amide rotamers) δ 13.4 (br s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.94 (d, J=9.6 Hz, 1H), 7.71 (s, 0.5H), 7.65 (s, 0.5H), 7.50 (t, J=8.6 Hz, 1H), 7.19-7.08 (m, 3.5H), 6.95 (d, J=7.6 Hz, 0.5H), 4.93 (br s, 2H), 4.63 (br s, 1H), 4.40-4.30 (br s, 1H), 4.15 (q, J=14.0, 6.8 Hz, 2H), 3.68 (br s, 2H), 3.46-3.42 (m, 2H), 3.30-3.20 (m, 2H), 2.74-2.62 (m, 2H), 1.44-1.27 (m, 4H), 1.22-1.20 (m, 3H), 1.19-1.16 (m, 4H), 0.95-0.72 (m, 6H); MS(ESI+) m/z 589.6 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[C:16]2=[CH:17][NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:14]([C:15]=32)[C:13](=[O:23])[NH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:26](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.ClCCl>[CH2:1]([N:8]([CH2:9][CH:10]1[C:16]2=[CH:17][NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:14]([C:15]=32)[C:13](=[O:23])[NH:12][CH2:11]1)[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NCC(CNCc2ccccc2)c2c[nH]c3cccc1c23
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CI
Product: CN(Cc1ccccc1)CC1CNC(=O)c2cccc3[nH]cc1c23
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
6.2 g of 3-benzylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole (see Example 2 for preparation) were dissolved in 250 ml of dimethylformamide. 0.81 ml of methyl iodide and 1.81 g of potassium carbonate were added to the stirred solution at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Subsequently, to work up, the dimethylformamide was stripped off under reduced pressure (oil pump vacuum) at 50° C. The remaining oily residue was taken up in a mixture of equal parts of water and dichloromethane, the dichloromethane phase was separated, and the aqueous phase was extracted twice more with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered and evaporated. 3.84 g of oily crude product remained as residue. This was purified by chromatography under moderately elevated pressure (=low pressure chromatography =LPLC under 3 to 6 bar) on silica gel (proprietary product LiChroprep® Si 60) using dichloromethane/methanol 9:1 as eluent. 3.26 g of oily 3-(N-benzyl-N-methylaminomethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH:15]=O)[CH:14]=[C:10]3[C:9](=[O:17])[NH:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.CCO.O.NN>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:10]3[C:9](=[O:17])[NH:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: O=Cc1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)NC2=O
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)NC2=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of 3.43 g. (10.15 mmol) of the end product of Example 15 in 60 ml. of absolute EtOH, was added 12 ml. of hydrazine-hydrate. The reaction was heated to reflux for 17 hours, then cooled and concentrated in vacuo. The residue was taken up in 60 ml. toluene; 1.0 g. potassium t-butoxide added and the mixture heated to reflux for 8 hours, then cooled to room temperature and stirred for 9 hours. The reaction was poured over ice and brine and toluene added. The toluene phase was separated and dried over Na2SO4. The aqueous phase was extracted well with CH2Cl2 and the combined extracts dried over Na2SO4. The dried solutions were combined and concentrated and the crude product recrystallized from THF/hexane to give the desired end product, mp 258°-261°. An analytical sample was prepared by an additional recrystallization from THF/hexane and was obtained as colorless crystals: mp 259°-261°.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:10][C:11]=2[CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)s2)c(CCCCO)o1
Reaction time: 1 h

Procedure:
Ethyl 4-(5-chloro-2-thienyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoate (1.80 g) was dissolved in 20 ml of tetrahydrofuran, to which was added gradually lithium aluminum hydride (210 mg) under ice-cooling. The resulting mixture was stirred for 1 hour. Water (0.5 ml) was carefully added to the reaction mixture, the resulting mixture was filtered, and the residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 4-(5-chloro-2-thienyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol. Recrystallization from hexane-ethyl acetate gave pale yellow prisms (497 mg, 31%). Melting point 77-79° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:9]1([C:17](O)=[O:18])[CH2:15][CH:14]2[O:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:40])=O.CN(C)C=O>ClCCl>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][N:8]([C:9]1([C:17]([Cl:40])=[O:18])[CH2:15][CH:14]2[O:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1)[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH3:2]
Reactant: CCOC(=O)CCN(C1(C(=O)O)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C1(C(=O)Cl)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of (15.1 mmol) of the product from Step E in 73 mL of dichloromethane is treated with 1.4 mL (17 mmol, 1.1 equivalents) of oxalyl chloride and 0.02 mL (0.3 mmol, 0.02 equivalents) of dimethylformamide at ambient temperature, causing some bubbling, and is stirred overnight. The resulting solution of the title compound is used in the next step without isolation.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:16][NH:17][CH3:18])=[CH:4][CH:3]=1.CN1C2C(=CC=CC=2)C=C1CNC.[CH3:34][C@@H:35]1[C:41](=[O:42])[N:40]([CH3:43])[CH2:39][C:38]2[CH:44]=[C:45]([C:48]([OH:50])=O)[CH:46]=[CH:47][C:37]=2[NH:36]1.C(C[C@@H]1C(=O)N(C)CC2C=C(C(O)=O)C=CC=2N1)(OC)=O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:16][N:17]([CH3:18])[C:48]([C:45]2[CH:46]=[CH:47][C:37]3[NH:36][C@H:35]([CH3:34])[C:41](=[O:42])[N:40]([CH3:43])[CH2:39][C:38]=3[CH:44]=2)=[O:50])=[CH:19][CH:20]=1
Reactant: C[C@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Reactant: CNCc1cc2ccccc2n1Cc1ccc(O)cc1
Agent: CNCc1cc2ccccc2n1C
Agent: COC(=O)C[C@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Product: C[C@H]1Nc2ccc(C(=O)N(C)Cc3cc4ccccc4n3Cc3ccc(O)cc3)cc2CN(C)C1=O
Yield: 89.2 %

Procedure:
According to the procedure of Example 1 (a), except substituting 1-(4-hydroxybenzyl)-2-(methylaminomethyl)indole (0.40 g, 1.50 mmole) for the 1-methyl-2-(methylaminomethyl)indole, and substituting (2R)-2,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid (0.32 g, 1.37 mmole) for the (2R)-2-[(carbomethoxy)methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid, the title compound (0.59 g, 90%) was prepared as an off-white solid: MS (ES) m/e 483 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:5]1[CH2:4][CH2:3][CH2:2][N:7]2[C:8](=[O:11])[S:9][CH2:10][C:6]=12
Reactant: O=C1N=C(NCCCO)CS1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1SCC2=NCCCN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 4-[(3-hydroxypropyl)amino]-1,3-thiazol-2(5H)-one (1.36 g) and triphenylphosphine (2.66 g) in THF (15 mL) was added 1.9M diisopropyl azodicarboxylate toluene solution (5.34 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (872 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH:15]([NH2:19])([CH2:17][CH3:18])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:15]([N:19]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)([CH2:17][CH3:18])[CH3:16]
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Reactant: CCC(C)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC(C)N1CCc2c(C)nc3ncnn3c21

Procedure:
A mixture of 2.3g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 1g of sec-butylamine, 1.8g of sodium carbonate and 20 ml of ethanol was refluxed for 2 hours. The hot reaction mixture was then filtered and the filtrate was concentrated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Br:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: SCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Brc1ccc(CSCc2ccc(Br)cc2)cc1
Yield: 91 %

Procedure:
To a solution of 1.85 g (9.11 mmol) of 4-bromobenzylmercaptan in dry dichloromethane (30 ml) were added 2.72 g (10.9 mmol) of 4-bromobenzyl bromide and 2.31 g (22.8 mmol) of triethylamine in an atmosphere of argon, and the mixture was allowed to react at room temperature for 16 hours. To the solution was added water followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with ethyl acetate-hexane (1:4) yielded 3.08 g (8.29 mmol) of bis(4-bromobenzyl)sulfide.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)NCCCNc1ccccn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=S)NCCCNc1ccccn1

Procedure:
A mixture of 2-(3-aminopropylamino)pyridine (6 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) is heated under reflux for one hour and concentrated to give N-benzoyl-N'-[3-(2-pyridylamino)propyl]thiourea. The benzoyl thiourea is added to a solution of potassium carbonate (1.4 g.) in water (80 ml.) at 60°. The solution is maintained at this temperature for 1 hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid is removed by filtration and the filtrate is basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohol and concentration, the title product is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:17])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])O)[CH:2]=1.[BH4-].[Na+].Cl.C(O)C[OH:23]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])([OH:23])[CH2:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[CH:2]=1
Reactant: O=C(c1cccnc1)C(O)c1ccccc1Br
Reactant: OCCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(O)(Cc1ccccc1Br)c1cccnc1

Procedure:
20 g (0.068 mol) of 1-(pyrid-3-yl)-2-(2-bromophenyl)-2-hydroxyethanone in 300 ml of methanol were reduced with 3 g (0.079 mol) of sodium borohydride at 0° C. Stirring was carried out for a few hours at room temperature (21° C.), the pH was brought to 2 with 4N hydrochloric acid and 4 ml of ethylene glycol were added. The solution was evaporated down, after which the residue was covered with a layer of ethyl acetate and neutralized with NaHCO3 solution. The ethyl acetate phase was washed twice with water and dried over Na2SO4. After the ethyl acetate had been distilled off, the product was obtained as a white powder of melting point 115° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:26]([C:27](=[O:29])[NH2:28])=[C:25](Cl)[N:24]=[C:23]([S:31][CH3:32])[N:22]=3)=[CH:16][C:15]=2[CH3:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:35][NH2:36]>O1CCOCC1>[C:27]([C:26]1[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[C:15]([CH3:33])[CH:16]=2)=[N:22][C:23]([S:31][CH3:32])=[N:24][C:25]=1[NH:35][NH2:36])(=[O:29])[NH2:28]
Reactant: NN
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)n1
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of the product of Example 17C (246 mg, 0.5 mmol) in 1,4-dioxane (10 mL) was added 85% hydrazine hydrate (125 mg, 2.5 mmol) dropwise. The mixture was stirred at room temperature for 3 hours, extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The residue was washed with petroleum ether to provide the title compound. MS: 489 (M+H+).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Na].[C:15]([C:19]1[CH:27]=[CH:26][C:22]([CH:23](Cl)[CH3:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH:23]([CH3:24])[C:22]2[CH:26]=[CH:27][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cl)c1ccc(C(C)(C)C)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(Sc1cnn(C(C)(C)C)c(=O)c1Cl)c1ccc(C(C)(C)C)cc1
Yield: 72.7 %

Procedure:
By conducting a procedure similar to that in Synthesis Example 3 except using 1.5 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, 10 ml of N,N-dimethylformamide, 1.0 g of anhydrous sodium carbonte and 1.4 g of 4-tert.-butyl-α-methylbenzyl chloride, there were obtained white needle-like crystals having the following physical properties (yield: 72.7%):
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH3:18])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH3:4].[CH2:19]([Zn]CC)C.ICI>C(Cl)Cl>[CH3:4][CH:3]1[CH2:19][CH:2]1[CH2:1][N:5]([CH2:16][CH2:17][CH3:18])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC[Zn]CC
Reactant: C/C=C/CN(CCC)C(=O)OCc1ccccc1
Solvent: ICI
Solvent: ClCCl
Product: CCCN(CC1CC1C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Cbz Protection A solution of propylamine (9.0 g, 152.4 mmol) and triethylamine (15.4 g, 152.4 mmol) in methylene chloride (350 mL) was cooled to 0° C. and treated with benzyl chloroformate (20.0 g, 117.2 mmol). Upon stirring at 0° C. for 1 hour the reaction was warmed to ambient temperature and quenched with 1N HCl. The reaction was partitioned between 1N HCl and methylene chloride. The organics were washed with 1N HCl, water and brine. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give benzyl propylcarbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 5.10 (s, 2H), 4.77 (bs, 1H), 3.16 (q, J=6.5 Hz, 2H), 1.52 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). Step B: Alkylation A solution of benzyl propylcarbamate (20.8 g, 107.9 mmol) in DMF (200 mL) was cooled to 0° C. and treated with sodium hydride (4.6 g, 194.2 mmol). The reaction was stirred to 0° C. for 15 minutes and subsequently treated with crotyl bromide (17.5 g, 129.5 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ether. The organics were washed with water (4×) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (silica, 0-10% EtOAc/hexanes) gave benzyl (2E)-but-2-enyl(propyl)carbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.57 (bt, 1H), 5.42 (bs, 1H), 5.13 (s, 2H), 3.82 (bm, 2H), 3.19 (bs, 2H), 1.68 (bs, 3H), 1.54 (bs, 2H), 0.87 (bs, 3H). Step C: Cyclopropanation A solution of benzyl (2E)-but-2-enyl(propyl)carbamate (5.0 g, 20.2 mmol) in methylene chloride (120 mL) was cooled to 0° C. and treated with diethylzinc (12.48 g, 101 mmol) followed by diiodomethane (54.1 g, 202 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (10% EtOAc/hexanes) gave 5.16 g (96%) of benzyl (2-methylcyclopropyl)methyl(propyl)carbamate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 3.16 (bm, 4H), 1.59 (bm, 2H), 1.01 (bs, 3H), 0.88 (bs, 3H), 0.68 (bs, 2H), 0.34 (bd, 1H), 0.22 (bs, 2H). Step D: Hydrogenation
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].O>CS(C)=O>[F:20][C:21]1[CH:28]=[C:27]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Reaction time: 8 h
Yield: 48.7 %

Procedure:
9.17 g (49.3 mmol) of tert-butyl piperazine-1-carboxylate and then 6.81 g (49.3 mmol) of potassium carbonate, respectively, are added to 7 g (49.3 mmol) of 2,4-difluorobenzaldehyde diluted in 60 ml of dimethylsulfoxide. The solution is carried at 60° C. for 8 hours and then water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The residue obtained is purified by silica gel chromatography (eluent: 7:3 cyclohexane/ethyl acetate) to yield 7.4 g (48%) of tert-butyl 4-(3-fluoro-4-formylphenyl)piperazine-1-carboxylate in the form of a white solid.