Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1)[C:21]#[N:22].[O:30]1CCCC1>O>[NH2:22][C:21]([C:20]1[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=[C:18]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=1)=[O:30]
Reactant: C1CCOC1
Reactant: N#Cc1cc(Cl)nc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(N)=O)cc(C(F)(F)F)n2)CC1
Reaction time: 0.75 h

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (0.37 g, 1.8 mmol, Aldrich) was added to sodium hydride (74 mg, 1.8 mmol, 60% in mineral oil) in tetrahydrofuran (2.1 mL). After stirring for 45 minutes, 2-chloro-6-(trifluoromethyl)isonicotinonitrile (0.24 g, 0.93 mmol, from Step A) in tetrahydrofuran (1.3 mL) was introduced. After stirring overnight, the mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes afforded product (0.20 g, 44%). 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=1.2 Hz, 1H), 7.23 (dd, J=1.3, 0.6 Hz, 1H), 6.15 (s, 1H), 5.75 (s, 1H), 5.30 (tt, J=1.1, 3.8 Hz, 1H), 3.95-3.62 (m, 4H), 3.33 (ddd, J=13.5, 8.4, 3.7 Hz, 2H), 3.02 (ddd, J=13.3, 9.8, 3.4 Hz, 2H), 1.58 (s, 9H); 19F NMR (282 MHz, CDCl3) 5-68.97 (s); LCMS (M+Na)+: 412.0.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[CH:3][C:4]=4[CH3:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1cc(N)ccc1Oc1ccc2nc(NC(=O)C3CC3)cn2c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2ccc(C)n(-c3ccc(F)cc3)c2=O)ccc1Oc1ccc2nc(NC(=O)C3CC3)cn2c1
Yield: 73.5 %

Procedure:
Using N-[6-(4-amino-2-methylphenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.31 mmol), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (99.7 mg, 0.403 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (107 μL, 0.620 mmol) and HATU (153 mg, 0.403 mmol) and in the same manner as in Example 57, the title compound (125.7 mg, 74%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:28]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:28]2)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: COC(=O)CCC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)OC)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 44.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with methyl 3-(morpholin-2-yl)propanoate (0.38 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.53 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1>C1COCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: Clc1ncnc2ccccc12
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ncnc3ccccc23)CC1
Yield: 92.1 %

Procedure:
Triethylamine (12.7 mL, 91.1 mmol) was added to a solution of 4-chloro-quinazoline (5.00 g, 30.4 mmol) and ethyl isonipecotate (4.78 g, 30.4 mmol) in THF (80 mL) at ambient temperature. After being refluxed for 12 hours, the mixture was concentrated in vacuo, and the resulting residue was partitioned between DCM and aqueous 0.1 M NaOH. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solids were suspended in Et2O and filtered to give 1-quinazolin-4-yl-piperidine-4-carboxylic acid ethyl ester (8.0 g, 28.0 mmol). This material was dissolved in EtOH (50 mL) and THF (50 mL) followed by the addition of NaOH (3.73 g, 93.4 mmol) in H2O (50 mL). After being stirred for 12 hours, the mixture was neutralized with 1.0N HCl (93.5 mL) and concentrated in vacuo. After the volatile organics are removed, a white precipitate forms in the resulting aqueous solution. The solid was filtered off and air-dried to give 1-quinazolin-4-yl-piperidine-4-carboxylic acid (6.5 g). 1H NMR (DMSO-d6, 400 MHz) δ 12.28 (bs, 1H), 8.57 (s, 1H), 7.91 (m, 1H), 7.75 (m, 2H), 7.49 (m, 1H), 4.13 (m, 2H), 3.22 (m, 2H), 2.57 (m, 1H), 1.93 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]([C:9]1[CH:13]=[CH:12][NH:11][N:10]=1)([CH3:8])[CH3:7].[Br:14]Br>C(O)(=O)C.O>[Br:14][C:13]1[C:9]([CH:6]([CH3:8])[CH3:7])=[N:10][NH:11][CH:12]=1
Reactant: CC(C)c1cc[nH]n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1n[nH]cc1Br
Reaction time: 15 h
Yield: 80.9 %

Procedure:
To a stirred solution of sodium acetate (19.7 g., 0.24 mole) in acetic acid (100 ml.) and water (15 ml.), 3-isopropylpyrazole (11.0 g., 0.1 mole) was added, followed by dropwise addition of bromine (16.0 g., 0.11 mole) keeping the internal temperature below 15° C. The mixture was kept at 25° C. for 15 hours, treated with water (200 ml.) and extracted with ethyl ether (3 × 50 ml.), and the ether layer washed with water (1 × 50 ml.) dried, (sodium sulfate) and evaporated under reduced pressure. The resultant pale yellow oil was distilled to give 4-bromo-3-isopropylpyrazole (15.3 g., 81%) with a boiling point of 85° C. at 0.06 mm Hg.
Reaction SMILES: [C:1]1([CH:7]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH2:8][C:9](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:23])=O.CN(C)[CH:28]=[O:29]>>[Cl:23][C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[S:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[CH:28]=[O:29]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1SC(CC(=O)O)c1ccccc1
Reactant: CN(C)C=O
Product: COc1cccc2c1SC(c1ccccc1)C(C=O)=C2Cl

Procedure:
As in example 18,but using 4.3 g 3-phenyl-3-(2-methoxyphenylmercapto)propionic acid, 40 ml dimethylformamide and 15 ml phosphorous oxychloride. After hydrolysis and work-up the residual oil is filtered over a small silicagel column and the residual solid is recrystallized in a mixture of hexane and ethyl acetate. Pure 4-chloro-3-formyl-8-methoxy-thioflav-3-ene is obtained as yellow crystals; m.p. 128°-130° C.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[OH:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23][C:22]=3[CH:29]=2)=[CH:14][CH:13]=1)[CH3:11].CC(C)=O>CS(C)=O>[OH:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][CH:24]([C:26]([O:28][CH3:3])=[O:27])[CH2:23][C:22]=3[CH:29]=2)=[CH:16][CH:17]=1)[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(O)c1ccc(-c2ccc3c(c2)CC(C(=O)O)O3)cc1
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: COC(=O)C1Cc2cc(-c3ccc(C(C)O)cc3)ccc2O1

Procedure:
23.3 g of methyl iodide and 7.6 g of potassium carbonate were added to a mixture of 7.8 g of 6C, 200 ml of acetone and 50 ml of dimethylsulfoxide. The resulting suspension was heated under reflux for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was stirred with 400 ml of water, the water was decanted, and the residue was dissolved in tetrahydrofuran. The solution was filtered and the filtrate was concentrated. The residue was mixed with 50 g of silica gel and purified by dry column chromatography, a 9/1 v/v chloroform/tetrahydrofuran mixture being used as eluent. The band containing product was extracted with tetrahydrofuran, the solvent was evaporated from the extract under reduced pressure and the residue was dried in a vacuum oven. The residue was stirred with ether and the solid was collected and dried to give methyl 2,3-dihydro-5-(4-(1-hydroxyethyl)phenyl)-2-benzofurancarboxylate (6D), mp: 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[CH3:18].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]>>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:9]2[C:4]3[C:3]([CH3:18])=[C:2]([Cl:1])[S:17][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: COc1ccccc1CCl
Reactant: Cc1c(Cl)sc2ncnc(NC3CCNCC3)c12
Product: COc1ccccc1CN1CCC(Nc2ncnc3sc(Cl)c(C)c23)CC1

Procedure:
The title compound was prepared (115 mg, 85%) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95 mg, 0.336 mmol) and 1-(chloromethyl)-2-methoxybenzene (58 mg, 0.37 mmol) by following the general procedure described for Preparation 0.12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 6.95 (m, 1H), 6.85 (d, 1H), 5.35 (d, 1H), 4.25 (m, 1H), 3.85 (s, 3H), 3.60 (s, 2H), 2.90 (m, 2H), 2.50 (s, 3H), 2.35 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m/z: Calculated: 402.94; Observed: 403.2 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[O:5])[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:31][C@H:30]([CH3:32])OS1(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:30]([CH3:32])[CH2:31][NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(C)c(C(F)(F)F)cc2[nH]1
Product: CCOC(=O)c1cc2cc(C)c(C(F)(F)F)cc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, m.p.: 103–105° C., EI-MS: m/e=428.1 (M+) and αD20=−40.3, was prepared in accordance with the general method of example 12b) from 5-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:23][C@H:24]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH2:14][CH3:15])[C:10]([N:27]1[CH2:28][C@H:24]([OH:23])[CH2:25][C@H:26]1[C:29]([O:31][CH3:32])=[O:30])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.5 %

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoic acid (all material from step 1, 1.00 g, 3.32 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate-HCl salt (0.663 g, 3.65 mmol), HATU (1.26 g, 3.32 mmol) and CH2Cl2 (30 mL). To the mixture was added N,N-diisopropylethylamine (1.75 mL, 9.95 mmol). The mixture was stirred at room temperature for 16 h. The mixture was transferred to a separatory funnel and was thrice washed with aq. HCl (1M); then brine. The organic solution was dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-methyl 1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylate as a yellow oil (1.53 g).
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH2:24][CH2:23][CH2:22][C:5]=2[S:6][C:7]=1[NH:8][C:9](=[O:21])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:11]([CH3:14])[CH2:12][CH3:13])#[N:2].N[C:26]1SC2CCCC=2C=1C#N>>[C:1]([C:3]1[C:4]2[CH2:24][CH2:23][CH2:22][C:5]=2[S:6][C:7]=1[NH:8][C:9](=[O:21])[CH:10]([CH:11]1[CH2:14][CH2:26][CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: CCC(C)C(C(=O)Nc1sc2c(c1C#N)CCC2)c1ccccc1
Reactant: N#Cc1c(N)sc2c1CCC2
Product: N#Cc1c(NC(=O)C(c2ccccc2)C2CCCC2)sc2c1CCC2
Reaction time: 20 h

Procedure:
Reaction of α-phenylcyclopentaneacetyl chloride (Prepared in Example 12, Step1) and 2-Amino-3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene (164 mg; 1.0 mmol) according to the procedure outlined in Example 5 for 20 h at room temperature provided after workup, crude product which triturated with diethylether to give 111 mg of which was further purified by recrystallization from ethylacetate/hexanes to provide 44 mg (%) of N-(3-Cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-2-cyclopentyl-2-phenyl-acetamide as a light brown solid. EI-HRMS m/e calcd for C21H32N2OS (M+) 350.1453, found 350.1456.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([OH:24])=O)=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C1(C(NO)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:26][OH:25])=[O:24])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nc(C(=O)O)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: ONC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1nc(C(=O)NO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Yield: 66.1 %

Procedure:
To a solution of 260 mg (0.81 mmol) of 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid in 50 mL of anhydrous dimethylformamide 111 mg of N-hydroxybenzotriazole (0.81 mmol), 0.16 mL of N-methylmorpholine, 205 mg (1.07 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 585 mg (2.13 mmol) of triphenylmethylhydroxylamine were added consecutively. After 48 hours at room temperature the solvent was removed under reduced pressure and the residue taken up with dichloromethane and washed with water. The organic layer was then dried over sodium sulfate and evaporated. The crude was treated with 10 mL of a mixture dichloromethane-trifluoroacetic acid and after 4 hours the volatiles were removed in vacuo. The residue was redissolved with dichloromethane and washed with aqueous NaHCO3 and the product purified by chromatography on a silica gel column, eluted with CH2Cl2—CH3COCH3 4/1, to give 180 mg (66% yield) of the title compound.
Reaction SMILES: [C:1]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([CH:18]=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])([O:3]CC)=O.[C:27]1([Li])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:15]([C:9]1[C:8]([CH2:18][OH:19])=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6]([CH:1]([OH:3])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:11]([CH:12]([CH3:13])[CH3:14])[N:10]=1)([CH3:17])[CH3:16]
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1nc(C(C)C)c(C(O)c2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and phenyllithium, according to the procedures described in Example 93. 1H NMR (300 MHz, CDCl3): δ 7.23 (m, 7 H), 7.06 (m, 2 H), 5.71 (d, J=5.14 Hz, 1 H), 4.38 (d, J=5.5 Hz, 2 H), 3.47 (septet, J=6.6 Hz, 1 H), 3.12 (septet, J=6.6 Hz, 1 H), 2.12 (d, J=5.1 Hz, 1 H), 1.57 (s, 1H), 1.29 (m, 10 H), 0.797 (d, J=6.6 Hz, 3 H). FAB-MS: calcd for (C25H28NFO2) 393, found 394 (M+H). Anal. Calcd for C25H28NO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 202-204° C. Rf=0.2 (20% ethyl acetate/hexane).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:18]([N:21]1[C:30]2[N:29]=[C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:41](O)=[O:42])=[C:36]4[C:40]=3[O:39][CH2:38][CH2:37]4)[N:27]=[CH:26][C:25]=2[N:24]([CH3:44])[C:23](=[O:45])[C@@H:22]1[CH2:46][CH3:47])([CH3:20])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:41]([C:35]4[CH:34]=[CH:33][C:32]([NH:31][C:28]5[N:27]=[CH:26][C:25]6[N:24]([CH3:44])[C:23](=[O:45])[C@H:22]([CH2:46][CH3:47])[N:21]([CH:18]([CH3:19])[CH3:20])[C:30]=6[N:29]=5)=[C:40]5[O:39][CH2:38][CH2:37][C:36]=45)=[O:42])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1.[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:41]([C:35]4[CH:34]=[CH:33][C:32]([NH:31][C:28]5[N:27]=[CH:26][C:25]6[N:24]([CH3:44])[C:23](=[O:45])[C@H:22]([CH2:46][CH3:47])[N:21]([CH:18]([CH3:19])[CH3:20])[C:30]=6[N:29]=5)=[C:40]5[O:39][CH2:38][CH2:37][C:36]=45)=[O:42])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Reactant: N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
(trans)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16b (350 mg, 1.48 mmol), 7-[[(7S)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 43e (607 mg, 1.48 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (475 mg, 1.48 mmol) and diisopropylethylamine (420 mg, 3.30 mmol) were dissolved in 40 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting solution was added with 50 mL of aqueous ammonia and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7S)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-Carboxamide 45 (360 mg, yield: 38.0%) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>CCOC(C)=O>[F:22][C:11]1[C:12]([N:16]2[CH2:17][CH:18]([O:20][CH3:21])[CH2:19]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: COC1CN(c2cccc(CO[Si](C)(C)C(C)(C)C)c2F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1CN(c2cccc(CO)c2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-3-methoxyazetidine (121 mg) was mixed with THF (4 ml), and a 1M TBAF/THF solution (0.8 ml) was added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain [2-fluoro-3-(3-methoxyazetidin-1-yl)phenyl]methanol (72 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:43])([CH3:42])[C:29]([NH:31][CH2:32][CH2:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)=[O:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([CH2:33][CH2:32][NH:31][C:29](=[O:30])[C:28]([CH3:42])([CH3:27])[CH3:43])=[CH:35][CH:36]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)C(=O)NCCc1ccc(CN)cc1
Product: CC(C)(C)C(=O)NCCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 70.3 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (106 mg, 0.251 mmol) and 4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamine (110 mg, 0.427 mmol). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (6:4) to obtain 7-chloro-6-{4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (90 mg, 70%). MS (ES+) m/z: 510 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=2)=[N:13][C:14]=1Br.CCOC(C)=O>CN1C(=O)CCC1.O>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=2)=[N:13][C:14]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)n1cc(-c2nc(-n3cccn3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
To a solution of pyrazole (106 mg) in NMP (1.0 ml), was added 60% NaH (52 mg) under ice-bath cooling. After 5 minutes stirring, 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg) was added to the mixture. And then the mixture was heated at 100° C. with stirring for 2 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was recrystallized from MeOH and dried in vacuo to give 5-[5-amino-3-phenyl-6-(1H-pyrazol-1-yl)-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (60 mg).