Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:71]1[CH2:76][CH2:75][N:74]([CH:77]2[CH2:82][CH2:81][CH:80]([NH2:83])[CH2:79][CH2:78]2)[CH2:73][CH2:72]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([N:71]1[CH2:72][CH2:73][N:74]([C@H:77]2[CH2:82][CH2:81][C@H:80]([NH:83][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([NH:21][C:19]4[N:18]=[CH:17][C:8]5[N:9]([CH3:16])[C:10](=[O:15])[C:11]6([CH2:14][CH2:13]6)[CH2:12][N:6]([CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[C:7]=5[N:20]=4)=[C:23]([O:31][CH3:32])[CH:24]=3)[CH2:79][CH2:78]2)[CH2:75][CH2:76]1)[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: NC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(Cc4ccccc4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-benzylpiperazin-1-yl)cyclohexanamine (Intermediate 18) (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide N-((trans)-4-(4-benzylpiperazin-1-yl)cyclohexyl)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzamide (white solid, 13 mg, 13%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O)=[O:55].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:51])[CH3:52])[C:41]([F:53])=[C:40]([CH:26]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:32][CH:33]=2)[C:4]2[N:5]([C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[C:2]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=3[CH:54]=[O:55])[N:3]=2)[CH:45]=1)[CH3:48]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 150 °C
Yield: 96.4 %

Procedure:
A suspension of Intermediate 66.3 (100 mg, 0.13 mmol), 2-formyl phenylboronic acid (30 mg, 0.2 mmol), Na2CO3 (56 mg, 0.52 mmol) in 3:1 DME/H2O (4 mL) was degassed and then added in Pd(PPh3)4 (10 mg). The reaction mixture was heated to 150° C. for 8 min in microwave. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated. The residue was subject to chromatographic purification (0-30% EtOAc/hexanes gradient), 100 mg (65%) of Intermediate 122.1 was obtained. LCMS (2 min gradient) RT 2.35 min, 798.3 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][CH2:24][CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[H-].[Na+].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([CH2:24][CH3:25])[C:28]1=[O:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNc1nc(SC)ncc1CNc1c(F)c(OC)cc(OC)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(SC)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of 4.92 g (11.58 mmol) of (5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-ethyl-amine in 85 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The reaction mixture was treated with 1.16 g (28.95 mmol) of sodium hydride and continued stirring at 0° C. for 30 minutes. After 30 minutes, 5.63 g (34.74 mmol) of 1,1′-carbonyldiimidazole was added and continued to stir at 0° C. for an additional 30 minutes. After 1 hour, the ice bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture heated at reflux overnight under nitrogen atmosphere. Evaporated the tetrahydrofuran and partitioned the residue between dichloromethane and water. The aqueous layer was extracted one time with 250 mL dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified using medium-pressure chromatography eluting with 2:1 hexanes/ethyl acetate to give 4.23 g (92%) of the title compound: mp 165° C.–168° C. MS (APCI) (m+1)/z 397.1.
Reaction SMILES: [C:1]12([N:6]3[C:10]4[N:11]=[C:12](Cl)[N:13]=[CH:14][C:9]=4[C:8]([C:16]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=4)=[O:17])=[CH:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]12([N:6]3[C:10]4[N:11]=[C:12]([NH:32][CH2:31][C:30]5[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[N:13]=[CH:14][C:9]=4[C:8]([C:16]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=4)=[O:17])=[CH:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: O=C(c1cncc(Br)c1)c1cn(C23CC(C2)C3)c2nc(Cl)ncc12
Reactant: COc1ccc(CN)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncc3c(C(=O)c4cncc(Br)c4)cn(C45CC(C4)C5)c3n2)cc1
Temperature: 110 °C
Yield: 84 %

Procedure:
To a solution of (7-Bicyclo[1.1.1]pent-1-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-bromo-pyridin-3-yl)-methanone (Preparation 284, 1.1 g, 2.72 mmol) and 4-methoxy benzyl amine (1.06 mL, 8.16 mmol) in dioxane (40 mL), DIPEA (1.7 mL, 10.8 mmol) was added and mixture was heated at 110° C. under microwave irradiation for 6 hours. The volatiles were removed in vacuo and the residue was partitioned between water (50 mL) ethyl acetate (150 mL). Organic phase was dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (gradient of EA:Hexane 25:75) to afford the title compound as off white solid in 84% yield, 1.15 g.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]1=[O:28].[OH-].[Na+]>C(O)C>[C:22]1([N:13]2[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])[C:12]2=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
The product is produced as described in example 18 from 8.2 g of 8-(3.4-diphenyl-2-oxo-4-imidazolin-1-yl) caprylic acid methyl ester and 0.84 g of NaOH in 20 cc. of ethanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1>C(#N)C.[I-].[K+]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([N:16]3[CH2:17][CH2:18][N:19]([CH2:29][CH2:30][CH2:31][C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[CH2:20][CH2:21]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: Cn1cc(CCCBr)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cn1cc(CCCN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cn1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.200 g, 0.604 mmol) in acetonitrile (10 mL). Add potassium carbonate (0.334 g, 2.415 mmol), potassium iodide (0.005 g, 0.030 mmol), and 4-(3-bromo-propyl)-1-methyl-1H-pyrazole (0.184 g, 0.906 mmol). Heat reaction at reflux for 14 hr. under nitrogen. Cool to room temperature and partition between water and ethyl acetate. Separate and extract aqueous with ethyl acetate. Combine organic portions, dry over sodium sulfate, filter, and concentrate in vacuo. Purify residue by flash chromatography eluting with chloroform:methanol 19:1 to afford 3′-(4-fluoro-phenyl)-4-[3-(1-methyl-1H-pyrazol-4-yl)-propyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.194 g). Dissolve in acetonitrile (1 mL) and add aqueous 1N HCl (0.561 mL, 0.561 mmol). Stir for 1 h at room temperature. Remove organics and lyophilize to afford the title compound (0.189 g, 75% yield). MS (m/z)=381[M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[OH-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O.C(OCC)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(OCCCCN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.4 g of 4-(4-aminobutoxy)benzonitrile hydrochloride (Example 52) is in 100 ml of water is treated successively with 3.5 ml of 10N NaOH and 3.5 g of 4-methylphenylsulfonyl chloride in 100 ml of diethyl ether. The mixture is stirred at room temperature for two hours, a precipitate forming. The solid is collected, washed with water and diethyl ether, dried, and recrystallized from 50% aqueous ethanol; m.p. 107°-108° C.; yield, 3.5 g.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH3:36])[CH:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH2:34][OH:35])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:19]1>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:35][CH2:34][C:32]2[O:31][N:30]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][CH:18]([N:17]([CH3:36])[CH3:16])[CH2:19]4)=[CH:28][CH:27]=3)[N:33]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C1CCN(c2ccc(-c3noc(CO)n3)cc2)C1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(-c3noc(COCc4ccc(F)cc4)n3)cc2)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-Fluorobenzyl bromide (18.9 mg) and potassium carbonate (27.6 mg) were added to a mixture of {3-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl][1,2,4]oxadiazol-5-yl}methanol (28.8 mg) and DMF (0.3 ml). The reaction mixture was stirred at 60° C. for 3 h, filtered and purified by preparative HPLC. The product with the molecular weight of 396.20 (C22H25FN4O2) was obtained in this way; MS (ESI): 397.27 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Cl:30].CN1CCOCC1.[C:43]1([N:49]=[C:50]=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC(N(C)C)=O>[Cl:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:50]([NH:49][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:51]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Cl)c(=O)n1-c1c(F)cccc1F
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2ccc(F)cc2CNC(=O)Nc2ccccc2)c(Cl)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.25 g, 0.48 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.06 mL, 0.53 mmol) and phenyl isocyanate (0.06 mL, 0.53 mmol). The reaction was stirred at RT for 1.5 h. Solvent distilled and crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to a white solid, dried in vacuo (0.18 g, 71%). 1H NMR (CD3OD/400 MHz) δ 7.60 (m, 1H), 7.54 (m, 1H), 7.33 (d, 2H, J=7.6 Hz), 7.22 (m, 5H), 7.06 (m, 1H), 6.95 (t, 1H, J=7.2 Hz), 6.73 (s, 1H), 5.44 (s, 2H), 4.53 (s, 2H), 2.07 (s, 3H). ES HRMS m/z 528.1304 (M+H calculated for C27H22ClF3N3O3 requires 528.1296).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH3:18])[C:3]=1[CH3:19].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]2[CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:4]([CH3:18])[C:3]=1[CH3:19]
Reactant: BrC1CCCC1
Reactant: Cc1c(I)ccc(N=C2NC3(CCCC3)CS2)c1C
Product: Cc1c(I)ccc(N=C2SCC3(CCCC3)N2C2CCCC2)c1C

Procedure:
4-Iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2,3-dimethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH3:18])[C:11](=[O:19])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>ClCCl>[CH2:30]([O:29][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH3:18])[C:11](=[O:19])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COCCN1CCN(c2ccc(N)cc2F)CC1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)fluorobenzene (3.5 g) was dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.33 ml) was added, and the mixture cooled to -20° C. Benzyl chloroformate (2.06 ml) was added, and the mixture stirred for 10 minutes at -20° C., before allowing the temperature to rise to ambient over 1.5 hours. Solvents were evaporated, the residue dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying (MgSO4) and evaporation of solvent, the residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 5-benzyloxycarbonylamino-2-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)fluorobenzene (3.28 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].B(OC)(OC)OC>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: COB(OC)OC
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 100.2 %

Procedure:
A flask purged with nitrogen was charged with 3-methyl-4-nitro-benzoic acid (72.5 g, 0.400 mol), trimethyl borate (166.2 g, 1.600 mol) and dry tetrahydrofuran (1449 mL). A solution of borane dimethyl sulfide complex (63.8 g, 79.8 mL, 0.840 mol) was added drop-wise to the stirred batch at 20-35° C. over at least 30 min. An exotherm and effervescence were observed during the addition. The mixture was stirred at 65° C. for at least 6 h or until in-process HPLC analysis showed that conversion was greater than 97%. Reaction was quenched at 20-40° C. with cooling by drop-wise addition of methanol (46 mL) followed by aq 5 N hydrochloric acid (144 mL) over at least 30 min. Exotherm and effervescence were observed during the quench. After stirring the batch at 50° C. for at least 1 h, it was concentrated under reduced pressure to a volume of 360 mL. The concentrated batch was washed with water (453 mL) and the solids were collected on a filter. The wet filter cake was dissolved in CH2Cl2 (2170 mL) at and the resulting solution dried over anhydrous magnesium sulfate (36 g). The dried filtrate solution containing the title compound (˜67 g, 100% yield) was used directly in the preparation of 3-methyl-4-nitro-benzaldehyde.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[NH2:17][C:18]([NH:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[C:30]([NH2:32])=[O:31])=[CH:27][CH:26]=[C:25]([C:33](OC)=[O:34])[CH:24]=2)=[O:19].O.CO>O1CCCC1>[NH2:17][C:18]([NH:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[C:30]([NH2:32])=[O:31])=[CH:27][CH:26]=[C:25]([CH2:33][OH:34])[CH:24]=2)=[O:19]
Reactant: COC(=O)c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)Nc1[nH]c2cc(CO)ccc2c1C(N)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.8 %

Procedure:
1.0 M Diisobutylaluminium hydride hexane solution (68 mL, 68 mmol) was added to a solution of 2-aminocarbonylamino-6-methoxycarbonylindole-3-carboxamide (Compound 2-17, 4.0 g, 15 mmol) in anhydrous tetrahydrofuran (50 mL) under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. Water (2 mL) and methanol (20 mL) were added to the reaction mixture, and the mixture was filtered throught Celite® pad with methanol (200 mL) and 1,4-dioxane (200 mL). After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (10 mL) and dried under reduced pressure to give the title compound (2.3 g) as a yellow solid (yield 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[N:9]=[C:8]([C:10]3[C:11](=[O:17])[NH:12][CH:13]=[CH:14][C:15]=3Cl)[NH:7][C:6]=2[CH:18]=1.[NH2:20][C@@H:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][OH:23].CN1CCOCC1>CN(C=O)C>[CH2:24]([C@H:21]([NH:20][C:15]1[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=1[C:8]1[NH:7][C:6]2[CH:18]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:19])[C:5]=2[N:9]=1)[CH2:22][OH:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 73.5 %

Procedure:
To a solution of 3-(6-bromo-4-methyl-1H-benzimidazol-2-yl)-4-chloro-1H-pyridin-2-one (1.42 g, 3.78 mmol) in DMF (15 mL) were added (S)-(−)-2-amino-3-phenyl-1-propanol (1.43 g, 9.45 mmol) and N-methyl morpholine (1.5 mL). The reaction mixture was heated to 80° C. for 6 h and cooled to room temperature. The solvent was removed with high vacuum and the residue was purified by flash chromatography (5% MeOH/CH2Cl2) to yield the title compound (1.26 g, 74%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 6.9–7.2 (8H, m), 5.86 (1H, d, J=7.1 Hz), 3.7–3.9 (3H, m), 2.9–3.1(2H, m), 2.57 (3H, s). LCMS (M+H)+ m/z 453 (t=2.03 min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:38])[CH3:37])=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:38])[CH3:37])=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: CC(=O)Nc1ccc2c(c1)CCCN2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(NC(C)=O)ccc43)CC2C)cc1OC
Yield: 7.1 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (350 mg, 1.07 mmol) prepared in Reference Example 1 and N-(1,2,3,4-tetrahydro-quinolin-6-yl)acetamide (475 mg, 2.50 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (38 mg, yield: 7%) as a colorless oil. (cis:trans=1:1.7)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[C:8]([C:25]2[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=2[CH3:37])[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])[C:9]2[CH2:14][NH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:10]=2[N:24]=1.[CH2:38]([NH2:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:23])[C:16]=1[N:11]1[C:10]2[N:24]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:40][CH2:38][CH3:39])[N:7]=[C:8]([C:25]3[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=3[CH3:37])[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])[C:9]=2[CH2:14][NH:13][C:12]1=[O:15]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCCl)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCNCC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To 3-[2-[(3-chloropropyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (265 mg, 0.50 mmol) in DMF (10 mL) was added ethylamine (1.25 mL, 2.0 M in THF, 2.5 mmol) and potassium carbonate (0.276 g, 2.0 mmol). The mixture was heated at 50° C. for about 20 hours, then at 80° C. for about 4 hours. The mixture was diluted with EtOAc (50 mL), washed with H2O (30 mL+15 mL×2) and brine (20 mL). The organic layers were collected and concentrated. Flash chromatograph afforded the title compound (134 mg, 50%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 0.96-1.02 (m, 6H), 1.61-1.72 (m, 2H), 1.85-1.96 (m, 2H), 2.30 (s, 3H), 3.07 (q, J=7.11 Hz, 2H), 3.19-3.29 (m, 3H), 3.33-3.40 (m, 3H), 3.83 (d, 1H), 3.90 (d, 1H), 6.83-6.99 (m, 3H), 7.51 (d, J=8.03 Hz, 1H), 7.69 (d, J=1.76 Hz, 1H), 7.87 (dd, J=7.91, 1.88 Hz, 1H).