Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6]CCCO)(=[O:5])[C:2](C)=[CH2:3].[C:11]1(=[O:18])[CH:16]=CC(=O)C=C1.CC1C(=CC(=CC=1)N=C=O)[N:22]=[C:23]=[O:24].OCC(CO)O>C=CC1C=CC=CC=1>[C:1]([OH:6])(=[O:5])[CH:2]=[CH2:3].[NH2:22][C:23]([O:18][CH2:11][CH3:16])=[O:24]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: C=C(C)C(=O)OCCCO
Reactant: O=C1C=CC(=O)C=C1
Solvent: OCC(O)CO
Solvent: C=Cc1ccccc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A vinyl terminated, fully reacted urethane acrylate was prepared from the glycerine-modified hydroxyalkylated novolac of Example 16 in the following manner: A mixture of 1155 parts of styrene solvent, 415 parts of hydroxypropyl methacrylate, and 0.4 parts of p-benzoquinone was stirred while 519 parts of toluene diisocyanate (a mixture of approximately 80 percent 2,4-isomer and 20 percent 2,6-isomer) was added slowly so that the temperature did not exceed 45° C. The temperature was then raised to 55° C and maintained thereat for about 30 minutes. Then 510 parts of glycerine-modified hydroxypropylated novolac, prepared as in Example 16 was added and the reaction mixture was heated to 65° C an maintained at that temperature for about 4 hours. The liquid resin, thus prepared had a Brookfield viscosity of 120 centipoises at 25° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:31][CH2:32][CH:33]1[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1)=[O:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[CH2:34][CH:33]([CH2:32][NH:31][C:19]2[CH:20]=[C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[CH:22]=[CH:23][C:18]=2[C:16]([NH:15][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]4[CH:3]=[C:2]([F:1])[CH:46]=[C:45]([F:47])[CH:44]=4)[CH:7]=3)[NH:11][N:10]=2)=[O:17])[CH2:36]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CN(C(=O)OC(C)(C)C)C3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CNC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
tert-butyl 3-({[2-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-5-(4-methylpiperazin-1-yl)phenyl]amino}methyl)azetidine-1-carboxylate (289 mg, 0.45 mmol) was dissolved in DCM (3 mL) and TFA (0.7 mL) was added. The resulting reaction solution was stirred overnight at room temperature. The mixture was diluted with DCM and extracted with 10% aqueous NH3. Organic phase was evaporated. Reverse phase column chromatography purification afforded 104 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2OCCOCP(OCC)(OCC)=O.C[O-].[Na+].[C:30](O)(=[O:32])C>CO>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][CH:5]=[N:6]2)=[C:2]([O:32][CH3:30])[N:10]=1
Reactant: CCOP(=O)(COCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2nc[nH]c12
Temperature: 50 °C

Procedure:
To a solution of 6-chloro-9-[2-(diethoxyphosphorylmethoxy)ethoxy]-2-formamidopurine (0.25 g, 0.61 mmol) in methanol (5 ml), was added sodium methoxide solution (30 wt % in methanol; 0.5 ml, 2.62 mmol). The mixture was stirred and heated at 50° C. for 4 hours. After cooling to ambient temperature, 80% aqueous acetic acid (0.5 ml) was added to give a solution of pH6. The solution was evaporated to dryness and the residue partitioned between dichloromethane (10 ml) and aqueous sodium bicarbonate solution (10 ml). The aqueous phase was washed with dichloromethane (2×10 ml), the combined organic extracts dried (magnesium sulphate), and evaporated to dryness under reduced pressure. The residue obtained was chromatographed on silica gel (eluant dichloromethane: methanol 90:10) to give a 2-amino-6-methoxypurine derivative (0.20 g) which was used without any further purification. The chromatographed material (0.20 g) was dissolved in dichloromethane (2 ml), trimethylsilyl bromide (0.7 ml, 5.3 mmol) added, and the solution left at ambient temperature for 2 days. The solvent was evaporated under reduced pressure and the residue obtained co-evaporated with methanol (×2) to leave a white solid which crystallised from hot water giving the title compound as a white solid (0.105 g, 56%) m.p. 275°-278° C., identical in all respects with the compound obtained in Method A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.[CH2:24]1C[O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:26](=[O:27])[CH:25]=[CH2:24])=[CH:11][CH:10]=2)#[N:13]
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C(C)C)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1.00 g (3.31 mmol) 6-amino-4-[(3-isopropylphenyl)amino]-3-quinolinecarbonitrile in 2.0 ml hot DMF, added 12 ml THF, and chilled to 0° C. under N2. Added 507 μl (3.64 mmol) triethylamine and 303 μl (3.64 mmol) acryloyl chloride. Removed ice bath at 15 minutes and at 1 hour stripped solvent. Slurried residue with dilute sodium bicarbonate, collected solids and washed with water. Recrystallized from ethyl acetate and dried in vacuo, giving 366 mg of orange solid: mass spectrum (electrospray m/e): M+H=357.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][CH:9]=1)([O-])=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[S:39]2)[S:34][CH2+:33]1SC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[S:39]2)[S:34][C:33]1=[N:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][CH:9]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)Nc1ccc(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)cn1

Procedure:
In a manner similar to Example 30, intermediate N-(5-nitropyridin-2-yl)acetamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (DMSO-d6): δ 10.45 (1H, s), 8.07 (1H, d), 7.97 (1H, d), 7.75 (1H, d), 7.33–7.46 (7H, m), 7.29 (1H, m), 7.22 (1H, m), 5.06 (2H, s), 3.79 (3H, s), 2.09 (3H, s); MS(ESI): 488 (MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)=[O:4].[CH2:22](Br)[CH:23]=[CH2:24].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[OH:4][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:17])([F:18])[F:19])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)([C:2]([F:20])([F:1])[F:21])[CH2:24][CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: N#Cc1cc2nc(C(=O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Agent: Cl
Agent: [In]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(O)(c1nc2cc(C#N)c(C(F)(F)F)cc2[nH]1)C(F)(F)F

Procedure:
2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile (0.31 g; 0.95 mmol), allyl bromide (0.82 mL; 9.5 mmol) and indium (1.09 g; 9.5 mmol) were suspended in THF (12 mL) and 0.03 M HCl (10 mL) and stirred vigorously overnight. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][OH:31])=C[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C(#[N:38])C.O>>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][OH:31])=[N:38][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CC#N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CO)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Solvent: O
Product: CC(C)(C)[C@@H](CO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F

Procedure:
Alcohol, 32, was synthesized in a manner similar to compound 70a utilizing the same deprotection procedure, starting with compound 54a: 1H NMR (400 MHz, CDCl3) δ 10.77 (brs, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 5.59 (brs, 1H), 4.36 (t, J=8.3 Hz, 2H), 4.11 (m, 1H), 3.72 (m, 2H), 1.06 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 348.13 (M+H) RT=1.83 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:25][C:26]1[C:31]([C:32](O)=[O:33])=[CH:30][C:29]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[Cl:25][C:26]1[C:31]([C:32]([NH:1][C:2]2[CH:24]=[CH:23][C:5]3[CH2:6][CH2:7][C:8]4[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[C:12]=4[C:4]=3[CH:3]=2)=[O:33])=[CH:30][C:29]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:28][CH:27]=1
Reactant: O=C(O)c1cc(N2CCOCC2)ncc1Cl
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(N4CCOCC4)ncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound of Example 244 (0.757 mmoles), 5-chloro-2-morpholin-4-ylisonicotinic acid, (1.38 mmoles), and HATU (1.57 mmoles) were dissolved in 5 mL DMF followed by the addition of 0.4 mL of triethylamine. The mixture was stirred at room temperature for 3 hrs and partially stripped of DMF. The reaction mixture was then added to water, filtered, and washed with water. The solid was dissolved in THF, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The THF was stripped and the solid triturated in diethyl ether three times, then triturated in ethanol, and twice more with acetonitrile, filtered and dried under vacuum. Mp: 309-313° C. 1H NMR (d6-DMSO, 400 MHz): δ 2.80-2.95 (m, 4H); 3.42 (t, 4H, J=5 Hz); 3.62 (t, 4H, J=5 Hz); 6.88 (s, 1H); 7.17-7.21 (m, 1H); 7.23-7.41 (m, 5H); 7.49-7.58 (m, 3H); 8.14 (s, 1H); 10.31 (s, 1H). 13C NMR (d6-DSMO, 100 MHz): δ 20.34, 29.70, 45.74, 66.50, 106.55, 114.97, 115.87, 117.09, 117.32, 120.05, 121.41, 126.67, 128.64, 128.73, 129.62, 133.47, 136.80, 136.82, 137.48, 139.64, 143.21, 145.28, 147.54, 158.30, 161.39, 163.85, 164.45. M+1=547.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1F)=O.O.[NH2:22][NH2:23]>CN(C1C=CN=CC=1)C>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]2[C:14]=1[NH:23][N:22]=[C:11]2[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)c(OC)c1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(OC)c1
Yield: 52.2 %

Procedure:
Prepared as in Example 104 from (2,4-dimethoxyphenyl)[2-fluoro-3-chlorophenyl]methanone (1.20 g, 4.1 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.618 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([N:20]=C)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([OH:24])=[O:23].Cl.[CH3:27][O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[O:31][CH2:32][C:33]([OH:35])=[O:34].[OH-].[Na+].[C:42]([O:45][CH2:46]C)(=[O:44])C>O>[CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([O:24][CH:46]1[O:45][C:42](=[O:44])[C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]1=2)=[O:23].[CH3:27][O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[O:31][CH2:32][C:33]([O-:35])=[O:34]
Reactant: COc1ccccc1OCC(=O)O
Reactant: CCOC(C)=O
Reactant: C=N[C@@H](C(=O)N[C@@H]1C(=O)N2[C@@H]1SC(C)(C)[C@@H]2C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)OC1OC(=O)c2ccccc21
Product: COc1ccccc1OCC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 20.4 g of phthalidyl ester of metampicillin in 100 ml of ethyl acetate there is added a solution of 40 ml of N hydrochloric acid in 120 ml of water. The mixture is maintained under stirring for 45 minutes at room temperature, the organic phase is separated off and the aqueous phase is washed twice with diethyl ether. The aqueous solution is let stand for 20 minutes at 20° C. under reduced pressure, and then it is filtered through asbestos pretreated with hydrochloric acid. To the clear solution thus obtained, there is added, quickly, drop by drop and under stirring a solution of 8 g of 2-methoxyphenoxyacetic acid in 100 ml of water containing 1.76 g of sodium hydroxide. The precipitate which forms is filtered, washed with water and dried on P2O5 at room temperature and under reduced pressure, to give the talampicillin 2-methoxyphenoxyacetate; m.p. 105°-110° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl-].[CH3:19][CH:20]([S:22]([CH2:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH3+:29])(=[O:24])=[O:23])[CH3:21]>C1COCC1.CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([CH2:25][S:22]([CH:20]([CH3:21])[CH3:19])(=[O:24])=[O:23])[CH:27]=2)[N:7]=1
Reactant: CC(C)S(=O)(=O)Cc1cccc([NH3+])c1
Reactant: Clc1ncnc(Cl)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)S(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Yield: 268 %

Procedure:
To a stirred solution of 2,4-dichloro-1,3,5-triazine (150 mg, ABCR GmbH & CO. KG) in THF/i-PrOH (1:1; 1.9 mL) DIPEA (0.52 mL) was added at −40° C. Then a suspension of 3-[(propan-2-ylsulfonyl)methyl]anilinium chloride (250 mg) in THF/i-PrOH (1:1, 0.94 mL) was added at this temperature. Under stirring the temperature of the reaction mixture was slowly raised over 3 hours to 0° C. The reaction mixture was then concentrated in vacuo to give the crude title compound (876 mg) which was used without further purification.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH:18]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[CH:18]1([CH:23]=[CH:3][C:1]#[N:2])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=CC1CCCC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=CC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A solution of diethyl cyanomethylphosphonate (7, 742.5 g, 4.2 mol, 1.1 equiv) in dry THF (5.75 L) was stirred under nitrogen on an ice-water-methanol bath and a solution of 1 M potassium tert-butoxide in THF (4 L, 4.0 mol, 1.05 equiv) was added at such a rate as to keep the temperature below 0° C. After addition of 1 M potassium tert-butoxide in THF was complete, the stirring was continued on the cold bath for 1 h and a solution of cyclopentanecarbaldehyde (6, 374 g, 3.81 mol) in dry THF (290 mL) was added at such a rate as to maintain the temperature below 0° C. The cold bath was removed, and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for overnight. When the reaction was deemed complete, the reaction mixture was partitioned between methyl tent-butyl ether (MTBE, 14 L), water (10 L) and brine (6 L). The two layers were separated, and the combined organic phase was washed with brine (6 L). The aqueous phase was extracted with MTBE (10 L) and washed with brine (6 L). The combined organic extracts were concentrated under reduced pressure and the residue was distilled (65-78° C./6 torr) to afford 3-cyclopentylacrylonitrile (8, 437.8 g, 461.7 g theoretical, 94.8% yield) as a colorless oil, which was found to be a mixture of E- and Z-isomer. For 8: 1H NMR (DMSO-d6, 400 MHz, for Z-isomer) δ ppm 6.58 (t, 1H, J=10.6 Hz), 5.55 (dd, 1H, J=10.8, 0.59 Hz), 2.85 (m, 1H), 1.9-1.46 (m, 6H), 1.34 (m, 2H) and (for E-isomer) δ ppm 6.83 (q, 1H, J=8.3 Hz), 5.66 (dd, 1H, J=16.5, 1.4 Hz), 2.60 (m, 1H), 1.9-1.46 (m, 6H), 1.34 (m, 2H); 13C NMR (DMSO-d6, 100 MHz, for Z-isomer) δ ppm 159.8, 116.6, 97.7, 42.3, 32.3, 25.1 and (for E-isomer) δ ppm 160.4, 118.1, 97.9, 43.2, 31.5, 24.8; C8H11N (MW, 121.18), GCMS (EI) m/e 120 (M+−H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[N:12]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][NH:17][C:16]1=[O:28])=[N+:13]=[N-:14].C(OCC)(=O)C>CN(C)C=O.O>[N:12]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:16]1=[O:28])=[N+:13]=[N-:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: [N-]=[N+]=N[C@@H]1CC[C@@H](c2ccccc2)CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@@H](N=[N+]=[N-])C1=O
Reaction time: 1.5 h

Procedure:
0.9 ml of t-butyl bromoacetate followed by 219 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, under a stream of nitrogen, to a solution of 1.05 g of 3(S*)-azido-6(R*)-phenylperhydroazepin-2-one (Isomer A) [prepared as described in Example 1(f)] in 10 ml of dimethylformamide, whilst ice-cooling. The mixture was stirred for 1.5 hours, and then ethyl acetate and water were added. The ethyl acetate layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography using a 1:4 by volume mixture of ethyl acetate and cyclohexane as eluent, to give 1.54 g of the title compound as crystals, melting at 119°-121° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[O:31])=[CH:17][N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 285.8 %

Procedure:
4-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.96 g, Example 10) was dissolved in dichloromethane (25 mL), cooled to 0° C. and treated with trifluoroacetic acid (12.5 mL). After stirring 1 hour at 0° C., the reaction mixture was concentrated in vacuo to give 4.29 g of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone as the trifluoroacetic acid salt. A portion of the crude product was purified on HPLC and then neutralized with sodium carbonate, washed with brine and dried to give [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone free base. -. HRMS, observed: 328.1771; Calcd for (M+H)+: 328.1768.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][N:7]=1)=O.[CH3:13][NH2:14]>CO.O1CCCC1>[CH3:13][NH:14][C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][N:7]=1)=[O:3]
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A suspension of 17.8 g (0.103 mol, 1 eq) of 4-chloro-pyridine-2-carboxylic acid methyl ester hydrochloride in 15 mL of methanol was cooled to 0° C. and slowly treated with a 2.0 M solution of methylamine in tetrahydrofuran at a rate that kept internal temperature below 5° C. The reaction mixture was stirred at 0° C. for 2 hours, then slowly allowed to warm up to ambient temperature and stirred for 18 hours. Solvent was removed in vacuum, approx. 200 mL of ethyl acetate was added and the resulting suspension was filtered. The precipitate was washed with 100 mL of ethyl acetate. The combined ethyl acetate solutions were washed three times with 100 mL of brine and dried over sodium sulfate. Solvent was removed in vacuum to yield 14.16 g of the product as orange oil. Yield: 80.5%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:40](OC)=[O:41])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:17]=2)=[N:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:44]C1C(C(OC)=O)=NC(Cl)=NC=1NCC1CCOCC1.C([Si](C(C)C)(C(C)C)[O:68][C:69]1C=CC=C([Sn](C)(C)C)C=1)(C)C>CN(C)C=O>[OH:22][C:18]1[CH:17]=[C:16]([C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:69](=[O:68])[N:8]3[CH2:9][CH:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[C:3]([C:40]([NH2:44])=[O:41])[N:4]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)[Si](Oc1cccc([Sn](C)(C)C)c1)(C(C)C)C(C)C
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc(NCC2CCOCC2)c1N
Reactant: COC(=O)c1nc(Cl)nc(NCC2CCOCC2)c1N
Solvent: CN(C)C=O
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 100 °C
Yield: 40 %

Procedure:
Methyl 5-amino-2-(3-(tert-butyldiphenylsilyloxy)phenyl)-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyrimidine-4-carboxylate. Methyl 5-amino-2-chloro-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyrimidine-4-carboxylate. (0.400 g, 1.33 mmol) triisopropyl(3-(trimethyl-stannyl)phenoxy)silane (0.772 g, 1.86 mmol) and bisdichloro(triphenylphosphine)palladium (0) (0.280 g, 0.400 mmol) were combined in dimethyl formamide (6 mL) and heated to 100° C. The reaction was monitored via thin layer chromatography. Once starting materials were consumed, the solution was condensed under reduced pressure and purified via Biotage chromatography (0-50% EtOAc in hexanes) to afford the title compound (0.276 g, 40%). MS (ESI) m/z 515.6 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24](CC(=O)C)[CH:23]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH:35](C1C=CC(C(O)=O)=CC=1)=[O:36]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:23]=[CH:24][C:25]([CH:35]=[O:36])=[CH:26][CH:27]=3)[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C=O)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using 4-formylbenzoic acid in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C24H30N5O3+ 436.2. found m/z=436.2 (M+H)+.