Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:21][C:20]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[N:16]2[C:17]=1[CH:18]=[N:19][C:14]([NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc4cccnc34)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc5cccnc45)n3n2)cc(OC)c1OC
Yield: 29.2 %

Procedure:
In a similar manner as described for Example 1, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)quinoline-8-carboxamide (Intermediate 41) (0.080 g, 0.17 mmol) in 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.13 mL, 1.4 mmol) gave 5-methyl-7-quinolin-8-yl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.022 g) as a yellow solid. 1H NMR (CDCl3): δ8.90 (dd, J=4.2, 1.8 Hz, 1H), 8.83 (s, 1H), 8.22 (dd, J=8.3, 1.8 Hz, 1H), 8.03 (dd, J=7.2, 1.5 Hz, 1H), 7.97 (dd, J=8.2, 1.5 Hz, 1H), 7.67 (dd, J=8.2, 7.1 Hz, 1H), 7.45-7.41 (m, 1H), 6.91 (bs, 1H), 6.58 (s, 2H), 3.69 (s, 3H), 3.25 (s, 6H), 2.67 (s, 3H). MS m/z 443 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[CH:33][C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH:43]=1)=[CH:40][CH:39]=[CH:38][CH:37]=3>CC(N(C)C)=O>[CH:33]1[C:34]2[NH:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]=2[CH:43]=[C:31]([O:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=1
Reactant: Oc1ccc2[nH]c3ccccc3c2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c5ccccc5c4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.595 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (411 mg, 2.98 mmol) and 3-hydroxycarbazole (142 mg, 0.774 mmol) in DMA (2.0 ml) was stirred at 85° C. for 3 hours then allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated to give a solid residue. The residue was purified by silica column chromatography with gradient elution using dichloromethane with 0%, 2%, 4%, 10% methanolic ammonia to give 4-(9H-carbazol-3-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (212 mg, 74%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=O)[CH2:4][CH2:3]1.[F:21][C:22]1[C:23]([CH3:30])=[C:24]([NH2:29])[C:25]([NH2:28])=[CH:26][CH:27]=1>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]2[N:28]=[C:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:14]=3)[NH:29][C:24]=2[C:23]=1[CH3:30]
Reactant: CN1CCC(OCCCOc2cccc(C=O)c2)CC1
Reactant: Cc1c(F)ccc(N)c1N
Solvent: CN(C)C=O
Product: Cc1c(F)ccc2nc(-c3cccc(OCCCOC4CCN(C)CC4)c3)[nH]c12
Yield: 37.8 %

Procedure:
6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phenyl}-1H-benzoimidazole. To a stirred solution of 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzonitrile (0187 g, 0.68 mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.5 M diisobutylaluminum hydride in toluene (1.02 mL, 1.02 mmol, 1.5 equiv). After 3 h, methanol (9 mL) and 1 M H2SO4 (10 mL) were added. The mixture was stirred for 30 min, then 1.0 M NaOH (10 mL) was added, followed by satd. aq. sodium potassium tartrate (40 mL) and dichloromethane (100 mL). After stirring for 30 min, the mixture was extracted three times with chloroform (50 mL) and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was partially purified by Method 2 to afford 106 mg of a mixture of 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde and several other unidentified products. A solution of the crude 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde (53 mg), 4-fluoro-3-methyl-benzene-1,2-diamine (27 mg), and Na2S2O5 in DMF was stirred at 90° C. for 18 h. The reaction mixture was loaded directly on silica gel and purified according to Method 2, which afforded 28.7 mg of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13]2)[CH:9]=1)=[O:7].[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>ClCCl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH:9]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC2C=C(C(=O)c3ccco3)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1=CC2CNCC2C1)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromofuran (0.11 g, 0.74 mmol) in THF (3 mL) at −78° C. was added n-BuLi solution (2.5 M solution in hexanes, 0.30 mL, 0.75 mmol) and the mixture was stirred for 1 h. A solution of N-methoxy-N-methyl-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-ene-7-carboxamide (0.20 g, 0.65 mmol) in THF (2 mL) was added, and the mixture was warmed to ambient temperature over 8 h. The reaction was quenched with water (0.2 mL), diluted with of ethyl (20 mL) acetate, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The crude product was purified on silica gel column chromatography to obtain 0.10 g of 2-furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone and 0.06 g of recovered starting material. A sample of 2-furanyl(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone (0.050 g, 0.16 mmol) was dissolved in dichloromethane (3 mL), treated with TFA (2.0 mL), and stirred at ambient temperature for 1 h. The volatiles were evaporated, and the product was vacuum dried to obtain 0.047 g of 2-furanyl(3-azabicyclo[3.3.0]oct-6-en-7-yl)methanone trifluoroacetate (1H NMR (CD3OD, 300 MHz): δ 7.81-7.80 (m, 1H), 7.38-7.36 (m, 1H), 6.91-6.88 (m, 1H), 6.65 (dd, J=3.66, 1.71 Hz), 3.95-3.86 (m, 1H), 3.56-3.40 (m, 3H), 3.27-3.16 (m, 1H), 3.14-3.02 (m, 2H), 2.77-2.68 (m, 1H); MS (m/z): 204 (M+1)). This material exhibited Ki values at rat and human α4β2 of 8 nM and 2 nM respectively and did not pass HTS for α7.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH3:13]
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1C(=O)C(=O)c2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-chloroisatin (CAS#6344-05-4, 3.64 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mmol). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered, and concentrated to provide 4-chloro-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 4-chloro-1-methyl-1H-indole-2,3-dione (1.55 g, 7.92 mmol) was then treated with hydrazine hydrate (14.8 ml, 475 mmol). The reaction was then placed at 70° C. and heated to 130° C. over 20 minutes. The reaction was stirred at 130° C. for 45 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were then separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 4-chloro-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 182.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[BH4-].[Na+].O>CO>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(CCOc1ccc(CO)cc1)c1ccccn1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 4-[2-(methyl-2-pyridylamino)ethoxy]benzaldehyde (15.0 g) in methanol (70 ml), sodium borohydride (1.11 g) was added at 0° C. In portions. After stirring for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and 4-[2-(methyl-2-pyridylamino)ethoxy]benzylalcohol (14.3 g, yield 94%) was obtained from a fraction eluted with ethyl acetate-hexane (1:1, v/v) as an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>CO.[C].[Pd]>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2ccncc2)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A suspension of 4-(4-(trifluoromethyl)phenyl)pyridine (500 mg, 2.24 mmol, 1.00 equiv), CF3COOH (1.27 g, 11.14 mmol, 5.00 equiv), and palladium carbon (100 mg, 5%) in methanol (50 mL) was hydrogenated overnight under an atmosphere of H2(g) at 30° C. in an oil bath. The reaction mixture was filtered and washed with methanol and concentrated in vacuo. The pH value of the solution was adjusted to 8-9 with aqueous sodium hydroxide (1 M). The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and concentrated under vacuum, yielding 350 mg (68%) of 4-(4-(trifluoromethyl)phenyl)piperidine as brown oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH2:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:16]#[C:17][CH3:18]>O1CCCC1>[CH2:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:16]#[C:17][CH3:18]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cccc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)Oc2c(C)cccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 0.50 g (3.012 mmol) of methyl 2-hydroxy-3-methyl-benzoate in 20 mL of tetrahydrofuran (THF) is added 0.133 g (3.313 mmol) of a 60% oil dispersion of sodium hydride. The reaction mixture is stirred for 1 h at room temperature and then 0.739 g (3.012 mmol) of 4-but-2-ynyloxy benzenesulfonyl chloride is added. The resulting mixture is stirred at room temperature for 15 h and then quenched with saturated ammonium chloride solution. The resulting mixture is extracted with ether and the combined organics are then washed with water and brine. The organic layer is then dried over MgSO4, filtered and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 0.93 g (83%) of methyl 2-({[4-(2-butynyloxy)phenyl]sulfonyl}oxy)-3-methylbenzoate as a white solid. Electrospray Mass Spec: 374.8 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[S:12])[NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Ca+2]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:12][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[N:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(C)(C)OC(=O)NCC(N)=S
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CCOC(=O)c1sc(CNC(=O)OC(C)(C)C)nc1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a solution of 5.02 g of (tert-butoxycarbonylamino)acetothioamide in 75 ml of ethanol were added 3.92 ml of ethyl 2-chloroacetoacetate and 2.75 g of calcium carbonate, and the mixture was stirred at 50° C. for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 5:1 mixture of toluene and ethyl acetate to give 5.65 g (yield 71%) of the title compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([C:19]([CH2:21][C:22](OCC)=[O:23])=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:19]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][CH:10]=3)=[CH:21][C:22](=[O:23])[O:5]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1cccc2ccccc12
Agent: Cl
Solvent: CCO
Product: O=c1cc(-c2cccc3ccccc23)c2ccc(O)cc2o1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of resorcinol (4.84g., 0.041 moles) and ethyl 1-naphthoylacetate (10g., 0.041 moles) in ethanol (50 ml.) was saturated with hydrogen chloride at room temperature (cooling with ice/water) and left to stand in a stoppered flask for 24 hours. The solution was filtered to give the required coumarin as an orange solid (7.8g., 66%, m.p. 292°-295° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].O[CH2:28][CH:29]1CC1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:29][CH2:28]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 5 h

Procedure:
A mixture of 8.0 g (24 mmol) of ethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 0.5 g (7.7 mmol) of potassium cyanide and 60 ml of hydroxymethyl-cyclopropane is stirred at 130° for 5 hours, during this time a small amount of solvent being distilled off four times by the application of a slight vacuum. The mixture is subsequently evaporated in vacuo, the residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are washed three times with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is crystallized from ethyl acetate and there is obtained cyclopropylmethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of decomposition point 183°-185° (partially racemized).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Si:9]([O:4][CH2:3][CH2:2][Br:1])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCBr
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 2-bromoethanol (50 g, 0.40 mol) in CH2Cl2 (50 mL) was added t-butyldimethyl-chlorosilane (63.4 g, 0.42 mol), triethylamine (45.4 g, 0.45 mol) and dimethylaminopyridine (0.5 g). After stirring overnight the reaction mixture was washed 3× with water. The organic fraction was dried with Na2SO4, filtered, and concentrated in vacuo to provide 85 g of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][NH:29][C@@H:30]2[CH2:35][CH2:34][C@H:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C=O.[CH3:42]C(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][N:29]([CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]2)[CH3:42])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)N2CCCC2CN[C@H]2CC[C@@H](C(=O)OC)CC2)ccc1NC(=O)Nc1ccccc1C
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(N(C)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
To a stirred solution of methyl cis-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]cyclohexanecarboxylate (300 mg, 0.55 mmol), HCHO (300 ml), and AcOH (66 mg, 1.1 mmol) in MeOH (10.0 ml) was added NaBH3CN (70 mg, 1.1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. After concentrated in vacuo, water was added and extracted with CH2Cl2. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by TLC with MeOH—CH2Cl2 (3:97, v/v) as eluent to give methyl 4-[N-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]cyclohexanecarboxylate (160 mg, 52%) as an amorphous solid. 1H-NMR (CDCl3) δ1.30-2.20 (m, 12H), 2.27-2.37 (m, 6H), 2.50-2.60 (m, 1H), 3.30-3.80 (m, 5H), 3.55 (s, 2H, 3.66-3.73 (m, 6H), 4.10-4.20 (m, 1H), 6.60-7.55 (m, 7H), 8.03 (m, 1H), 8.15 (m, 1H).
Reaction SMILES: [CH:1]1([N:6]([CH2:17][CH2:18][C:19]([O:21]C)=O)[C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Cl:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.[Fe]>[Cl:16][C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:19](=[O:21])[CH2:18][CH2:17][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:7]=2[N:8]=1
Reactant: COC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Yield: 30.7 %

Procedure:
Methyl 3-(N-cyclopentyl-N-(2-chloro-5-nitropyrimidin-4-yl)amino)propionate (2.0 g, 6.1 mmol) in glacial acetic acid at 70° C. was treated in portions with iron powder (0.7 g, 12.4 mmol) over 6 hours. The mixture was concentrated and triturated with dichloromethane and filtered. The filtrate was absorbed onto silica gel and soxhlet extracted over 7 hours with ethyl acetate. The extract was concentrated to a black oil and triturated with methanol to give pale brown crystals of 2-chloro-9-cyclopentyl-8,9-dihydro-5H-pyrimido[4.5-b][1,4]diazepin-6(7H)-one (499 mg, 31%). NMR 1.46-1.58 (4H, m), 1.60-1.72 (2H, m), 1.75-1.85 (2H, m), 2.64 (2H, d), 3.55 (2H, d), 4.92-5.03 (1H, m), 7.83 (1H, s), 9.72 (1H, s).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]([PH:17](=[O:19])[OH:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C@@H:21]([CH3:39])[C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]([PH:17]([O:18][CH:21]([CH3:39])[C:22]([N:24]2[CH2:38][CH2:37][CH2:36][C@H:25]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:23])=[O:19])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCC(NC(=O)OCc1ccccc1)[PH](=O)O
Reactant: C[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCC(NC(=O)OCc1ccccc1)[PH](=O)OC(C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1-[[(phenylmethoxy)carbonyl]amino]pentylphosphinic acid (490 mg., 1.72 mmole) and 1-[(S)-2-hydroxy-1-oxopropyl]-L-proline, phenylmethyl ester (255 mg., 0.92 mmole) in dry tetrahydrofuran (5 ml.) is treated with dicyclohexylcarbodiimide (285 mg., 1.38 mmole) and dimethylaminopyridine (50 mg.) and stirred at room temperature for 2.5 hours. The mixture is filtered, diluted with ethyl acetate, and washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride solutions, dried over sodium sulfate, and evaporated to give crude (S)-1-[2-[[[1-[[(phenylmethoxy)carbonyl]amino]pentyl]phosphinyl]oxy]-1-oxopropyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[C:30]([CH3:38])[CH:29]=2)=[O:26])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:38][C:30]1[CH:29]=[C:28]([NH:27][C:25](=[O:26])[NH:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][CH:16]([NH:15][S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:17][CH2:18]2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1
Reactant: Cc1cc(NC(=O)NCCN2CCC(N)CC2)c2ccccc2n1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)c2ccccc2n1
Temperature: 40 °C

Procedure:
A solution of 4-trifluoromethyl-benzenesulfonyl chloride (0.03 mmol) in THF (1 mL) is added to a mixture of 1-[2-(4-amino-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea (0.025 mmol), DIPEA (6 μL) and THF (1 mL). The reaction mixture is heated at 40° C. for 18 h, and then is evaporated to dryness. The residue is taken up in formic acid (1 mL), and purified by preparative HPLC to provide the title compound.