Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:53]=[CH:52][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][OH:51])[CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:54][CH3:55]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:53]=[CH:52][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][OH:51])[CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:54][CH3:55])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 20 %

Procedure:
A mixture of 0.112 g (0.34 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.097 g (0.51 mmole) of toluenesulfonic acid monohydrate, 0.10 g (0.34 mmole) of 4-amino-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 170 degrees in a microwave reactor for 2 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was by preparative thin layer chromatography, eluting with dichloromethane-methanol (90:10) to give 0.040 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-methoxy-benzamide (I-267).
Reaction SMILES: [NH2:1][CH:2]([CH3:50])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]5[CH2:35][O:34][C:33]([C:42]6[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=6[F:49])([CH2:36][N:37]6[CH:41]=[N:40][CH:39]=[N:38]6)[O:32]5)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[CH:51](=O)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.S1C=CC=C1>CO.[Pd]>[F:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[C:33]1([CH2:36][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[O:32][CH:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:13]=[CH:12][C:11]([N:8]5[CH:7]=[N:6][N:5]([CH:3]([CH3:4])[CH:2]([NH:1][CH2:51][C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[CH3:50])[C:9]5=[O:10])=[CH:16][CH:15]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH2:35][O:34]1
Reactant: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CC(NCc1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O

Procedure:
A mixture of compound 37 (0.0029 mol) and benzaldehyde (0.0029 mol) in methanol (250 ml) was hydrogenated at 50° C. overnight with Pd on activated carbon 10% (2 g) as a catalyst in the presence of thiophene solution (2 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and 2-propanol, filtered off and dried, yielding 1.1 g (48%) of [2S-[2α,4α(S*,R*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(phenylmethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (compound 106; mp. 154.3° C.).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH2:11])=[CH:2]1.Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1.C(N(C(C)C)C(C)C)C>CCO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:13]2[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=2)=[CH:2]1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1c[nH]c2ncccc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCc1c[nH]c2ncccc12
Temperature: 150 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A mixture of (1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine (intermediate A) (442 mg, 3.0 mmol), 3,5-dibromopyrazin-2-amine (758 mg, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (1160 mg, 9.0 mmol) in EtOH (70 mL) was stirred at 150° C. overnight. After being cooled to room temperature, it was concentrated and purified by chromatography to afford the title compound (70 mg) MS (m/z): 319 (M+1)+.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:25])[C:23]#[N:24])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(C4(C#N)CCC4)=C(F)C=3)CC(O)=C(CC3N=C4N=C(C)C=C(C)N4N=3)C(=O)O2)CCCC1.[CH3:67][C:68]1[CH:69]=[N:70][C:71]2[N:72]([N:74]=[C:75]([CH:77]=O)[N:76]=2)[CH:73]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:25])[C:23]#[N:24])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:77][C:75]3[N:76]=[C:71]4[N:70]=[CH:69][C:68]([CH3:67])=[CH:73][N:72]4[N:74]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1cnc2nc(C=O)nn2c1
Agent: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CCC5)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(C(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared analogously to example A(236) substituting 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-propionitrile from example A(241) in place of 1-(4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-cyclobutanecarbonitrile and 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ: 1.66-2.00 (m, 8H), 2.30 (s, 2H), 2.36 (s, 2H), 2.49-2.62 (m, 4H), 2.69-2.85 (m, 3H), 3.49-3.59 (m, 1H), 3.89-3.94 (m, 1H), 4.01-4.08 (m, 2H), 4.18 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Br:8])[CH2:5][CH2:6][Br:7].[CH3:10][NH2:11]>>[CH3:10][NH:11][C:3](=[O:2])[CH:4]([Br:8])[CH2:5][CH2:6][Br:7]
Reactant: CN
Reactant: COC(=O)C(Br)CCBr
Product: CNC(=O)C(Br)CCBr

Procedure:
In a second step of the reaction, the methyl-2,4-dibromobutyrate is reacted with methylamine in an aqueous solution at a temperature of below ambient in order to form N-methyl-2,4-dibromobutyramide. Then butyramide is then recovered and purified to obtain the solid intermediate product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([OH:6])=[O:5].[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)C>[NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([O:6][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:5]
Reactant: C=C(C)C
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Yield: 78 %

Procedure:
The tert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionate was prepared as follows. 10 g (42 mmol) of (S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4 in an autoclave under an N2 pressure of 20 atm for 3 days. Excess isobutylene was blown out and 150 ml of diethyl ether and 150 ml of saturated NaHCO3 solution were added to the remaining solution. The phases were separated and the aqueous phase was extracted 2× using 100 ml of diethyl ether each time. The combined organic phases were washed with 2×100 ml of water and dried over Na2SO4. After removal of the solvent in vacuo, 9.58 g (78%) of tert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionate were obtained as a pale yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[OH:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:18][CH3:19])[N:12]=1>>[OH:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([N+:1]([O-:4])=[O:2])=[C:13]([O:18][CH3:19])[N:12]=1
Reactant: COc1cc(O)nc(O)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1nc(O)nc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of barbituric acid (51.2 g) in methanol (1 L) was added concentrated sulfuric acid (80 mL) in a dropwise manner over 20 minutes, and the mixture was stirred at room temperature for 22 hours. The crystals were collected by filtration. The collected crystals were washed with methanol, cold water and diethyl ether successively, and dried under reduced pressure to give 2,4-dihydroxy-6-methoxypyrimidine (52.9 g). To a mixture of fuming nitric acid (20 mL) and concentrated sulfuric acid (10 mL) was added 2,4-dihydroxy-6-methoxypyrimidine (14.2 g) slowly at around 15° C., and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ice water (150 mL), and the mixture was stirred at room temperature for 30 minutes. The crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give the title compound (7.4 g).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: O=C(O)CCCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCCC(=O)O)cc2)cc1
Temperature: 130 °C

Procedure:
In a microwave reaction vial was placed (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50 mg, 0.185 mmol), 4-(4-bromophenyl)butanoic acid (49.6 mg, 0.204 mmol), dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (2.63 mg, 3.71 μmol), and K2CO3 (51.3 mg, 0.371 mmol) in toluene (1.2 mL) and H2O (0.2 mL). The reaction was heated at 130° C. for 120 min under microwave irradiation. The aqueous layer was collected, acidified with 1M HCl, and purified by HPLC to give the title compound. LCMS m/z=352.4 [M+H]+; 1.26 (d, J=6.8 Hz, 0.4H), 1.46 (d, J=6.5 Hz, 2.6H), 1.70-1.82 (m, 1H), 1.87-1.94 (m, 2H), 2.01-2.10 (m, 2H), 2.21-2.30 (m, 1H), 2.33 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.7 Hz, 2H), 3.06-3.18 (m, 4H), 3.35-3.45 (m, 1H), 3.50-3.60 (m, 1H), 3.74-3.84 (m, 1H), 7.31 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[NH:7][C:8]([CH2:12]Cl)=[N:9]2)=[CH:4][C:3]=1[CH3:15].[C:16]([O-:19])(=[O:18])[CH3:17].[Cs+]>CN(C=O)C>[C:16]([O:19][CH2:12][C:8]1[NH:7][C:6](=[O:14])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([CH3:15])[CH:4]=2)[N:9]=1)(=[O:18])[CH3:17]
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2cc1Cl
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-chloro-2-chloromethyl-6-methyl-3,4-dihydroquinazolin-4-one (0.500 g, 2.06 mmol), anhydrous DMF (14 ml) and cesium acetate (1.58 g, 8.24 mmol) was placed in an oil bath preheated to 85° C., then stirred at this temperature for 2 hours and 15 min under argon. The reaction mixture was then allowed to cool to room temperature and the solvent was removed in vacuo. The residue was treated with hexanes (20 ml), collected by filtration, washed with hexanes (20 ml), water, and dried in vacuo over P2O5 (0.476 g, 87%), mp 220-225° C., 1H-NMR (DMSO-d6) 2.14 (s, 3H, CH3CO), 2.45 (s, 3H, 6-CH3), 4.95 (s, 2H, 2-CH2O), 7.70, 8.06 (2×s, 2H, 5-H and 8-H), 12.44 (s, 1H, N3—H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=[O:3])[CH3:2].[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([S:4][CH2:5][CH:6]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-benzoic acid prepared in Example 68-(b)-[1] (0.3 g), 4-dimethylaminopyridine (0.01 g) and benzyl alcohol (0.1 g) are dissolved in dichloromethane (25 ml), and thereto is added EDC.HCl (0.18 g), and the mixture is stirred at room temperature three nights. The reaction mixture is washed with saturated aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by a silica gel column chromatography (eluant, chloroform) to give the title compound (0.26 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.CO.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+]>O>[C:15]1([N:21]([C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: NNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NN(C(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture consisting of 101.2 g. (0.602 mole) ethyl p-fluorobenzoate, 250 ml. methanol, 70.0 g. (0.646 mole) phenylhydrazine, and 33.6 g. (0.621 mole) sodium methoxide (mixed in that order) was heated at the reflux temperature for 16 hrs. After cooling the reaction mixture to about 25°C it was poured into 1500 ml. water. The aqueous mixture was filtered, and the filter cake was washed with water and recrystallized from 95% aqueous ethanol. The crystals melted at 174° to 178°C. An analytical sample of p-fluorobenzoic acid phenylhydrazide melting at 177° to 179°C. was obtained by recrystallizing once from a mixture of ethyl acetate and Skellysolve B (essentially a mixture of isomeric hexanes boiling in the range of 146° to 156°F.), and once from 75% aqueous ethanol.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:24]([N:26]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25]>>[CH2:24]([N:26]([CH:37]1[CH2:42][CH2:41][N:40]([CH2:1][C@@H:3]2[CH2:5][C@@:4]2([CH2:12][N:13]([CH3:23])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:39][CH2:38]1)[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25]
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Reactant: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Product: CCN(C(=O)OCc1ccccc1)C1CCN(C[C@@H]2C[C@@]2(CN(C)S(=O)(=O)c2ccccc2)c2ccccc2)CC1

Procedure:
N-{[(1S,2R)-2-formyl-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide and benzyl ethyl(piperidin-4-yl)carbamate (incorporating by reference as needed Bioorg. and Med. Chem. Lett., 11 (2001), 2475) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, DMSO-d8) δ 7.70-7.56 (m, 5H), 7.40-7.17 (m, 10H), 5.09 (s, 2H), 3.88 (d, J=13.3 Hz, 1H), 3.75 (m, 1H), 3.19 (q, J=6.6 Hz, 2H), 3.09-3.05 (m, 1H), 2.91-2.87 (m, 1H), 2.83 (d, J=13.3 Hz, 1H), 2.58-2.52 (m, 1H), 2.52 (s, 3H), 2.44-2.38 (m, 1H), 2.08-1.92 (m, 2H), 1.77-1.58 (m, 4H), 1.41-1.37 (m, 0.1H), 1.07 (t, J=6.6 Hz, 3H), 1.07-0.99 (m, 1H), 0.78 (m, 1H). ES-LCMS m/z 576.1 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Oc3ccc(Cl)cc3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), 4-chlorophenol (0.22 mL), potassium carbonate (0.76 g) and DMF (10 mL) was stirred at 100° C. for 16 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(4-chlorophenoxy)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.59 g, 84%) as a white powder.
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[N+:8]([C:3]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ncccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ncccc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-2-nitropyridine (3.32 g, 23.38 mmol) and 2-aminopyridine (2.0 g, 21.25 mmol) in DMF (35.4 mL) was added potassium tert-butoxide (4.77 g, 42.5 mmol). The solution was stirred under nitrogen at rt overnight. After 22 h, the mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). After drying with MgSO4, the solution was filtered and concentrated in vacuo to provide the crude material as a orange solid. The orange solid was purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(2-nitropyridin-3-yl)pyridin-2-amine as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.53 (1H, s), 8.58 (1H, dd, J=8.4, 1.6 Hz), 8.15 (1H, dd, J=4.3, 1.4 Hz), 8.10-8.14 (1H, m), 7.66-7.76 (2H, m), 7.05 (1H, dt, J=8.4, 0.8 Hz), 6.93 (1H, ddd, J=7.2, 5.0, 0.9 Hz); LC-MS (ESI) m/z 217.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCC1.ClC1C=C2C(/C(=C/C3C=CC=C(Cl)C=3)/C(=O)N2)=CC=1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Temperature: 65 °C

Procedure:
To the mixture of 6-bromooxindole (16.2 g, 92 mmol) (Combi-block) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) dropwise. The mixture was then heated at 65° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 16.2 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[O:15][CH:16]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]([CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[O:15][CH:16]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1coc(CN2CCN(C)CC2)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1-c1coc(CN2CCN(C)CC2)c1
Yield: 99.8 %

Procedure:
To a solution of 1-{[4-(2-methoxy-5-nitrophenyl)-2-furyl]methyl}-4-methylpiperazine (396 mg, 1.19 mmol) in 20 mL of methanol was added 10% palladium on carbon (40 mg). The resulting mixture was shaken with hydrogen in a Parr shaker until hydrogen uptake ceased. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to give 358 mg (100%) of (4-methoxy-3-[5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine as a brown oil, 1H NMR (DMSO-d6) δ 2.14 (s, 3H), 2.29 (broad s, 4H), 2.40 (broad s, 4H), 3.49 (s, 2H), 3.72 (s, 3H), 4.61 (s, 2H), 6.47 (d, J=8 Hz, 1H), 6.58 (s, 1H), 6.78 (d, J=9 Hz, 1H), 6.80 (s, 1H), 7.91 (s, 1H); MS 302.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].CCN(CC)CC.[CH3:22][NH:23][CH2:24][CH:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[CH2:27][CH2:26]1>O1CCOCC1>[CH2:1]([O:4][C:5]([C:7]1[C:8]([N:23]([CH3:22])[CH2:24][CH:25]2[CH2:32][CH2:31][C:28]3([CH2:29][CH2:30]3)[CH2:27][CH2:26]2)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: CNCC1CCC2(CC1)CC2
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1cnc(Cl)nc1N(C)CC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a solution of the 2,4-dichloropyrimidine-5-carboxylic acid allyl ester (1.6 mmol) in dioxane (6 mL) is added Et3N (2.4 mmol) at room temperature. A solution of methyl-spiro[2.5]oct-6-ylmethylamine (1.6 mmol) in dioxane (2.0 mL) is added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 12 h and the reaction is quenched by the addition of water. The mixture is extracted with CH2Cl2. The organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the title compound (370 mg); 1H NMR (CDCl3) δ 0.15-0.19 (m, 2H), 0.25-0.29 (m, 2H), 0.87-0.91 (m, 2H), 1.08-1.20 (m, 2H), 1.60-1.85 (m, 5H), 2.95 (s, 3H), 3.59 (d, 2H), 4.77-4.78 (m, 2H), 5.29-6.08 (m, 1H), 8.48 (s, 1H).
Reaction SMILES: [CH2:1]([CH2:5][PH:6](Cl)=[O:7])[CH:2]=[CH:3][CH3:4].[O-:9][C:10]#[N:11].[Na+]>C(#N)C>[CH2:1]([CH2:5][PH:6]([N:11]=[C:10]=[O:9])=[O:7])[CH:2]=[CH:3][CH3:4]
Reactant: N#C[O-]
Reactant: CC=CCC[PH](=O)Cl
Agent: [Na+]
Solvent: CC#N
Product: CC=CCC[PH](=O)N=C=O
Reaction time: 4.5 h
Yield: 70.3 %

Procedure:
170 g (1.1 mol) of crotylmethylphosphinic acid chloride were dissolved in 300 ml of acetonitrile and heated with 73 g (1.1 mol) of sodium cyanate to 55° C. with stirring. After 4.5 hours, the precipitate was filtered off by suction and washed with acetonitrile; the filtrate was concentrated and the residue distilled at a temperature of 76°-78° C. and at a pressure of 27 Pa. 123 g of crotylmethylphosphinic acid isocyanate (70% of theory) were obtained.