Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:24][NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)=[O:27].C([O-])(O)=O.[Na+].O[Li].O.Cl>O.CO.O1CCOCC1>[CH3:16][C:12]([N:8]1[C:7](=[O:18])[C:6]2([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]2[C:4]2[N:3]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[CH:34][CH:33]=3)[N:11]=[CH:10][C:9]1=2)([CH3:17])[C:13]([OH:15])=[O:14]
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C(=O)O)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3C(C)(C)C(=O)O)cc1
Temperature: 100 °C

Procedure:
To crude 2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoic acid (79 mg, about 0.233 mmol, as a mixture with its methylester) was added 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.077 g, 0.28 mmol), Pd(dppf)C12-dichloromethane, 1,4-dioxane (3 mL) and NaHCO3 (sat., 1.5 mL). It was heated under an air-filled balloon (1 atm) at 100° C. (bath temperature) for 1.5 hours and then LiOH.H2O (100 mg) was added and heated continued at 80° C. (bath temperature) for 1 hour and 40 minutes The mixture was diluted with water and MeOH, passed through a microfilter. The filtrate was acidified with concentrated HCl (0.1 mL) to pH<7 and then purified on the HPLC (20-20% of AcCN [containing 0.035% TFA] in water [containing 0.05% TFA], Phenomenex Gemini 5 μm C18, 75×30 mm column) to give 2-methyl-2-(6a-methyl-2-(4-(3-methylureido)phenyl)-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)propanoic acid as a clear semisolid (10.2 mg). 1H NMR (400 MHz, METHANOL-d6) δ ppm 1.55 (s, 3H) 1.68 (s, 3H) 1.81 (s, 3H) 2.80 (s, 3H) 3.49 (m, 1H) 3.69 (dd, J=12, 4 Hz, 1H) 3.74 (d, J=12 Hz, 1H) 4.05 (d, J=12 Hz, 1H) 4.15 (dd, J=12, 4 Hz, 1H) 4.48 (d, J=12 Hz, 1H) 7.62 (d, J=8 Hz, 2H) 8.10 (s, 1H) 8.14 (d, J=8 Hz, 2H). MS [M+H] found 455.4.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([C:38](C)(C)[O:39][SiH2]C(C)(C)C)[CH2:37][CH2:36][CH:35]=[CH:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH2:38][OH:39])[CH2:37][CH2:36][CH:35]=[CH:34][CH2:33]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2(C(C)(C)O[SiH2]C(C)(C)C)CC=CCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CC=CCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 92 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 117b (2.6 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[Na+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](C=O)C1
Temperature: 0 °C
Yield: 101 %

Procedure:
A solution of (R)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (50.0 g, 248.4 mmol, 1.0 eq.) in DCM (883 mL) was combined with TEMPO (1.9 g, 12.4 mmol, 0.05 eq.) and sodium bromide (2.6 g, 24.8 mmol, 0.1 eq.). The solution was cooled to 0° C. A solution of sodium hypochlorite (272.1 mL, 1.5 eq.) and sodium bicarbonate (31.2 g, 1.5 eq.) was added. Upon completion of the reaction, the mixture was extracted with DCM (3×200 mL) and dried over Na2SO4, to yield (R)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (50 g).
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:28]=[CH:29][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.03 min, MH+ 521. NMR: δH [2H6]-DMSO 10.12,(1H, s), 9.33,(1H, t), 9.15,(1H, s), 8.78,(1H, b), 8.36-8.32,(2H, m), 7.86,(1H, s), 7.78,(1H, d), 7.69-7.65,(3H, m), 7.31,(2H, m), 7.21,(1H, s), 7.11,(2H, m), 4.51,(2H, d), 2.99,(3H, s), 2.32,(3H, s).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][O:16]1>>[O:1]=[C:2]1[C:10](=[CH:24][C:23]2[NH:22][CH:21]=[C:20]3[C:15](=[O:14])[O:16][CH2:17][CH2:18][C:19]=23)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-carboxylic acid was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([F:19])[C:12]=2[N:11]=1.Br[CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:15]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[CH:17][C:18]=3[F:19])[N:14]2[CH2:28][CH2:27][CH2:26]1
Reactant: CCN(CC)c1ccc(F)c2nc(Nc3ccc(Cl)cc3Cl)[nH]c12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(F)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 35.7 %

Procedure:
A mixture of N2-(2,4-dichlorophenyl)-N7,N7-diethyl-4-fluoro-1H-benzimidazole-2,7-diamine (96.7 mg, 0.263 mmol), 1,3-dibromopropane (72.6 mg, 0.360 mmol) and potassium carbonate (113 mg, 0.819 mmol) in N,N-dimethylformamide (6 mL) was stirred at 80° C. for 3 hr. After ethyl acetate was added, the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and preparative HPLC eluting with a 10-100% acetonitrile/water gradient mixture to give the title compound as a pale pink solid (38.2 mg, 0.0938 mmol, 36%).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH2:12])=[CH:10][C:5]=2[N:4]=[CH:3]1.[N:13]([C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([O:27]CC)=O)=[C:14]=[S:15].C([N:32](CC)CC)C>CN(C=O)C.ClCCl>[NH:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH2:12])=[CH:10][C:5]=2[N:4]=[CH:3]1.[S:15]=[C:14]1[NH:13][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25](=[O:27])[NH:32]1
Reactant: CCOC(=O)c1c(N=C=S)sc2c1CCCC2
Reactant: CCN(CC)CC
Agent: Cl
Agent: NCc1ccc2[nH]cnc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c(=S)[nH]c2sc3c(c12)CCCC3
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(1H-benzo[d]imidazol-5-yl)methanamine (14) (0.08 g, 0.46 mmol) and ethyl 4,5,6,7-tetrahydro-2-isothiocyanatobenzo[b]thiophene-3-carboxylate (0.12 g, 0.46 mmol) were dissolved in 1mL DMF and dichloromethane. Triethylamine (128 μL, 0.92 mmol) was added to the mixture. The mixture was stirred for 12 hours at ambient temperature. The solvent was removed and the resulted residue was dissolved in ethanol. Triethylamine (128 μL, 0.92 mmol) was added and the mixture was heated under reflux for 12 hours. The solvent was removed and the resulted residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate, filtrated and the solvent was removed. The product was purified by means of flash-chromatographie using silica gel and a CHCl3/MeOH-gradient.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CN(C)C=O>[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])=[CH:19][CH:18]=1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: NCc1ccc(N)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (406 mg, 2.0 mmol) in N,N-dimethylformamide (250 μL) is added 4-aminobenzylamine (244 mg, 2.0 mmol). The reaction mixture is shaken at ambient temperature for 1.5 hours, then concentrated. Ethyl acetate is added to the solid residue that remained and the solid is recovered by filtration, rinsing with diethyl ether, and drying to yield 555.5 mg of 4-[(4-Amino-benzylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:13])[C:4](=[S:12])[S:5][C:6]=1[C:7]([O:9]CC)=O.Cl.[C:15](N)(=[NH:17])[CH3:16].C[O-].[Na+]>C(O)C.CO>[CH3:13][N:3]1[C:2]2[N:1]=[C:15]([CH3:16])[NH:17][C:7](=[O:9])[C:6]=2[S:5][C:4]1=[S:12]
Reactant: CC(=N)N
Reactant: CCOC(=O)c1sc(=S)n(C)c1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1nc2c(sc(=S)n2C)c(=O)[nH]1
Yield: 73.3 %

Procedure:
Ethyl 4-amino-3-methylthiazoline-2-thione-5-carboxylate (1.4g, 6.4 mmoles), prepared according to the procedure of Gewald, J. Prakt. Chem., 32, 26-30 (1966), was suspended in approximately 40ml of ethanol. Acetamidine hydrochloride (0.6g, 6.4 mmole) and 2.77g (12.8 mmole) of a 25% solution of sodium methoxide in methanol were added to the suspension and the resultant mixture refluxed for approximately 20 hours. The ethanol was removed in vacuo and the residue was suspended in water and neutralized with concentrated hydrochloric acid. The resultant precipitate was filtered and dried to provide 1 g of 3,5-dimethyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20](=[O:21])[C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17](=[O:26])[C:16]=1[CH3:27])(=O)C>Cl.CO>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20](=[O:21])[C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17](=[O:26])[C:16]=1[CH3:27]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCOC(C)=O)=C(C)C1=O
Agent: Cl
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reaction time: 8 h
Yield: 59.9 %

Procedure:
In a mixture of 0.04 ml of concentrated hydrochloric acid and 11 ml of methanol was dissolved 216 mg of 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, and the solution was left standing overnight at room temperature. The reaction solution was concentrated under reduced pressure and the concentrate was diluted with water, which was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, then dried. The solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethylacetate to yield 115 mg of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as orange-colored needles, m.p. 52°-53° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:12]2[CH:7]1[CH:8]([CH3:16])[CH2:9][CH2:10][CH:11]2[CH:13]([CH3:15])[CH3:14])=[O:5])C.Cl>[OH-].[Na+]>[CH:13]([C@@H:11]1[CH2:10][CH2:9][C@@H:8]([CH3:16])[CH:7]2[CH:12]1[CH:6]2[C:4]([OH:5])=[O:3])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C1C2C(C)CCC(C(C)C)C12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)[C@@H]1CC[C@@H](C)C2C(C(=O)O)C21

Procedure:
1.9 g of 2-isopropyl-5-methyl-bicyclo[4.1.0]heptane-7-carboxylic acid ethyl ester (66%) from synthesis example 1a are boiled under reflux for 3 hours with 20 ml of 10% sodium hydroxide solution. 25 ml of 10% hydrochloric acid are added and the mixture is extracted twice with 50 ml of diethyl ether. The organic phases are dried with sodium sulfate and the solvent is distilled off under vacuum. 1.37 g of a crude product containing 69% of the 2-isopropyl-5-methyl-bicyclo[4.1.0]heptane-7-carboxylic acid isomers are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]1[O:13][C:12]2[CH:14]=[C:15]([Cl:20])[C:16]([CH2:18]Cl)=[CH:17][C:11]=2[O:10]1.O>ClCCl.[OH-].[Na+].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:1][C:2]1[C:7]([O:8][CH2:18][C:16]2[CH:17]=[C:11]3[O:10][CH2:9][O:13][C:12]3=[CH:14][C:15]=2[Cl:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: ClCc1cc2c(cc1Cl)OCO2
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ncccc1OCc1cc2c(cc1Cl)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of 2-amino-3-hydroxypyridine (9.75 g, 0.0886 mol) in dichloromethane (55 ml) and 40% sodium hydroxide (55 ml) was added Adogen 464 (5 ml) and 6-chloropiperonyl chloride (20 g, 0,0975 mol) with vigorous stirring. The mixture was stirred at room temperature for 16 hours. Water (55 ml) was added and the mixture extracted with dichloromethane. The combined organic layers were dried and evaporated, and the residue purified by flash chromatography (silica, 1% methanol/dichloromethane) and trituration with ether to yield the title compound (6 g), m.p. 100°-104° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:16][C:17]#[N:18])[CH:13]=[CH:14][CH:15]=2)=[C:4]([CH3:19])[N:3]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(O)CCC>[NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:16][C:17]#[N:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:7]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1cccc(CC#N)c1
Reactant: CCCCCN
Solvent: CCCCO
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CC#N)c1
Temperature: 110 °C

Procedure:
The product from step (iii) (Ig) was combined with butan-1-ol (25 mL) and pentan-1-amine (4 mL) was added. The reaction mixture was heated to 110° C. for 18 h. The solvents were evaporated and the product purified using chromatography to give the subtitle compound as an orange oil, 600 mg.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:19]([CH2:20][CH2:21][C@:3]13[CH3:4])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2>C1(C)C=CC=CC=1>[OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:19]([CH2:20][CH2:21][C@:3]13[CH3:4])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH:15]=[CH:16]1)[CH2:11][CH2:10]2
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Solvent: Cc1ccccc1
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312

Procedure:
17β-Hydroxy-14α,15α-methylene-androst-4-ene-3-one (4 g) in 160 mL of toluene is stirred for 6 days at 85° C. with 3.2 g of 2,3-dichloro-5-6-dicyanobenzoquinone. The precipitate is filtered off, washed with a little toluene and the filtrates and washings are evaporated to dryness. The residue is purified by chromatography, 17β-Hydroxy-14α,15α-methylene-androsta-1,4-diene-3-one being obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([C:32]1[C:33](Cl)=[N:34][CH:35]=[CH:36][CH:37]=1)#[N:31]>>[C:30]([C:32]1[C:33]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:34][CH:35]=[CH:36][CH:37]=1)#[N:31]
Reactant: N#Cc1cccnc1Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncccc2C#N)C3)cc1

Procedure:
Compound eh was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 3-cyano-2-chloropyridine. LC-MS: m/z=+499 (M+H)−.
Reaction SMILES: N#N.[CH:3](O)=[O:4].CC(OC(C)=O)=O.[NH2:13][CH:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[C:20]([CH:14]([NH:13][CH:3]=[O:4])[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=CO
Agent: N#N
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)NC=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
Under a nitrogen atmosphere (N2), HCOOH (2.44 g, 53 mmol) was added to Ac2O (6.48 g, 63.6 mmol) at 0° C. After it was allowed to warm to ambient temperature the reaction was heated at 50° C. for 15 hr. It was allowed to cool to ambient temperature. This mixed acid anhydride was then added dropwise to a solution of ethyl 2-amino-2-cyanoacetate (128 mg, 1 mmol) in dry THF (5 mL) at 0° C. After the cooling bath was removed, the reaction was maintained at ambient temperature for additional 1 hr. The reaction mixture was concentrated and purified by silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl 2-cyano-2-formamidoacetate (110 mg, 70%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1.[Na].[CH2:14]([OH:16])[CH3:15]>C(OCC)C>[CH2:14]([O:16][C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1)[CH3:15]
Reactant: CCO
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Agent: [Na]
Solvent: CCOCC
Product: CCOc1cc(CCl)nc(C(C)C)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 9.6 g (0.047 mol) of 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61) in 40 ml of absolute ethanol is treated dropwise during 3 hours at 0° C. with a solution of 1.24 g (0.054 mol) of sodium in ethanol and the mixture is stirred at 0° C. for 3 hours and then at room temperature for 16 hours. The mixture is then taken up in diethyl ether and the solution is washed neutral with sodium chloride solution, dried over anhydrous sodium sulphate and freed from solvent under reduced pressure. After distillation of the oily residue in a high vacuum there is obtained 6-ethoxy-4-chloromethyl-2-isopropyl-pyrimidine, b.p. 52° C./0.07 mmHg, nD21 1.4955.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[OH:30][CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH2:31][OH:30])=[CH:41][CH:40]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(OCCO)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(OCCO)cc4)nc23)CC1)Nc1nccs1
Temperature: 85 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.060 g, 0.15 mmol, 1 eq), EtOH (2.6 mL) and DMF (0.35 mL), 4-(2-hydroxyethoxy)benzaldehyde (0.028 g, 0.17 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a off-white solid (0.021 g, 27%); 1H-NMR (500 Mz, DMSO-d6): 2.74-2.81 (m, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2), 3.69-3.79 (m, 6H, piperazine N(CH2)2 and OCH2), 4.07 (t, J=5.0 Hz, 2H, OCH2), 4.88 (t, J=5.5 Hz, 1H, OH), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.23 (d, J=3.5 Hz, 1H) and 7.49 (d, J=3.5 Hz, 1H) (thiazole H-4, H-5), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.12 (d, J=9.0 Hz, 2H, ArH, C6H4); LC (Method B)-MS (ESI, m/z) 3.69 min—514/516 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [ClH:1].[OH:2][CH2:3][C:4]([NH2:12])([CH2:8][CH2:9][CH2:10][NH2:11])[C:5]([OH:7])=[O:6].Cl.[CH3:14]O>>[ClH:1].[ClH:1].[OH:2][CH2:3][C:4]([NH2:12])([CH2:8][CH2:9][CH2:10][NH2:11])[C:5]([O:7][CH3:14])=[O:6]
Reactant: CO
Reactant: NCCCC(N)(CO)C(=O)O
Agent: Cl
Product: COC(=O)C(N)(CO)CCCN

Procedure:
2-Hydroxymethyl-2,5-diaminopentanoic acid hydrochloride (5 g or 2.5×10-2 mol) is suspended in 75 ml of absolute methanol and the solution is saturated with dry hydrogen chloride. The homogenous solution is then heated under reflux for 48 hours. The reaction mixture is regularly saturated with dry hydrogen chloride. The solvent is evaporated under reduced pressure and the hygroscopic residue is dried under high vacuo (6.2 g) to give methyl 2-hydroxymethyl-2,5-diaminopentanoate dihydrochloride. The ester (6.2 g) is dissolved in 100 ml of absolute methanol, and 175 ml of a methanolic solution of sodium methylate (1.15 g of Na or 5×10-2 mol) is added. The reaction mixture is stirred at room temperature under nitrogen for 24 hours. The solvent is evaporated under reduced pressure and the residue is extracted many times with hot chloroform to yield analytically pure 3-hydroxymethyl-3-amino-2-piperidone (2.9 g): m.p. 145° C.