Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[F:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:35][NH2:36]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[F:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:35][NH2:36])(=[O:3])[NH2:2]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 28C (497 mg, 1 mmol) in 1,4-dioxane (10 mL) was added hydrazine hydrate (0.3 mL). After stirring at ambient temperature for about 4 hours, the mixture was concentrated. The residue was washed with hexane and dried under vacuum to give the title compound, which was used in the next step without further purification. MS: 493 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccn(CCCO)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 51 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (99 mg, 74%) as a white foam: [α]30589=−27.3° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C20H25N3O2Cl2 (M+H)+ 410.1397, observed 410.1398; 1H NMR (400 MHz, DMSO-d6) δ 1.10 (m, 2H, CH2), 1.35-1.78 (m, 8H, 4×CH2), 1.85 (m, 2H, CH2), 2.04 (m, 1H, CH), 3.34 (t, J=6.4 Hz, 2H, OCH2), 3.79 (m, 1H, ArCHCO), 4.02 (t, J=6.8 Hz, 2H, NCH2), 4.56 (br, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.35 (dd, Jm=2.0 Hz, Jo=8.4 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.59 (d, Jo=8.4 Hz, 1H, Ar), 7.59 (s, 1H, Ar), 10.71 (s, 1H, NH).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8].[C:16]([C:18]1[S:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][C:22]=1[OH:23])#[N:17]>C(#N)C>[C:16]([C:18]1[S:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][C:22]=1[O:23][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCCCOc1cc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=O)(OCC)OCC)c(C#N)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
7.7 g of potassium carbonate and 8.6 g of O,O-diethyl chlorophosphate were added to a solution of 11 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 16 hours at room temperature and was then filtered. The filtrate was evaporated to dryness and the residue was taken up in ethyl ether. The ether phase was washed with an aqueous solution of 100 g/l of sodium chloride and then with an aqueous 0.1N sodium hydroxide solution containing 100 g/l of sodium chloride. The solution was dried, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 15.5 g of 2-cyano-3-(diethoxyphosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 = 1.500.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([CH3:21])([CH3:20])[C:13](=[O:19])[NH:14]2>CCCCCC>[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([CH3:21])([CH3:20])[C:13](=[O:19])[NH:14]2
Reactant: COc1cccc2c1C(C)(C)C(=O)N2
Agent: Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC1(C)C(=O)Nc2cccc(O)c21
Temperature: 220 °C
Reaction time: 0.75 h
Yield: 68.9 %

Procedure:
Pyridine hydrochloride (51.10 g, 442.2 mmol) and 4-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (21.61 g, 113.0 mmol) are combined and stirred in a melt at 220° C. for 45 minutes. Heating is removed and when the mixture cooled to 100° C., water (60 mL) is added, followed by ethyl acetate (150 mL) at 65° C. The layers are separated and the aqueous phase is extracted five times with ethyl acetate (50 mL). The combined organic layers are extracted first with a combination of aqueous hydrochloric acid (1N, 10 mL) and a saturated solution of sodium chloride (10 mL), then with a combination of a saturated solution of sodium bicarbonate (10 mL) and a saturated solution of sodium chloride (10 mL). After drying over magnesium sulfate, the solvent is removed via rotary evaporation. The crude material is dissolved in ethyl acetate (200 mL) and hexane (200 mL) at 60° C. Crystallization is allowed to begin slowly over 1 hour at 50° C. After stirring for 12 hours at 24° C., the slurry is cooled to 0° C. for 1 hour, then vacuum filtered washing twice with cold 1:1, ethyl acetate:hexane (35 mL, 0° C.) to provide 13.8 g (98.6% purity, 68% yield) of 4-hydroxy-3,3-dimethyl-1,3-dihydro-indol-2-one, mp 224-225° C. MS (ES+) m/z 178 (M++1). From the filtrate a second crop (5.0 g, 98.4% purity, 25% yield) is obtained to give a total yield of 93%.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([C:20]3[S:19][CH:23]=[CH:22][N:21]=3)[CH:25]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2nccs2)c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 395.12 g/mol.
Reaction SMILES: O[CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]Br>CN(C)C=O>[Br:32][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: BrBr
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
To 1-Hydroxymethyladamantane (366 gm.) and triphenylphosphine (598 gm.) in 1600 ml. dimethylformamide was added a solution of 366 gm. bromine in 800 ml. dimethylformamide over a 5 hour period. The mixtue was left overnight at room temperature and then distilled (under aspirator) to remove solvent and product. The distillate was poured into 8 liters of water and filtered. The solid was dissolved in petroleum ether (30°-60°), washed with K2CO3 solution, then with water, dried, and concentrated to dryness. The residue recrystallized from 2.5 liters methanol gave 426.6 gm., m.p. 43°-4°. (1st crop plus additional crops obtained on concentration of the mother liquors.)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([OH:22])[C:12]1[O:13][C:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][N:16]=1)[CH2:9][CH3:10])(C)(C)C.[ClH:24]>ClCCl.O1CCOCC1>[ClH:24].[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:12]1[O:13][C:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][N:16]=1)[OH:22]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1ncc(-c2cccs2)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC(N)[C@H](O)c1ncc(-c2cccs2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {(S)-1-[hydroxy-(5-thiophen-2-yl-oxazol-2-yl)-methyl]-propyl}-carbamic acid tert-butyl ester (361 mg, 1.07 mmol) in dry dichloromethane (3 mL) is added 4N HCl in dioxane (3.0 mL, XS). The mixture is stirred at room temperature for 16 h, then concentrated in vacuum to afford (S)-2-Amino-1-(5-thiophen-2-yl-oxazol-2-yl)-butan-1-ol hydrochloride as a solid (quant.).
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])([CH2:3][CH3:4])[CH3:2].CN(C)CCN(C)C.[H-].[K+].C(S([C:27]1[O:28][CH:29]=[C:30]([CH3:32])[N:31]=1)=O)CCC>S1(CCCC1)(=O)=O.O>[CH:1]([N:5]([C:27]1[O:28][CH:29]=[C:30]([CH3:32])[N:31]=1)[C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])([CH2:3][CH3:4])[CH3:2]
Reactant: CCCCS(=O)c1nc(C)co1
Reactant: CCC(C)NC(=O)C(C)C
Agent: CN(C)CCN(C)C
Agent: [H-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCC(C)N(C(=O)C(C)C)c1nc(C)co1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
N-s-Butyl-isobutyramide (2.30 g, 0.016 m) and tetramethylethylenediamine (1.87 g, 0.016 m) were stirred at 40° C. in sulpholane (20 ml) under nitrogen during the portionwise addition of a 50% potassium hydride/oil dispersion (1.29 g, 0.016 m). After the addition, the mixture was warmed to 70° C. and 2-n-butylsulphinyl-4-methyloxazole (3.0 g, 0.016 m) in sulpholane (20 ml) was added. The mixture was stirred at 70° C. for 6 hours and then hydrolysed with water. Removal of the solvent in vacuo and column chromatography on silica using diethyl ether gave the title compound, which was a colourless oil after distillation in vacuo, b.p. 82° C./0.8 mm.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].[NH3:36].O>CN(C)C=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([NH2:36])[N:11]=1)=[O:9]
Reactant: N
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(N)ncc1-c1ccccc1
Yield: 65 %

Procedure:
To a solution of 0.3 g (0.58 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 20 ml N,N-dimethylformamide a stream of NH3-Gas was introduced during 10 Min. The reaction mixture was poured onto 100 ml H2O. The aqueous layer was extracted three times with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 140:10:1) to give 0.17 g (65%) 2-amino-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 181.5-182.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[O-:11][C:12]#[N:13].[Na+]>>[CH:6]([C:5]1[NH:13][C:12](=[O:11])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:4]=1)([CH3:9])[CH3:7]
Reactant: COc1ccc(CN)cc1
Reactant: N#C[O-]
Agent: [Na+]
Product: COc1ccc(Cn2cc(C(C)C)[nH]c2=O)cc1

Procedure:
3-Methylbutan-2-one was brominated with bromine in methanol to give 1-bromo-3-methylbutan-2-one which was reacted with 4-methoxybenzylamine and cyclized with sodium cyanate to give 4-isopropyl-1-(4-methoxybenzyl)-1H-imidazol-2(3H)-one.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[CH3:15].[H-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C.O>[Cl:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:7]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=3)[C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:13]=12
Reactant: COC(=O)Cc1c(C)[nH]c2nccc(Cl)c12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CC(=O)O)c2c(Cl)ccnc2n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a cooled (0° C.) stirred solution of (4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.1 g, 0.42 mmol) in dry DMF (2.5 ml) is added sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mmol). After stirring at room temperature for 5 hours, the reaction mixture is re-cooled to 0° C. and treated with 4-methylsulfonylbenzyl bromide (0.105 g, 0.42 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is diluted with water (3 ml) and extracted with ether (3×15 ml). The organic portions are combined, washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting crude residue is loaded on a pre-packed Isolute™ silica column and eluted with iso-hexane:ethyl acetate (1:8) to yield the titled compound as a white powder. (MH+ 407).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1>C(O)C>[C:11]1([C:10]2[C:3]3[C:2]([C:27]4([CH2:30][OH:31])[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1CCNCC1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: OCC1(c2ncnc3scc(-c4ccccc4)c23)CCNCC1
Temperature: 50 °C
Yield: 93.3 %

Procedure:
4-Chloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 4.05 mmol) was dissolved in ethanol (15 ml) to give a yellow solution. To this was added triethylamine (1.7 ml, 12.2 mmol) and 4-piperidinemethanol (0.58 g, 5 mmol). The reaction mixture was heated to 50° C. and stirred for 1.5 hours until no 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine was present by TLC. The reaction mixture was allowed to cool to room temperature before being poured over ice water (50:50 mix). The resultant precipitate was collected by filtration to give the product as a pale yellow solid (1.23 g, yield 90%). LCMS: RT=4.05 min, M+1=326.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)[CH:3]=1.[C@@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:28].CN1CCCC1=O>CO>[NH2:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:29][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)[CH:3]=1
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
A mixture of 6-chloro-4-(5-(methylsulfonyl)pyridin-2-ylamino)pyridazine-3-carboxamide (60 mg, 0.183 mmol), cis-cyclohexane-1,2-diamine (125 mg, 1.1 mmol) and N-methyl-2-pyrrolidinone (2 mL) was heated to 150° C. After 18 h, the reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (spherical silica 20-45 uM, 23 g, Versaflash Supelco, 0 to 5% MeOH containing 10% NH4OH in CH2Cl2, 20 min) gave a solid residue. This residue was dissolved in MeOH and CH2Cl2, then precipitated by addition of cyclohexane. The solid formed was obtained by decantation of the mother liquor, then dried to give 6-(cis-2-aminocyclohexylamino)-4-(5-(methylsulfonyl)pyridin-2-ylamino)pyridazine-3-carboxamide (19 mg, 45.6 μmol, 25%) as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.21 (s, 1H) 8.73 (d, J=2.27 Hz, 1H) 8.48 (br. s., 1H) 8.16 (s, 1H) 8.12 (dd, J=8.69, 2.64 Hz, 1H) 7.75 (br. s., 1H) 7.14 (d, J=8.69 Hz, 1H) 7.03 (d, J=7.93 Hz, 1H) 4.06 (br. s., 1H) 3.26 (s, 3H) 3.09 (br. s., 1H) 1.24-1.78 (m, 10H). LCMS (EI/CI) m/z: 406 [M+H].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH2:8][C@@H:9]([C:11]2[C:12]([CH3:21])=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[O:15][CH2:14]3)[OH:10])[CH2:5]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[N:23].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:2][CH2:3][CH:4]2[CH2:7][N:6]([CH2:8][C@H:9]([OH:10])[C:11]3[C:12]([CH3:21])=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[O:15][CH2:14]4)[CH2:5]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c([C@@H](O)CN2CC(CN)C2)ccc2c1COC2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c([C@@H](O)CN2CC(CNS(=O)(=O)c3ccc(C#N)cc3)C2)ccc2c1COC2=O
Reaction time: 24 h

Procedure:
To a vial containing (R)-5-(2-(3-(aminomethyl)azetidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 12] (0.17 g, 0.54 mmol) was added commercially available 4-cyanobenzene-1-sulfonyl chloride (0.20 g, 1.0 mmol) as a solution in DMF (500 μL) followed by diisopropylethylamine (0.16 g, 1.2 mmol). The vial was shaken for 24 hours, and then was concentrated in vacuo. The resulting residue was dissolved in DMSO (1 mL) and purified by HPLC to provide (R)-4-cyano-N-((1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)azetidin-3-yl)methyl)benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:19]=[N:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23]N(C)C=O.S(OC)(OC)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([N:15]3[CH:19]=[N:18][N:17]([CH3:23])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N2CCN(n3cn[nH]c3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(N2CCN(n3cnn(C)c3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 4.5 parts of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-3H-1,2,4-triazol-3-one, 0.8 parts of sodium hydride dispersion 78% and 27 parts of N,N-dimethylformamide is stirred for one hour at room temperature. Then there are added 2.5 parts of dimethyl sulfate and stirring at room temperature is continued for another hour. Water is added to the reaction mixture and the product is extracted twice with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 3.3 parts (71%) of 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-methyl-3H-1,2,4-triazol-3-one; mp. 178.2° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnn(Cc2ccccc2)c1N
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnn(Cc2ccccc2)c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
To a solution (50 mL) of 1-benzyl-4-methyl-1H-pyrazol-5-amine (5 g) and tetrahydro-4H-pyran-4-one (3.2 g) in acetic acid was added sodium cyanoborohydride (6.8 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.9 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:34][CH3:35])[C:28]=1[O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:34][CH3:35])[C:28]=1[O:29][S:30]([CH3:33])(=[O:31])=[O:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:53][CH2:52][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:56][CH2:55]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OS(C)(=O)=O
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OS(C)(=O)=O)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]=12.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>CN1CCCC1=O.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:30]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCCCCCC2
Reactant: COc1ccc(NN)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2nc3c4c([nH]cc-3c2=O)CCCCCCCC4)cc1

Procedure:
A mixture of 2.00 g of ethyl 4-chloro-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate and 1.12 g of 4-methoxyphenylhydrazine are stirred for eight hours in 20 ml of N-methylpyrrolidinone at 105°. The solution is then diluted with 50 ml of water and twice extracted with ether. The combined ether fractions are extracted twice with 20 ml of 1 N NaOH and the combined alkaline fractions are back-extracted with ether. The alkaline aqueous solution is then treated with an aqueous solution of 2.14 g of ammonium chloride, stirred until a solid forms; the precipitate is filtered off and dried to give 2-(4-methoxyphenyl)-2,3,6,7,8,9,10,11,12,13-decahydrocyclodeca[b]pyrazolo[3,4-d]pyridin-3(5H)-one, m.p. 143°-150°, the compound of example 5/ g.