Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C.FC(F)(F)C(O)=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)=[CH:12][CH:11]=2)([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH:29]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:21][CH:22]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc(OC2CCCCO2)cc1)(c1ccc(OC2CCCCO2)cc1)c1ccc(OC2CCCCO2)cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
2.53 g (8.26 mmol) of 1,1,1-tris(4-hydroxyphenyl)ethane was dissolved in 20 mL of ethyl acetate in a round bottom flask. 8 mL of 2,3-dihydropyran and 8 drops of trifluoroacetic acid were added to the mixture. After stirring overnight, a white precipitate had formed in the flask. This precipitate was collected by filtration and dissolved in 20 mL of dichloromethane to which was added 8 mL of 2,3-dihydropyran and 6 drops of trifluoroacetic acid. After stiffing for two days, 20 mL of 0.261 N TMAH was added; the organic phase was extracted, washed with water (20 mL) twice, and dried with MgSO4. The solvent was removed in vacuo to yield 2.82 g of THPE-THP as a white powder. Yield: 77%. 1H-NMR (300 MHz, CDCl3) δ (ppm) 1.5-2.0 (18H), 2.09 (3H), 3.60 (3H), 3.92 (3H), 5.37 (3H), 6.91 (6H), 6.98 (6H).
Reaction SMILES: [Na].[C@@H:2]1(N2C=C(C)C(=O)NC2=O)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[Cl:19][C:20]1[N:28]=[C:27]2[C:23]([NH:24][CH:25]=[N:26]2)=[C:22]([NH2:29])[N:21]=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.ClC1N=C2C(NC=N2)=C(N=CN(C)C)N=1>>[CH2:3]1[C@H:2]([N:26]2[C:27]3[N:28]=[C:20]([Cl:19])[N:21]=[C:22]([NH2:29])[C:23]=3[N:24]=[CH:25]2)[O:9][C@H:6]([CH2:7][OH:8])[C@H:4]1[OH:5]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: CN(C)C=Nc1nc(Cl)nc2nc[nH]c12
Agent: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Na]
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
Stereoselective glycosylation of sodium salts of halopurines and analogues with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride gave β-nucleoside anomers via predominant Walden inversion,17,18 and ammonolysis/deprotection gave CldAdo.19 Although the sodium salt glycosylation usually gave good anomeric stereoselectivity, minor quantities of α anomers and >10% of N7 regioisomers were usually formed.20,21 This requires separations and results in diminished yields of the desired N9 product. Carson et al.1 had reported an enzymatic transfer of the 2-deoxy sugar from thymidine to 2-chloroadenine (ClAde). Holy and coworkers noted that cells of a strain of Escherichia coli performed glycosyl transfer from 2′-deoxyuridine to 2-chloro-6-[(dimethylaminomethylene)amino]purine to give a derivative of CldAdo.22 Very recently Barai, Mikhailopulo, and coworkers23 described an E. coli-mediated glycosyl transfer synthesis of 2,6-diamino-9-(3-deoxy-β-D-erythro-pentofuranosyl)purine,24 and its enzymatic deamination to 3′-deoxyguanosine.24 They reported glycosyl transfer from 2′-deoxyguanosine to ClAde, and claimed a yield of 81% of CldAdo (based on ClAde).23 However, a 3:1 ratio of dGuo/ClAde was employed, so the yield of CldAdo was <27% based on dGuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[NH:42]([CH2:46][CH2:47][OH:48])[CH2:43][CH2:44][OH:45]>>[OH:45][CH2:44][CH2:43][N:42]([CH2:46][CH2:47][OH:48])[C:2]1[N:3]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:36])([CH3:37])[N:33]([O:38][CH3:39])[C:32]([CH3:40])([CH3:41])[CH2:31]2)[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:23])([CH3:24])[CH2:14]2)[N:7]=1
Reactant: OCCNCCO
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)nc(N(CCO)CCO)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and diethanolamine according to the procedure of Example 1.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.C(Cl)(=O)C(Cl)=O.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.CN1CCOCC1>ClCCl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:20](=[O:22])[CH2:19][N:3]2[CH2:4][CH2:5][C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]2=[O:1])=[N:34][CH:35]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)Nc1ccc(Cl)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) in dichloromethane (0.5 mL) at room temperature was added a solution of oxalyl chloride in dichloromethane (2.0 M, 0.102 mL, 0.203 mmol). The reaction was stirred for 1 hour and then concentrated under a stream of nitrogen. The resulting acid chloride was dissolved in dichloroethane (0.5 mL), and 5-chloropyridin-2-amine (0.024 g, 0.186 mmol) was added followed by N-methyl morpholine (0.028 mL, 0.254 mmol). The reaction was heated to 70° C. After stirring for 3 hours, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the product was eluted using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). The product was contaminated with aminopyridine starting material. A second silica gel column chromatography (SF15-24, Analogix®) eluting with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes over 30 minutes (flow=30 mL/minute) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.44-8.46 (br s, 1H), 8.22 (dd, J=2.5, 0.7 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.65 (ddd, J=8.8, 2.6, 0.5 Hz, 1H), 7.21-7.39 (m, 10H), 4.19 (s, 2H), 3.54 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H); MS (ESI+) m/z 406 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=O.N1C=CC=CC=1.Cl.[O:21]([NH2:23])[CH3:22]>O>[CH3:22][O:21][N:23]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH3:13])=[C:2]([OH:1])[CH:3]=1
Reactant: CCCOc1ccc(C=O)cc1O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCOc1ccc(C=NOC)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.9 %

Procedure:
An amount of 3-hydroxy-4-propoxybenzaldehyde (150 mg, 0.83 mmol) is added pyridine (4.0 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (101.2 mg, 1.2 mmol). The mixture is stirred at ambient temperature for 24 h, and 4 mL of water is added. After the solvents were evaporated, the residue is dissolved 8 mL of anhydrous ether, washed successively with 2 mL of aqueous sodium bicarbonate, 2 mL of sodium bisulfite, and 2 mL of brine. Dried over magnesium sulfate, evaporated to give a yellow solid (210 mg). MS (ESI) m/z 210.5 (M+1)
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[NH:5][C:6]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]([C:10](N(OC)C)=[O:11])=[CH:8][N:7]=1)[CH3:2].[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.C(Cl)Cl>[C:10]([C:9]1[C:16]([NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:25])=[N:7][CH:8]=1)(=[O:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)N(C)OC)cn1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)c2ccccc2)cn1
Temperature: 25 °C
Yield: 82 %

Procedure:
Compound 83 (15 mg, 0.044 mmol) was dissolved in dry THF (0.8 mL) and this solution added to the phenyl magnesium bromide (1M, 0.2 mL, 0.20 mmol) at 0° C. The mixture was stirred and allowed to warm slowly to RT. The mixture was quenched with MeOH/HCl (2M) (1 mL:0.1 mL) then NH4Cl (sat.) added and the mixture diluted with water and EtOAc (pH of aqueous ˜7). The mixture was extracted into EtOAc and the organics combined and dried with brine then Na2SO4. The solvent was removed to afford 20 mg crude residue. This was dissolved in DCM (2 mL) and applied to a silica column, eluting with EtOAc/heptane, to afford Compound 112 (13 mg).).
Reaction SMILES: N([O-])=O.[Na+].[I:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](N)[N:12]=2)=[CH:9][N:8]([CH:18]([CH3:20])[CH3:19])[N:7]=1.FC(F)(F)C(O)=[O:24]>>[I:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([OH:24])[N:12]=2)=[CH:9][N:8]([CH:18]([CH3:20])[CH3:19])[N:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1cc(-c2ccnc(N)n2)c(I)n1
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)n1cc(-c2ccnc(O)n2)c(I)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrite (314 mg, 4.55 mmol) was added in portions to a stirred mixture of Intermediate 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-amine (500 mg, 1.52 mmol) and trifluoroacetic acid (15 ml) at 0° C. The mixture was allowed to warm to rt and was stirred for 1 h, then the solvent was removed under vacuum. The crude mixture was diluted with ethyl acetate and washed with saturated aqueous potassium carbonate solution and brine to provide the title compound as a solid. MS m/z 331.0 (M+1).
Reaction SMILES: [CH:1]([C:5]([CH3:13])([CH:9]([CH3:12])[CH2:10][CH3:11])[C:6](Cl)=[O:7])([CH2:3][CH3:4])[CH3:2].[CH2:14]([CH2:16][NH2:17])[OH:15]>C1C=CC=CC=1>[OH:15][CH2:14][CH2:16][NH:17][C:6](=[O:7])[C:5]([CH:9]([CH2:10][CH3:11])[CH3:12])([CH3:13])[CH:1]([CH3:2])[CH2:3][CH3:4]
Reactant: CCC(C)C(C)(C(=O)Cl)C(C)CC
Reactant: NCCO
Solvent: c1ccccc1
Product: CCC(C)C(C)(C(=O)NCCO)C(C)CC

Procedure:
A solution of 2-sec-butyl-2,3-dimethylpentanoyl chloride (2.0 g) in benzene (10 ml) was added to a stirred solution of ethanolamine (2.0 g) in benzene (100 ml). After 16 hours the benzene solution was washed with dilute hydrochloric acid and water, dried (MgSO4) and concentrated to give a pale yellow syrup. Distillation of this syrup gave N-(2-hydroxyethyl)-2-sec-butyl-2,3-dimethylpentanamide bp. 125°-130°/0.03 mm which slowly solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:44][CH2:43][C:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccn2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccn4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(pyridin-2-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:8])([F:7])[CH2:4][O:5][NH2:6].[C:9]([CH:12]1[CH2:15][N:14]([C:16](=[O:30])/[CH:17]=[CH:18]/[C:19]2[CH:20]=[C:21]3[C:26](=[N:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]3)[CH2:13]1)(=O)[CH3:10]>CO>[O:30]=[C:16]([N:14]1[CH2:15][CH:12](/[C:9](=[N:6]\[O:5][CH2:4][C:3]([F:8])([F:7])[F:2])/[CH3:10])[CH2:13]1)/[CH:17]=[CH:18]/[C:19]1[CH:20]=[C:21]2[C:26](=[N:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reactant: NOCC(F)(F)F
Agent: Cl
Solvent: CO
Product: C/C(=N/OCC(F)(F)F)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
2,2,2-Trifluoroethoxyamine hydrochloride (37 mg, 0.24 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (50 mg, 0.16 mmol) in methanol (4 mL). The reaction mixture was stirred at room temperature for 3 hours. After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (95:5) as eluent to obtain the title product as a white solid (47 mg, 50%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][O:26][C:27]2=[O:28])=[CH:23][CH:22]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:30]=[C:29]2[C:24](=[CH:23][CH:22]=1)[CH2:25][O:26][C:27]2=[O:28])[CH3:14]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc2c(c1)C(=O)OC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: c1ccncc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)C(=O)OC4)c2cc1OCC
Temperature: 100 °C
Yield: 95 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 230 mg (1.54 mM) of 6-Aminophthalide and 161 mg of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 535 mg of 6,7-Diethoxy-4-(3-oxo-1,3-dihydro-isobenzofuran-5-ylamino)-quinoline-3-carbonitrile as a white solid: mass spectrum (electrospray, m/e): M+H 390.1, mp=280-284° C.
Reaction SMILES: C(O[C:9](=[O:38])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([F:37])[CH:25]=1)C1C=CC=CC=1.F[C:40](F)(F)C(O)=O>C1(SC)C=CC=CC=1>[CH:34]1([NH:33][C:31](=[O:32])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:14]3[C:13]4[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([NH:10][C:9](=[O:38])[CH3:40])[CH:12]=4)[N:17]=[CH:16][CH:15]=3)=[CH:25][C:26]=2[F:37])[CH2:35][CH2:36]1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1NC(C)=O

Procedure:
{4-[4-(cyclopropylureido)-3-fluorophenoxy]-7-methoxyquinolin-6-yl]carbamic acid benzyl ester (11 mg) was heated and stirred in a mixture of trifluoroacetic acid (3 ml) and thioanisole (0.5 ml) at 60° C., in the same manner as Example 264, for debenzylation. The resulting amino compound was acetylated in the same manner as Example 265 to obtain the title compound (2 mg) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N:9]1([CH2:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncc(CN2CCCC2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cncc(CN2CCCC2)c1
Temperature: 50 °C

Procedure:
A mixture of 3-bromo-5-(pyrrolidin-1-ylmethyl)pyridine (0.76 mmol), ethynyltrimethylsilane (0.91 mmol), Pd(PPh3)4 (0.038 mmol), CuI (0.076 mmol), and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF can be heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture is concentrated and the crude product is purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2C(=O)NCC[C:6]3=[C:7](C4C=CC(C=O)=CC=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1(C2NC3C=CC=C4C(=[O:43])NCCC=2C=34)C=CC=CC=1.BrC1N(F)C2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=CC(B(O)O)=CC=1)=O.N1CCCC1>>[N:8]1[C:9]2[C:5]([CH:4]=[CH:3][C:2](=[O:43])[CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: O=C1NCCc2c(Br)n(F)c3cc(F)cc1c23
Agent: O=Cc1ccc(B(O)O)cc1
Solvent: C1CCNC1
Product: O=C1C=CC2=CC=NC2=C1

Procedure:
In a manner similar to that described for Compound PPP, 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl) benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with pyrrolidine (115 mg, 1.62 mmol) to yield 8-fluoro-2-(4-pyrrolidin-1-ylmethyl-phenyl)-1,3,4,5-tetrahydro-azepinop5,4,3-cd]indol-6-one, 16 mg (14%) as a yellow solid: m.p. 264-265° C. (dec), 1H NMR (300 MHz, d6-DMSO) δ 1.72 (m, 4H), 2.49 (m, 4H), 3.04 (m, 2H), 3.39 (m, 2H), 3.64 (br s, 2H), 7.31 (dd, J=9.3, 2.4 Hz, 1H), 7.43 (m, 3H), 7.58 (d, J=8.1 Hz, 2H), 8.25 (br t, 1H), 11.66 (br s, 1H). HRMS (MALDI MH+) Calcd for C22H22N3OF: 362.1825. Found: 364.1810. Anal. (C22H22N3OF.0.5 H2O) C, H, N.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:17]=[C:12]2[CH2:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])C=C>>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:32]([O:36][CH2:37][CH3:38])=[O:35])[C:13]3=[N:14][C:15]=2[C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:23][CH:22]=1
Reactant: C=CC(=O)OCC
Reactant: C=CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Product: CCOC(=O)/C=C/CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21

Procedure:
The title compound was prepared from 5-(hept-6-enyl)-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (step 1) and ethyl acrylate analogously to (E)-Methyl 7-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)hept-3-enoate (Example 10.1 step 2).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH2:14][O:15][CH2:16][C:17]=3[C:18](OC)=[O:19])[CH:8]=2)=[N:3]1.C[O-].[Na+].C([NH2:28])=O>>[C:18]([C:17]1[CH2:16][O:15][CH2:14][C:13]=1[C:9]1[CH:8]=[C:7]([C:4]2[O:5][CH2:6][C:2]([CH3:22])([CH3:1])[N:3]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:19])[NH2:28]
Reactant: NC=O
Reactant: COC(=O)C1=C(c2cccc(C3=NC(C)(C)CO3)c2)COC1
Agent: C[O-]
Agent: [Na+]
Product: CC1(C)COC(c2cccc(C3=C(C(N)=O)COC3)c2)=N1
Temperature: 100 °C

Procedure:
A mixture of 4,4-dimethyl-2-[3-(4-methoxycarbonyl-2,5-dihydrofuran-3-yl)phenyl]-4,5-dihydrooxazole (1.92 g) and sodium methoxide (0.96 g) in formamide (70 ml) was heated at 100° C. for three hours. The reaction mixture was cooled to room temperature and was poured onto ice-water. The product was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and acetone (5:1). The fractions containing the desired product were collected and evaporated in vacuo to give 2-[3-(4-carbamoyl-2,5-dihydrofuran-3-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](/B(O)O)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1csc(Nc2ncc(/C=C/c3ccccc3)cc2OCc2ccccc2)n1
Temperature: 80 °C
Yield: 98.6 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.300 g, 0.797 mmol), (E)-styrylboronic acid (0.142 g, 0.957 mmol), Pd(PPh3)4 (0.0461 g, 0.0399 mmol), and sodium carbonate (0.254 g, 2.39 mmol) were added to DME (10 mL) and water (5 mL) and heated at 80° C. for 18 hours. An additional 0.5 eq of (E)-styrylboronic acid, Pd(PPh3)4, and 2M sodium carbonate were added and the reaction was heated at 80° C. for an additional 6 hrs. The reaction mixture was cooled and partitioned between water and dichloromethane. The layers were separated, dried, filtered, and concentrated to provide the title compound (0.314 g, 98.6% yield). 1H NMR (CDCl3) δ 8.03 (d, 1H), 7.63 (d, 2H), 7.49 (m, 2H), 7.39 (m, 5H), 7.32 (m, 2H), 6.98 (s, 2H), 6.39 (s, 1H), 5.42 (s, 2H), 2.46 (s, 3H). Mass spectrum (apci) m/z=400.0 (M+H).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][C:13]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][C:20]=2[F:36])([OH:16])[CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(OCC)(=O)C.CO>[F:36][C:20]1[CH:21]=[C:22]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:23]=[CH:24][C:19]=1[O:18][CH2:17][C:13]1([OH:16])[CH2:14][CH2:15][NH:11][CH2:12]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNC3)c(F)c2)C(=O)O1

Procedure:
A suspension of 660 mg 3-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (MW: 501.51, 1.31 mmol) and 20 mg palladium 10% on activated carbon in 20 ml of a 1/1 ethyl acetate/methanol mixture was stirred for twelve hours under hydrogen. The catalyst was filtered on a glass fiber filter paper and the filtrate evaporated under reduced pressure to afford a colorless oil. Yield: 400 mg, 83.2%. MS: 368.4 (M+H)+, Method ESI+.