Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Br:30])=[CH:25][C:24]=2[O:31][CH3:32])=[C:13](/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([Br:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:17](=[O:18])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Cl)c(Br)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A flask was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (73.2 g, 137 mmol) and MeOH (687 ml) to give a yellow suspension. Sodium methoxide (25 wt % in MeOH) (15.01 ml, 54.9 mmol) was added and a reflux condenser was attached. The flask was lowered into a 70° C. heating bath and stirred at 70° C. for 18 h. The mixture was cooled to rt and poured through a 3 inch silica plug to remove black particulates. The product that was crashed out on the silica plug was washed through the plug with DCM. The mother liquor was concentrated to half its volume, then IPA (500 mL) was added and the solution concentrated again. An additional 500 mL of IPA was added and a tan solid precipitated. The tan solid was collected by vacuum filtration to give 6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one (50.34 g, 103 mmol, 75% yield) as a dark tan powdery solid. m/z (ESI) 486.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C@H:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[K+].O.CO>C(OCC)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C@H:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C2=N[C@@H](C(C)C)CO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(C)[C@H]1COC(c2ccc(C(=O)O)cc2)=N1
Temperature: 75 °C

Procedure:
A mixture of 3 g of (S)-2-(4-[methoxycarbonyl]phenyl)-4-isopropyl-2-oxazoline, 3 g of potassium hydroxide, 5 ml of water and 50 ml of methanol is heated at 75° C. on an oil bath for 4 hours. The cooled mixture is treated with 10 ml of ice-cold 3N hydrochloric acid and the liberated acid is taken up in 150 ml of diethyl ether. The separated aqueous phase is back-extracted twice with 100 ml of diethyl ether each time. The combined organic phases are washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Recrystallization of the resulting crude product from ethanol yields (S)-2-(4-carboxyphenyl)-4-isopropyl-2-oxazoline.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[C:11]([C:13]1[CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=[N:17][CH:18]=1)#[N:12].N1C(C)=CC=CC=1C>COCCOC>[Br:1][C:2]1[C:3](=[O:10])[N:4]=[C:5]([CH3:9])[NH:6][C:7]=1[NH:12][CH2:11][C:13]1[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[N:17][CH:18]=1
Reactant: N#Cc1cncc(CN)c1
Reactant: Cc1nc(O)c(Br)c(Cl)n1
Solvent: COCCOC
Solvent: Cc1cccc(C)n1
Product: Cc1nc(=O)c(Br)c(NCc2cncc(C#N)c2)[nH]1
Temperature: 90 °C
Yield: 31 %

Procedure:
A stirred suspension of 5-bromo-6-chloro-2-methyl-4-pyrimidinol (1.57 g, 7.04 mmol), 5-cyano-3-aminomethylpyridine (1.03 g, 7.74 mmol), and 2,6-lutidine (2.00 mL, 17.4 mmol) in 1,2-dimethoxyethane (7.0 mL) was heated at 90° C. for 15 hours. Solvent was removed in vacuo, and the residue was suspended in water. The white precipitate was isolated by filtration with aqueous rinse, and then recrystallized from methanol/diethyl ether to afford crude product (922 mg, 41%). The crude product was adsorbed onto silica gel. The product was eluted with 4:1 ethyl acetate:hexane (150 mL) followed by methanol (300 mL). The methanol eluant was concentrated in vacuo, and the residue was recrystallized from methanol/diethyl ether to give the title compound in analytically pure form (705 mg, 2.20 mmol, 31% yield): mp 260.0°-260.5° C.; Rf 0.51 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ11.0 (s, 1H), 8.88 (d, J=1.69 Hz, 1H), 8.77 (d, J=1.64 Hz, 1H), 8.16 (s, 1H), 7.34 (t, J=6.14 Hz, 1H), 4.60 (d, J=6.00 Hz, 2H), 2.16 (s, 3H); IR (KBr) 3280 (NH), 2620-3000 (CH), 2230 (CN), 1645, 1605, 1585 (C=C, C=N); UV (MeOH)λ275.5 (ε10900).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:15]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1
Reactant: COC(=O)C[C@H]1CCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.5 %

Procedure:
To a solution of 2.0 g (0.012 mole) of D-beta-homoproline hydrochloride in 20 mL of methanol was added slowly 1.8 mL (0.024 mole) of thionyl chloride at 0 degrees. The mixture was stirred overnight, then concentrated under reduced pressure. The solid was slurried in ether, and collected by filtration to give 2.2 g of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride as a white solid. A solution of 2.2 g (0.012 mole) of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride in 3 mL of chloroform was added over 5 minutes to a cooled (0 degrees) mixture of 2.34 g (0.012 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.1 g (0.060 mole) of sodium bicarbonate and 25 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-70:30) gave 3.3 g of [(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (IV-102) as a yellow thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:14][O:15][C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]2[CH2:17][C:16]([O:15][CH3:14])=[O:24])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC1CCCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of 3,4-dichlorobenzenesulfonyl chloride (1.88 g, 7.65 mmol) in DCM (15 ml) was added at 0° C. to a solution, cooled to 0° C., of piperidin-2-ylacetic acid methyl ester hydrochloride (1.3 g, 8.4 mmol) in DCM (33 ml) and triethylamine (2.66 ml, 21 mmol), and stirring was then carried out for 90 minutes at room temperature. 0.5 M HCl (20 ml) was then added, and stirring was carried out for a further 15 minutes. The organic phase was separated off, washed with water and dried over sodium sulfate. The solvent was removed using a rotary evaporator and the product was used in the next stage without being purified further. Yield: 1.9 g (63%)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:34])[C@@H:14]([NH:16][C:17](=[O:33])[C@@H:18]([NH:20][C:21](=[O:32])[C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])[CH3:19])[CH3:15])=[N:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CCO.O>[OH:2][CH2:1][C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:34])[C@@H:14]([NH:16][C:17](=[O:33])[C@@H:18]([NH:20][C:21](=[O:32])[C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH3:23])[CH3:19])[CH3:15])=[N:5][CH:4]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCNc1ncc(CO)s1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Following the procedure as described in Example 32, except using material from Example 73 (2.5 mg, 5.01 μmol), EtOH/H2O (4:1) (500 μlit), sodium borohydride (1.1 mg, 29.0 μmol) and stirring at room temp for 40 min, the title compound is isolated (quantitative yield) and is used crude in the next step. LC/MS (Condition A): ret. T=2.22 min, (M+H)+ 501.29.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[CH:24]=[C:23]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[F:35])[N:22]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([C:21]3[N:26]([CH3:27])[C:25](=[O:28])[CH:24]=[C:23]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][C:30]=4[F:35])[N:22]=3)[CH2:14]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: CN(C)CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of N2,N2-dimethyl-N1-(4-((2S)-morpholin-2-yl)phenyl)glycinamide obtained in Reference Example 13 (0.21 g, 0.8 mmol), 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.15 g, 0.64 mmol), and triethylamine (0.40 g, 4 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to afford N2,N2-dimethyl-N1-(4-((2S)-4-(3-methyl-4-oxo-3,4-dihydro-6-(3-fluoropyridin-4-yl)pyrimidin-2-yl)-morpholin-2-yl)phenyl)glycinamide (0.15 g, 50%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl>>[ClH:1].[O:15]([CH2:14][CH2:13][O:12][C:11]1[C:2]([N:3]2[CH2:4][CH2:9][NH:10][CH2:11][CH2:2]2)=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nc2ccccc2nc1OCCOc1ccccc1
Agent: Cl
Product: c1ccc(OCCOc2nc3ccccc3nc2N2CCNCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)quinoxaline (0.65 g, 2 15 mmol) yield 0.44 g (58%) as the free base A portion of the free base was converted to its hydrochloride salt mp 123-126° C.; HRMS m/z calcd for C20H22N4O2 (M)+ 350.1743, found 350.1748 Anal. (C20H22N4O2.1.75 HCl .0.5 H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]1[NH:8][C:9]([CH3:26])=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:12]=1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:26][C:9]1[NH:8][C:7]([C:3]2[N:4]=[CH:5][S:6][C:2]=2[Cl:1])=[N:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncsc2Cl)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2ncsc2Cl)=NC1c1ccc(Cl)cc1Cl
Yield: 48.3 %

Procedure:
Ethyl 2-(5-chlorothiazol-4-yl)-4-(2,4-dichlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (5.77 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.3 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH:34]([CH3:36])[CH3:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1)[C:7]([NH:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH:34]([CH3:35])[CH3:36])=[O:8])[CH3:2]
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, ˜0.313 mmol) and 3-(aminomethyl)-6-methyl-4-(propan-2-yl)-1,2-dihydropyridin-2-one HCl salt (88.0 mg, 0.407 mmol) in DMSO (2.4 mL) was added PyBOP (244 mg, 0.470 mmol) and hunig base (164 ul, 0.939 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water and diluted with ethylacetate. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=20/1+5% triethylamine). The crude compound was dissolved with DMSO, diluted with water. The precipitated solid was collected and triturated with ethylacetate/TBME/hexane to give the titled compound as a white solid (80.0 mg, 51% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.26 (s, 1H), 7.03-7.10 (m, 1H), 6.04 (s, 1H), 4.59 (d, J=6.0 Hz, 2H), 3.49-3.55 (m, 1H), 3.09 (q, J=6.8 Hz, 2H), 2.81-2.84 (m, 2H), 2.70-2.78 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.86-1.89 (m, 2H), 1.68-1.71 (m, 4H), 1.22 (d, J=6.4 Hz, 6H), 0.84 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 507.2, [M+Na] 529.2; HPLC 97.7% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@H:18]([NH:19][C:20]([C:22]3[S:23][C:24]4[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=4[N:30]=3)=[O:21])[CH2:17][N:16]([S:32]([CH2:35][C:36]([O:38]C)=[O:37])(=[O:34])=[O:33])[CH2:15]1)=[O:12])=[CH:5]2.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@H:18]([NH:19][C:20]([C:22]3[S:23][C:24]4[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=4[N:30]=3)=[O:21])[CH2:17][N:16]([S:32]([CH2:35][C:36]([OH:38])=[O:37])(=[O:34])=[O:33])[CH2:15]1)=[O:12])=[CH:5]2
Reactant: COC(=O)CS(=O)(=O)N1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@@H]3CN(S(=O)(=O)CC(=O)O)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 4 h
Yield: 89.1 %

Procedure:
The compound (100 mg) obtained in Example 100 was dissolved in tetrahydrofuran (4 ml)-water (1 ml), and the mixture was cooled with ice. Lithium hydroxide monohydrate (7.8 mg) was added, and the resultant mixture was heated to room temperature and stirred for 4 hours. After the reaction mixture was neutralized with 1N hydrochloric acid, it was concentrated. Deposits were collected by filtration, washed with water and 50% ethanol and dried overnight at 50° C. under reduced pressure to obtain the title compound (87 mg).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][NH:4][C:3]2=[O:21].[CH:22](Cl)(Cl)Cl.CO>>[CH2:22]=[C:9]1[C:10]2[C@:15]([CH3:16])([CH:14]=[CH:13][C:12](=[O:20])[CH:11]=2)[C@@H:17]2[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[NH:4][CH2:5]3)[CH2:8]1
Reactant: ClC(Cl)Cl
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)NC[C@@H]12
Solvent: CO
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)NC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12

Procedure:
The procedures of Example 14 were repeated using 21 mg of 16-azaandrosta-1,4-diene-3,17-dione in place of 16-oxaandrosta-1,4-diene-3,17-dione, and the resultant crude product was purl fie d by TLC [developing solvent; chloroform: methanol (9:1 )] to obtain 2 mg of 6-methylene-16-azaandrosta-1,4-diene-3,17-dione.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28].O1CCOCC1>O1CCOCC1>[ClH:28].[C:2]1([C:1]([C:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:11][CH:10]=2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccccc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of tert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (1 g, 2.7 mmol) in dioxane (20 mL) was added 4 M HCl-dioxane (20 mL), and the reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was completed. The mixture was directly concentrated to give phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone HCl salt as a yellowish solid (0.95 g, 90%). MS (ES+) C15H16N4O requires: 268, found: 269 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([NH2:13])[CH2:10][C:11]#[CH:12].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[CH2:9]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C:11]#[CH:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCNC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
Add triethylamine (3 mL) to a suspension of but-3-ynylamine hydrochloride (200 mg, 2.1 mmol) in DCM (10 mL) and stir for 10 min at room temperature under nitrogen. Add then neat pivaloyl chloride (284.9 μL, 2.31 mmol) and stir at room temperature overnight under nitrogen. Concentrate in vacuo, take up the residue in methanol and filter through a SCX-2 cartridge eluting with methanol to obtain the title compound (265 mg, 65%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3].CO.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C=CCOc1cc(N)ccc1C#N
Temperature: 65 °C
Reaction time: 0.83 h
Yield: 93.7 %

Procedure:
Iron powder-325 mesh (5.7 g, 98.0 mmol) was taken in a round bottom flask charged with a mixture of 2-(allyloxy)-4-nitrobenzonitrile (4.0 g, 19.6 mmol), absolute methanol (40 mL), water (8 mL) and ammonium chloride (5.2 g, 98 mmol). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 65° C. with vigorous stirring for 50 min. The reaction mixture was filtered, and washed with methanol. The solvent was removed in vacuo. EtOAc was added to the residue, and the solution was washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 2-(allyloxy)-4-aminobenzonitrile (3.2 g, 94% yield) as a light-brown solid. LC-MS (M+H)+=175.2 1H NMR (400 MHz, CDCl3) δ ppm 7.29 (d, 1H, J=8.4 Hz), 6.22 (dd, 1H, J=2.0, 8.4 Hz), 6.14 (s, 1H), 6.07-5.98 (m, 1H), 5.48 (dd, 1H, J=1.6, 3.2 Hz), 5.44 (dd, 1H, J=1.6, 3.2 Hz), 4.59 (d, 2H, J=1.6 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[I:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:20][C:19]2[CH:22]=[CH:23][C:16]([I:15])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: ClCc1ccc(I)cc1
Product: N#Cc1ccc(N(Cc2ccc(I)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-iodobenzyl chloride
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:20])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1.Br[C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1>C(O)C>[CH3:27][N:26]1[C:22]([NH:1][CH2:2][CH:3]([OH:20])[CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:8]=2)=[N:23][N:24]=[N:25]1
Reactant: Cn1nnnc1Br
Reactant: NCC(O)CCOc1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: Cn1nnnc1NCC(O)CCOc1cccc(CN2CCCCC2)c1
Yield: 55.6 %

Procedure:
A solution of 1-amino-4-[3-(1-piperidinylmethyl)phenoxy]-2-butanol (1.39 g) and 5-bromo-1-methyl-1H-tetrazole (0.82 g) in absolute ethanol (10 ml) was heated in an autoclave at 125° for 18 h. The solution was evaporated and the residue dissolved in 1M hydrochloric acid (25 ml). The acidic solution was washed with ethyl acetate, basified with excess sodium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to leave a solid which was triturated with dry diethyl ether to give a white solid (1.0 g). This solid was recrystallised from methyl acetate-light petroleum (b.p. 60°-80°) to give the title compound (0.6 g) as white crystals, m.p. 138°-9°.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O=[CH:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]2)[CH2:18][CH2:17]1
Reactant: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(OC2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (290 mg, 1.0 mmol), tert-butyl 4-(2-oxo-ethyl)piperidine-1-carboxylate (300 mg 1.3 mmol) and acetic acid (one drop) in 1,2-dichloroethane (5.0 ml) was added sodium triacetoxyborohydride (530 mg, 2.5 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=30/70) to afford tert-butyl 4-{2-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]ethyl}piperidine-1-carboxylate as a colorless solid (340 mg, 0.67 mmol, 67%).