Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11]3=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1.CCOC(C)=O>C1COCC1>[C:1]1([CH:7]2[N:12]3[C:32](=[O:33])[NH:17][C:13]4=[CH:14][CH:15]=[CH:16][C:10](=[C:11]34)[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1NC(c1ccccc1)CO2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cccc3c2n1C(c1ccccc1)CO3
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
The 3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (0.95 g, 4.2 mmol) was dissolved in THF (30 mL) and DIPEA (1.5 mL, 8.4 mmol) at room temperature (room temperature). The N,N-carbonyldiimidazole (0.82 g, 5.0 mmol) was added portion wise over 10 min. The reaction was heated to 70° C. for 1 h and allowed to cool to room temperature and stirred overnight. To the reaction mixture was added EtOAc, and then the mixture was washed with water, sodium bicarbonate water and brine, then dried over magnesium sulfate and concentrated to give crude product as a dark oil. The oil was triturated with ethyl ether to give a precipitate. The solids were triturated twice with ethyl ether and then the solids were collected and air dried to give 4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a brown solid (0.51 g, 48%). LCMS calc. for C15H13N2O2 (M+H)+: m/z=253.1. found: 253.1. 1H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.39-7.22 (m, 3H), 7.15-7.04 (m, 2H), 6.88 (t, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 5.45 (s, 1H), 4.54 (dd, J=11.6, 2.2 Hz, 1H), 4.37 (dd, J=11.6, 3.0 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][C:37]([CH3:42])([CH3:41])[CH2:36]1)(=[O:34])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:41][C:37]1([CH3:42])[CH2:36][N:35]([S:32]([CH3:31])(=[O:33])=[O:34])[CH2:40][CH2:39][N:38]1[C:18]([C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2)=[O:19]
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCN(S(C)(=O)=O)CC3(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (117 mg, 0.26 mmol), 1-methanesulfonyl-3,3-dimethylpiperazine (51 mg, 0.26 mmol) and HATU (100 mg, 0.26 mmol) in DMF (1 mL) was added NEt3 (720 μL, 5.18 mmol). The resulting mixture was allowed to stir at r.t. for 16 h then partitioned between EtOAc and H2O. The organic phase was dried (MgSO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%). The resulting solid was recrystallised from EtOAc and Et2O affording 715 (50 mg, 33%). LCMS (method I): RT 3.68 min, [M+H]+ 582.2. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.03 (1 H, m), 7.76-7.75 (1 H, m), 7.31-7.27 (2 H, m), 4.35 (4 H, brd s), 4.03 (2 H, t, J=5.39 Hz), 3.95 (3 H, s), 3.87 (4 H, t, J=4.70 Hz), 3.50 (2 H, t, J=5.40 Hz), 3.37 (2 H, q, J=7.47 Hz), 3.31 (2 H, s), 2.90 (3 H, s), 1.68 (6 H, s), 1.45 (3 H, t, J=7.47 Hz)
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH3:27])[C:6]1[C:7]2[CH2:15][C:14](=[O:16])[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].[O:28]=P(Cl)(Cl)Cl.C(N(CC)CC)C.CNC>C(#N)C>[CH2:1]([N:5]([CH2:26][CH3:27])[C:6]1[C:7]2[C:15](=[O:28])[C:14](=[O:16])[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1nc(C)nc2c1CC(=O)N2c1c(C)cc(C)cc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: CNC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCN(CC)c1nc(C)nc2c1C(=O)C(=O)N2c1c(C)cc(C)cc1C

Procedure:
To a solution of 4-(butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (76 mg, 0.207 mmol), POCl3 (0.039 ml, 0.415 mmol), triethylamine (0.059 ml), and dimethylamine (1 ml) in 2 ml acetonitrile was heated at reflux for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a brown form (105 mg). After silica gel column chromatography, the title compound was isolated as a yellow glass (10 mg). 1H NMR (CDCl3) δ 7.00 (s, 2H), 3.95-4.15 (m, 2H), 3.65-3.85 (m, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 2.10 (s, 6H), 1.55-1.75 (m, 2H), 1.35-1.55 (m, 2H), 1.25 (t, 3H), 1.00 (t, 3H) ppm.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])Cl>>[CH2:1]([N:5]1[CH2:7][CH2:8][CH2:9][Si:10]1([CH3:13])[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: C[Si](C)(Cl)CCCCl
Product: CCCCN1CCC[Si]1(C)C
Temperature: 10 °C

Procedure:
An initial charge of 508 g (6.94 mol) of 1-butylamine is admixed dropwise over the course of 2.5 h with 171 g (1.00 mol) of chloropropyldimethylchlorosilane and the mixture is heated at reflux for 12 h. Following distillative removal of the excess 1-butylamine, the residue is diluted with 350 ml of toluene and cooled to 10° C. The precipitate it forms is filtered off and the filtrate is distilled in vacuo. This gives 134.5 g of N-butyl-1,1-dimethyl-1-sila-2-azacyclopentane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[CH:13][C:14]#[N:15])=[CH:5][CH:4]=1.N.C(O)C>C(O)C.[Ni]>[NH2:15][CH2:14][CH2:13][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)C(=CC#N)CCC2
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)C(CCN)CCC2
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of (1,2,3,4-tetrahydro-7-methoxy-1-naphthylidene)acetonitrile (1.0 g, 5.02 mmol) in ethanol (10 ml) were added a saturated ammonia/ethanol solution (5 ml) and Raney nickel (W-2, 1 g). The mixture was stirred for 4 hours at 50° C. under hydrogen atmosphere (3-4 kgf/cm2). The Raney nickel was filtered off and, then, the solvent was distilled off under reduced pressure to give 1-(2-aminoethyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene. To a solution of this 1-(2-aminoethyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene and triethylamine (0.76 g, 7.53 mmol) in THF (20 ml) was gradually added dropwise, under ice-cooling, cyclopropanecarbonyl chloride (0.63 g, 6.02 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water. The organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography (ethyl acetate:hexane=2:8) to give the above-titled compound (1.04 g, yield 76%, oil).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:41][CH:42]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Cc1ccc(N)c(C)c1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1ccc(NC(=O)c2ccc(CN3C(=O)C4(COc5cc6c(cc54)CCO6)c4ccccc43)cc2)c(C)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2,4-dimethylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,4-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]benzamide was obtained (59%) as a colorless solid: mp 249-251° C.; 1H NMR (300 MHz, CDCl3) δ7.91-7.83 (m, 2H), 7.76-7.69 (m, 1H), 7.56 (s, 1H), 7.50-7.43 (m, 2H), 7.28-7.17 (m, 2H), 7.09-7.01 (m, 3H), 6.80-6.74 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.60-4.51 (m, 2H), 3.11-2.92 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 165.2, 161.9, 161.3, 141.7, 139.6, 135.3, 134.6, 132.9, 132.6, 131.2, 129.8, 128.7, 127.7, 127.4, 124.0, 123.6 (2C), 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0, 20.9, 17.8; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[NH:21][C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:12]=[C:11]([CH3:30])[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>[CH3:29][O:28][C:25]1[N:24]=[CH:23][C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[C:13]2[N:12]=[C:11]([CH3:30])[N:10]=[C:9]([NH2:8])[N:14]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccncc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2cnccc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A glass microwave reaction vessel was charged with N,N-bis(4-methoxybenzyl)-4-(3-(6-methoxypyridin-3-ylamino)pyridin-4-yl)-6-methyl-1,3,5-triazin-2-amine (7 mg, 0.013 mmol) and trifluoromethane sulfonic acid (3.38 μL, 0.038 mmol) in TFA (0.1 mL). The reaction mixture was stirred and heated in an oil bath at room temperature for 2 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow solid. The crude product was purified by silica gel chromatography eluting with EtOAc to give 4-(3-(6-methoxypyridin-3-ylamino)pyridin-4-yl)-6-methyl-1,3,5-triazin-2-amine (3.2 mg, 10.35 μmol, 81% yield). 1H NMR (300 MHz, CDCl3) δ 10.38 (s, 1H); 8.38 (s, 1H); 8.24 (d, J=5.12 Hz, 1H); 8.13 (s, 1H); 8.07 (d, J=4.97 Hz, 1H); 7.58 (dd, J=8.77, 2.05 Hz, 1H); 6.81 (d, J=8.77 Hz, 1H); 5.41 (s, 2H); 3.96 (s, 3H); 2.54 (s, 3H). m/z (ESI, +ve ion) 310.0 (M+H)+.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]1[CH:29]=[CH:28][C:11]([O:12][CH2:13][C:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[O:15])=[CH:10][CH:9]=1.[O:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].N1CCCCC1>C(O)(=O)C>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:17][C:16]=1[C:14](=[O:15])[CH2:13][O:12][C:11]1[CH:28]=[CH:29][C:8]([CH2:7][CH2:6][CH:2]=[C:34]2[O:30][C:31](=[O:36])[NH:32][C:33]2=[O:35])=[CH:9][CH:10]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CCC2OCCO2)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CCC=C2OC(=O)NC2=O)cc1

Procedure:
A mixture of 4-[4-[2-(1,3-dioxolan-2-yl)ethyl]phenoxyacetyl]-5-methyl-2-phenyloxazole (1.8 g), 2,4-oxazolidinedione (0.925 g), piperidine (0.12 g) and acetic acid (30 ml) was heated for 15 hours under reflux. The reaction mixture was concentrated under reduced pressure. To the concentrate was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The chloroform layer was washed with water, dried (MgSO4), followed by distilling off the solvent. The oily residue was subjected to a silica gel column chromatography. From the fractions eluted with methanol-chloroform (1:30, v/v) was obtained 5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]phenyl]propylidene]-2,4-oxazolidinedione. This compound was dissolved in tetrahydrofuran (THF) (30 ml), to which was added palladium-carbon (5%, 0.3 g). The mixture was subjected to catalytic hydrogenation. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The oily residue was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:1, v/v), 5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxyaphenyl]propyl]-2,4-oxazolidinedione (0.32 g, 16%) was obtained as an oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]=1.C(#N)C.C(Cl)Cl>CN(C=O)C.C(N(CC)CC)C.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: c1ccc(COc2ccc(N3CCNCC3)nc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc(COc2ccc(N3CCN(Cc4nc5ccccc5[nH]4)CC3)nc2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
The product from Example 29C and 2-chloromethyl-1H-benzoimidazole (0.88 mg) were combined and dissolved in DMF (7 mL)/triethylamine (1.5 mL). After stirring at 23° C. for 2 hours, the mixture was treated with acetonitrile (20 mL) and then allowed to stir for 24 hours. The reaction mixture was partitioned between CH2Cl2 (100 mL)/n-butanol (5 mL) and water (800 mL)/NH4OH (5 mL). The organic phase was separated, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography to provide the title as a white solid (1.169 g (55%). mp 62-64° C.; Rf=0.26 (95:5 CH2Cl2:methanol:0.1% NH40H); MS 400 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 12.3 (bs, NH, 1H), 7.90 (d, 1H, J=3 Hz), 7.55 (m, 1H), 7.3-7.5 (m, 8H), 7.15 (m, 2H), 6.80 (d, 1H, J=9 Hz), 5.05 (s, 2H), 3.76 (s, 2H), 3.39 (t, 4H, J=5.1 Hz), 2.57 (t, 4H, J=5.1 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:25][CH:24]=1
Reactant: CSc1ccc(N)cc1
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Product: CSc1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(O)CC3)n2)cc1

Procedure:
The title compound was prepared by treating 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol (0.3 g, 1.04 mmol) with 4-methylsulfanyl-phenylamine (0.15 g, 1.04 mmol) according to the procedure as described above.
Reaction SMILES: C[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.CCN(CC)CC.[Si]([I:29])(C)(C)C.II>C(Cl)Cl>[I:29][N:7]1[C:8](=[O:9])[CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][C:6]1=2
Reactant: C[Si](C)(C)I
Reactant: CC1C(=O)Nc2ccccc2-c2ccccc21
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 3-A) and Et3N (2.66 mL, 19.12 mmol) was stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 mL, 9.54 mmol). After stirring for 15 minutes I2 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2. and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 mL and diluted with an additional 20 mL of hexanes. The title compound was isolated as a tan precipitate by filtration.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20]N=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.ClC1[C:31]([O:32][CH3:33])=CN=C2NC=CC=12.C(OC(N1CCNCC21CC2)=O)(C)(C)C>>[CH2:10]1[C:9]2([CH2:12][N:13]([C:16]3[C:31]([O:32][CH3:33])=[CH:20][N:19]=[C:18]4[NH:22][CH:23]=[CH:24][C:17]=34)[CH2:14][CH2:15][NH:8]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: COc1cnc2[nH]ccc2c1Cl
Agent: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: COc1cnc2[nH]ccc2c1N1CCNC2(CC2)C1

Procedure:
Prepared in a sequence similar to the sequence described for intermediates 1 and 2, starting from 4-chloro-5-methoxy-1H-pyrrolo[2,3-b]pyridine and 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:13](F)=[CH:12][N:11]=1>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:13]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:12][N:11]=1
Reactant: Fc1cnc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cnc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.81 %

Procedure:
To a mixture of 2.0 ml 2,2,2-trifluoroethanol in 35 mL dry DMF was added 1.1 g sodium hydride was added and the mixture was stirred at room temperature for 15 minutes. The resulting solution was added drop wise at −10° C. to a solution of 7 g 2-chloro-4-(3,4-dichloro-phenyl)-5-fluoro-pyrimidine in 50 mL dry DMF during 39 min. The reaction mixture was then stirred at room temperature for 2 h. The resulting brown mixture was partitioned between water and ethyl acetate, the phases were separated the organic phase was dried over MgSO4 and purified by chromatography on silica gel with a gradient of heptane:dichloromethane=1:1 to dichloromethane to yield 5.575 g (61.81%) of the title compound as light yellow solid, MS 356.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[S:10][C:5]=2[C:4](=[O:21])[NH:3]1.[NH3:23].CO>O1CCOCC1>[NH2:23][C:13]1[N:12]=[C:11]([C:9]2[S:10][C:5]3[C:4](=[O:21])[NH:3][C:2]([CH3:22])([CH3:1])[NH:7][C:6]=3[CH:8]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CC1(C)NC(=O)c2sc(-c3ccnc(S(C)(=O)=O)n3)cc2N1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2sc(-c3ccnc(N)n3)cc2N1
Yield: 53 %

Procedure:
A mixture of 2,2-dimethyl-6-[2-(methylsulfonyl)pyrimidin-4-yl]-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.044 g, 0.13 mmol) and 7 M ammonia in methanol (2.0 mL, 14 mmol) in 1,4-dioxane (8 mL) was microwave-irradiated at 120° C. for 75 min. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified twice by flash chromatography (Combiflash, silica gel, ethyl acetate to 90:10 ethyl acetate/methanol) to give the title compound (0.019 g, 53%) as a yellow solid:
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([C:24]1[O:28][N:27]=[C:26]([NH2:29])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[O:28][N:27]=[C:26]([NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: CC(C)(C)c1cc(N)no1
Product: CCc1cc(-c2cncc(C(=O)Nc3cc(C(C)(C)C)on3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (5-tert-butyl-isoxazol-3-yl)-amine to afford the title compound. MS: m/e=381 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH3:27])[CH:18]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:25])[CH3:26])=[C:19]([CH3:27])[CH:18]=3)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Yield: 104 %

Procedure:
8-Benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (10 mg, 0.02 mmol), K2CO3 (12 mg, 0.09 mmol) and iodomethane (2 μL, 0.03 mmol) in DMF (0.1 mL) was stirred for 1 hour. The mixture was diluted with ethyl acetate (5 mL), washed with water (2 mL) and brine (2 mL), dried over magnesium sulfate, filtered and evaporated to give methyl 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylate (10 mg, 100%). ESI-MS m/z calc. 480.6. found 481.5 (M+1)+; Retention time: 1.82 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C.Cl.O>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:2]([Br:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(SCc2ccncc2)c(Br)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(SCc2ccncc2)c(Br)c1
Temperature: 60 °C

Procedure:
4-[(2-Bromo-4-nitrophenylthio)methyl]pyridine (D14) (0.800 g, 2.56 mmol) was dissolved in ethanol (40 ml) and heated to 60° C. with stifling. A solution of tin (II) chloride (1.696 g, 8.96 mmol) in conc. HCl (8 ml) was then added dropwise. The reaction mixture was heated under reflux for 2 h, then allowed to cool, diluted with water (40 ml) and basified to pH14 by the addition of 10% sodium hydroxide. The reaction mixture was concentrated in vacuo and the aqueous residue was extracted with dichloromethane (2×70 ml). The combined organic layers were then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a brown oil, which was dried in vacuo (0.670 g, 93%).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>CCCCO>[Cl:9][C:6]1[N:5]=[C:4]([NH2:10])[N:3]=[C:2]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:7]=1[NH2:8]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: CCCCO
Product: COc1ccc(CNc2nc(N)nc(Cl)c2N)cc1

Procedure:
A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and 1-aminomethyl-4-methoxybenzene was refluxed in n-BuOH for 15 h, following the general procedure 1. HPLC RT was 4.675 min. 1HNMR (CDCl3) δ 7.29–7.27 (d, 2H), 6.91–6.89 (d, 2H), 5.62 (br. t, 1H) 4.67 (s, 2H), 4.56–4.54 (d, 2H), 3.84 (s, 3H), 2.74 (s, 2H).