Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([OH:7])[CH:5]=[CH:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].[C:10]([O:14][C:15](=[O:18])[CH2:16]Br)([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.C1COCC1>[C:10]([O:14][C:15](=[O:18])[CH2:16][O:6][CH:3]1[CH2:2][CH:1]([OH:7])[CH:5]=[CH:4]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O[C@@H]1C=C[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COC1C=CC(O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 2.0 g (20 mmol) of cis-4-cyclopentene-1,3-diol in 1.5 ml of DMF and 15 ml of THF and, at 0° C., add 799 mg (60% strength, approx. 20 mmol) of sodium hydride in portions. After the end of the addition, warm the mixture to RT and stir at RT for a further 1 h, before adding 2.7 ml (18.2 mmol) of bromoacetic acid tert-butyl ester. Then stir the mixture at RT overnight. Then add water, extract with dichloromethane, wash the organic phase with satd. sodium chloride solution, concentrate under reduced pressure and dry the residue under high vacuum. Isolate the product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1→2:1). 1.10 g (25.6% of theory) of the target compound are obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][CH2:23][CH2:24][O:25][C:26](=[O:30])[CH:27](Br)[CH3:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:22][CH2:23][CH2:24][O:25][C:26](=[O:30])[CH:27]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH3:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(Br)C(=O)OCCOCc1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1ccccc1
Temperature: 60 °C

Procedure:
12.1 g of hydroquinone were dissolved in 60 ml of dry dimethylformamide, 31.7 g of potassium carbonate were added thereto in a slow stream of nitrogen, and then the mixture was heated to 90° to 95° C. for one hour with stirring. The mixture was cooled to 60° C., and to it were added dropwise 28.7 g of 2-benzyloxyethyl-2-bromopropionate. The reaction mixture was heated at 90° C. for two hours. After cooling the reaction solution to room temperature, it was poured into ice-water and adjusted to pH7, then extracted with 100 ml of toluene. The toluene layer was dried and filtered, and then toluene was removed under reduced pressure. The colorless oily product of 2-benzyloxyethyl-2-(4-hydroxyphenoxy)propionate was obtained in a yield of 24.6 g. (nD21.5 1.5390)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23](=[CH:25][C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:24]>C(O)C>[CH3:20][C:19]1[NH:22][C:23]([CH3:24])=[C:25]([C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: CC(N)=CC(=O)CCC(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CCC(C)C)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 35 mg (0.227 mmol) of 2-amino-7-methyloct-2-en-4-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 45.3 mg (61% of theory) of the title compound as a white solid.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH2:13][CH:14]2[C:19](=[O:20])[NH:18][CH:17]=[CH:16][N:15]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.C(Cl)CCl.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[O:20]=[C:19]1[NH:18][CH:17]=[CH:16][N:15]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:14]1[CH2:13][C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:6][CH:7]=1)=[O:31]
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)Nc2ccc(CCC=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)Nc2ccc(CCCN3CCCCC3)cc2)cc1

Procedure:
To a 20 mL flask equipped with stirring was added N-[4-(3-oxo-propyl)-phenyl]-2-[3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetamide (45 mg, 0.102 mmol), ClCH2CH2Cl (2 mL), piperidine (Aldrich, 0.02 mL, 0.204 mmol) and one drop of HOAc. NaBH(OAc)3 was added after 5 min. The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 (40 mL). The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative TLC (10% MeOH—CH2Cl2) afforded the title compound. MS (ESI): 511 (M+H)+.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)cc1

Procedure:
2,3,4-Trifluorobenzoic acid and methyl 4-aminobenzoate were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B, to afford after workup, crude 3,4-difluoro-2-[[4-(methoxycarbonyl)-phenyl]amino]benzoic acid as a cream solid. This material was then coupled directly with 2-(aminooxy)ethanol by the general procedure of Example 1; Step E, and purified on flash silica (10% EtOAc as eluant) to give methyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]amino]benzoate (48%) as a white solid; m.p. (EtOAc/hexanes) 158–160° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.64 (br s, 1 H), 8.76 (br s, 1 H), 7.78 (d, J=8.8 Hz, 2 H), 7.41–7.27 (m, 2 H), 6.80 (dd, J=8.8, 1.8 Hz, 2 H), 4.67 (br s, 1 H), 3.78 (s, 3 H), 3.76 (t, J=4.8 Hz, 2 H), 3.50 (t, J=4.6 Hz, 2 H). Anal. Calcd for C17H16F2N2O5: C, 55.7; H, 4.4; N, 7.7. Found: C, 55.7; H, 4.4; N, 7.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=NO)C1C(=CC=CC=1)O.Br[C:24]1[CH:25]=[CH:26][C:27]([Cl:31])=[C:28]([CH3:30])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu]=O>[CH3:30][C:28]1[CH:29]=[C:24]([N:10]2[CH:11]=[CH:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:9]2)[CH:25]=[CH:26][C:27]=1[Cl:31]
Reactant: Clc1cccc(-c2cc[nH]n2)c1
Reactant: Cc1cc(Br)ccc1Cl
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccc(-c3cccc(Cl)c3)n2)ccc1Cl
Temperature: 140 °C
Yield: 21.7 %

Procedure:
A mixture of 3-(3-chlorophenyl)-1H-pyrazole (5.3 g, 29.8 mmol) (prepared according to the method given in European Patent Publication EP 538156), salicylaldoxime (0.58 g, 4.25 mmol), 5-bromo-2-chlorotoluene (2.8 g, 21.3 mmol), copper oxide (0.15 g, 1.06 mmol) and cesium carbonate (11.8 g, 36.2 mmol) in 20 mL of N,N-dimethylformamide was heated at 140° C. overnight and then allowed to cool to room temperature. The resulting suspension was filtered and the filtrate was concentrated under reduce pressure. The resulting residue was purified by medium pressure liquid chromatography (2 to 10% gradient of ethyl acetate in hexanes as eluant) to give the title compound as a white solid (1.4 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[CH2:27]([Al+]CC(C)C)[CH:28](C)C.[Cl-].[NH4+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC>C(Cl)Cl.O1CCCC1.C(OCC)C.CCCCCC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:27]=[CH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
After a solution of 1,4-dibenzyl-2-(ethoxycarbonyl)piperazine (6.76 g) in methylene chloride (250 ml) was cooled to −78° C., diisobutylaluminum hydride (a 1.0 mol/l hexane solution, 39.90 ml) was added dropwise and the mixture was stirred at −78° C. for 2 hours. A saturated aqueous solution of ammonium chloride and methylene chloride were added to the reaction mixture. The water layer was extracted three times. The organic layers were combined, washed with distilled water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was provided for the subsequent reaction without purification. After cooling a tetrahydrofuran solution (150 ml) of methyltriphenylphosphonium iodide (8.07 g) to −78° C., n-butyl lithium (a 1.52 mole hexane solution, 13.14 ml) was added dropwise and the mixture was stirred at −78° C. for 2 hours. A solution of the residue, which residue had been obtained above, in tetrahydrofuran was then added. The reaction mixture was heated from −78° C. to 0° C. while stirring for 4 hours and then, a saturated aqueous solution of ammonium chloride was added to terminate the reaction. Diethyl ether was added and the water layer was extracted three times. The organic layers were combined, washed with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:50), whereby the title compound (3.22 g) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:28][C@H:27]([F:30])[C@@H:26]3[C@H:22]2[CH2:23][NH:24][CH2:25]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:24]1[CH2:23][C@@H:22]2[C@@H:26]([C@@H:27]([F:30])[CH2:28][CH2:29][C:21]2([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25]1)=[O:12]
Reactant: F[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Product: CN(C)c1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2F
Yield: 27 %

Procedure:
By carrying out the procedure as in Example 9 below, using 0.16 g of 2-dimethylaminophenylacetic acid and 0.30 g of (3aR, 7S, 7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, 0.11 g of (3aR, 7S, 7aR)-2-[(2-dimethylaminophenyl)acetyl]4,4-diphenyl-7-fluoroperhydroisoindole is obtained in the form of a white meringue.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].O.C(O)(=O)C.[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCC(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCN1CCC(C2CCNCC2)CC1

Procedure:
A solution of 7.6 g (0.023 mol) of 1-ethyl-4-[1-(phenylmethoxycarbonyl)-4-piperidinyl]piperidine in a mixture of 70 ml of methanol, 30 ml of water and 10 ml of glacial acetic acid was hydrogenated in the presence of 10% palladium/charcoal at room temperature and 3 bar of hydrogen pressure until the uptake of hydrogen had ceased. After working up in the usual way the desired compound was obtained as a colourless oil in a quantitative yield.
Reaction SMILES: C1([C@@H:7]([NH:9]C2C=C(C3C=CC=C4C=3C=CC=N4)N=CC=2N)C)C=CC=CC=1.[C:27]1([C@@H:33]([N:35]2[C:43]3[CH:42]=[C:41]([C:44]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:45]=4[CH:46]=[CH:47][CH:48]=[N:49]5)N=C[C:38]=3[NH:37][C:36]2=[O:54])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.NC(N)=O.O>CN1CCCC1=O>[C:27]1([C@@H:33]([N:35]2[C:43]3[C:38](=[N:9][CH:7]=[C:41]([C:44]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:45]=4[CH:46]=[CH:47][CH:48]=[N:49]5)[CH:42]=3)[NH:37][C:36]2=[O:54])[CH3:34])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@@H](c1ccccc1)n1c(=O)[nH]c2cnc(-c3cccc4ncccc34)cc21
Reactant: C[C@H](Nc1cc(-c2cccc3ncccc23)ncc1N)c1ccccc1
Agent: NC(N)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 185 °C
Yield: 19.2 %

Procedure:
(S)-1-(1-Phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one ((1S)-1-Phenylethyl)(3-amino-6-(5-quinolyl)(4-pyridyl))amine (450mg, 1.32 mmol) and urea (158 mg, 2.64 mmol) were combined in 1-methylpyrrolidin-2-one (4 mL) and heated at 185° C. for 2 h. Water (10 mL) was added and the crude product was collected by filtration. The product was purified by reverse-phase preparative HPLC (20-95% acetonitrle in water, over 30 min) to give the product (92.9 mg, 19%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.91 (dd, J=4.10, 1.76, 1H), 8.39 (d, J=0.78, 1H), 8.33 (ddd, J=8.00, 1.27, 1.07, 1H), 8.05 (d, J=8.40, 1H), 7.80 (dd, J=8.49, 7.13, 1H), 7.59 (dd, J=7.13, 1.27, 1H), 7.41-7.47 (m, 3H), 7.29-7.41 (m, 3H), H), 5.75 (d, J=7.22, 1H), 4.16 (d, J=0.78, 1H), 1.87 (d, J=7.22, 3 H); MS (ESI) m/z 367.0 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][N+:5]=1[O-:13].[CH3:14][CH:15]([OH:17])[CH3:16]>>[CH:15]([O:17][C:8]1[CH:7]=[CH:6][N+:5]([O-:13])=[C:4]([CH3:3])[CH:9]=1)([CH3:16])[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(OC(C)C)cc[n+]1[O-]
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 1.06 g) in 2-propanol (30 ml) was added 2-methyl-4-nitropyridine N-oxide (3.08 g), and the mixture was stirred at 60° C. for 1 hour. The residue was evaporated under reduced pressure and purified by column chromatography (silica gel 75 g, 5% methanol in dichloromethane) to give 4-isopropyloxy-2-methylpyridine N-oxide (0.78 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:15][CH2:14]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:48][CH3:49].C(O)(C(F)(F)F)=O>>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]5[CH2:31][CH2:32][C@H:33]([N:36]6[CH2:41][CH2:40][N:39]([CH2:42][CH:43]7[CH2:45][CH2:44]7)[CH2:38][CH2:37]6)[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 2) (0.14 g, 0.45 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.26 g, 0.67 mmol, 1.5 eq) and TFA (0.17 mL, 2.2 mmol, 5 eq) in TFE (3 mL) were heated together at 80° C. for 18 hours. Further quantity of Intermediate 2 (0.14 g) was added and the reaction further heated for 48 hours. RM was concentrated in vacuo and the residue was purified by flash column chromatography on silica eluting with 0→20% ammonia/MeOH in DCM gradient followed by preparative HPLC (Preparative—4) then finally preparative RP-HPLC-MS (Preparative—1) to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (0.11 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][N:24]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[5-Chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[5-chloro-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.075 g, 0.160 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.025 mL, 0.239 mmol) in a manner analogous to Example 313 to give product (0.030 g, 34%). MP=190-191° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.50 (m, 3H), 7.30 (d, 1H), 7.05 (m, 2H), 6.25 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 3.75 (m, 7H), 2.55 (m, 4H). MS=556 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:40][C:41]([NH:43][CH:44]([CH:51]([CH3:53])[CH3:52])[C:45]([O:47][CH:48](Cl)[CH3:49])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17](=[O:18])[C:19]4[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=4[F:33])=[CH:15][N:14]([CH:48]([O:47][C:45](=[O:46])[CH:44]([NH:43][C:41]([O:40][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:42])[CH:51]([CH3:52])[CH3:53])[CH3:49])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(Cl)OC(=O)C(NC(=O)OC(C)(C)C)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 64.8 %

Procedure:
The title compound was prepared according to the procedure as described in Example 14 step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL), KOH (69 mg, 1.22 mmol) and a solution of 1-chloroethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (172 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) to afford the title compound as orange oil (0.29 g, 65%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:11]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH3:10])[CH2:8][NH:9][C:37](=[O:38])[CH2:36][N:19]2[CH2:20][CH2:21][CH2:22][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]2=[O:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: CC(CN)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(CNC(=O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2-diphenylpropan-1-amine (0.10 g, 0.5 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.16 g, 0.50 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.19 g, 1.00 mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.05-7.35 (m, 20H), 6.0-6.1 (m, 1H), 3.98 (s, 2H), 3.95 (s, 2H), 3.2-3.4 (m, 2H), 2.4-2.5 (m, 2H), 1.65-1.75 (m, 2H), 1.5 (s, 3H); MS (ESI+) m/z 503 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:8](=[O:29])[C:7]1=[O:30].[C:31]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)#[N:32].C(N(CC)CC)C.Cl>O1CCCC1.O.C(OCC)(=O)C>[C:31]([C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[C:8](=[O:29])[C:7]2=[O:30])(=[O:41])=[O:40])=[CH:37][CH:38]=1)#[N:32]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCN1CCN(CC(=O)OC(c2ccccc2)c2ccccc2)C(=O)C1=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)NCCCN2CCN(CC(=O)OC(c3ccccc3)c3ccccc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
In 7 ml of tetrahydrofuran was dissolved 0.70 g of diphenylmethyl [4-(3-aminopropyl)-2,3-dioxopiperazin-1-yl]acetate hydrochloride, and 0.36 g of 4-cyanobenzenesulfonyl chloride and then 0.58 ml of triethylamine were added thereto under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was added to a mixed solvent of 20 ml of ethyl acetate and 20 ml of water and the pH was adjusted to 3 with 2N hydrochloric acid. The organic layer was separated, washed with water and then a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform : methanol=20:1) to obtain 0.43 g of diphenylmethyl [4-[3-(4-cyanobenzenesulfonyl-amino)propyl]-2,3-dioxopiperazin-1-yl]acetate as a yellow foamy substance.