Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:20])([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:7]2[CH2:6]1)=[O:4].Cl[CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[CH3:21][N:2]([CH3:1])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([NH:20][CH2:23][C:24]([N:26]3[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]3[C:32]#[N:33])=[O:25])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(N)(Cc3ccccc3)CC2C1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)CC2C1

Procedure:
5-Amino-5-benzyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14f (0.1 g, 0.35 mmol) was dissolved in 4 mL of the solvent mixture of dichloromethane/N,N-dimethylformamide (V/V=1/1) followed by addition of (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (66.5 mg, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol). The reaction mixture was reacted at 40° C. for 12 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-5-[(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14g (87 mg, yield 56%) as a white solid.
Reaction SMILES: C1C=CC(C(Cl)([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][CH:15]=2)C2C=CC=CC=2)=CC=1.I[C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([C:35]([OH:37])=[O:36])[O:32][C:33]=2[CH3:34])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:20][C:19]1[CH:14]=[CH:15][C:16]([C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]3[CH:30]=[C:31]([C:35]([OH:37])=[O:36])[O:32][C:33]=3[CH3:34])=[CH:25][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 3.8 %

Procedure:
2-Chlorotrityl chloride resin (2.55 g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (20 mL). After draining, a solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (26) (1.18 g) and diisopropylethylamine (2.3 mL) in dichloromethane (30 mL) was added and the mixture was shaken at room temperature for 72 hours. The resin was drained, washed sequentially with dichloromethane/triethylamine/methanol (20:1:3 by volume) (3×30 mL), dichloromethane (6×30 mL), N,N-dimethylformamide (2×25 mL), dichloromethane (6×25 mL), and diethyl ether (2×25 mL) and dried at 40° C. in vacuo, (ii) A stirred mixture of the resin from (i) (0.38 g), 4-chlorophenylboronic acid (0.30 g), [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (30 mg), potassium acetate (0.20 g) in N,N-dimethylformamide (15 mL) was heated at 40° C. for 48 hours. The resin was drained, then washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, diethyl ether and then dried at 45° C. in vacuo. The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (20 mL) for 20 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by HPLC to afford compound 27 as a white solid (43 mg). LC/MS System D: Rt=8.83 mins, m/z (ES−)=341 (M− for C19H15ClO4).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cccc(CN2CCCCC2)n1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (25 g, 135 mmol) in dichloromethane (500 ml) was slowly added piperidine (12.6 g, 149 mmol) at 10° C. After stirring for 15 minutes at 10° C., acetic acid (8.9 g, 149 mmol) was added, followed by the portionwise addition of sodium triacetoxyborohydride, while the temperature was kept at 5-10° C. After stirring for 2 h at room temperature the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate. The product was extracted into dichloromethane and the combined organic phases were washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography afforded 2-bromo-6-(piperidin-1-ylmethyl)pyridine (30 g) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl[C:13]1[N:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CS(C)=O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:13]3[N:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(O)ccc21
Reactant: N#Cc1cccnc1Cl
Solvent: O
Solvent: CS(C)=O
Product: Cn1ncc2cc(Oc3ncccc3C#N)ccc21
Temperature: 110 °C
Yield: 89.3 %

Procedure:
1-Methyl-1H-indazol-5-ol (1n) (synthesized as described in Example 94) (0.10 g, 0.68 mmol) and 2-chloro-nicotinonitrile (2n) (0.11 g, 0.81 mmol) were suspended in DMSO (2 mL). The reaction mixture was heated to 110° C. for 18 hours. The reaction mixture was diluted with water and extracted into EtOAc. The combined organics were dried, Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by flash column chromatography (20-100% EtOAc/Hexanes) furnished the desired product (3n), (0.152 g, 90% yield). 1H NMR (400 mHz, CD3OD) δ 8.27-8.25 (m, 1H), 8.23-8.20 (m, 1H), 8.01 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.28-7.26 (m, 1H), 7.23-7.20 (m, 1H), 4.10 (s, 3H); MS (ESI+) m/z 251 (M+H) detected.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@H:18]([N:23]1[CH2:28][CH2:27][CH2:25][CH2:24]1)[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:12]2)[CH2:15][CH2:14]1)=[O:29]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(C)(=O)=O)C[C@H]21)N1CCCC1

Procedure:
The title compound was prepared by substituting (2S)—N-[(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-4-methyl-2-pyrrolidin-1-ylpentanamide from Example 250 for (S)—N-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide and methanesulfonyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedures described in Example 319: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.24-8.26 (m, 1H), 4.35 (p, J=6.8 Hz, 1H), 3.79 (dd, J=9.9, 2.6 Hz, 1H), 3.50 (dd, J=9.9, 7.0 Hz, 1H), 3.35 (dd, J=9.6, 7.0 Hz, 1H), 3.17-3.21 (m, 2H), 3.04 (s, 3H), 2.67-2.75 (m, 4H), 2.60-2.63 (m, 2H), 1.99-2.07 (m, 1H), 1.78-1.95 (m, 3H), 1.58-1.68 (m, 6H), 1.32-1.39 (m, 1H), 0.99 (d, J=6.2 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:27])=[O:26])[N:21]=[C:20]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:27])[N:21]=[C:20]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:39][CH:40]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccn2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccn2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Phenyl chloroformate (0.390 mL, 3.10 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-2-ylsulfonylmethyl)pyrimidin-2-yl]aniline (1.1 g, 2.59 mmol) and sodium hydrogen carbonate (0.434 g, 5.17 mmol) in dioxane (25 mL) at RT. The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash silica chromatography using gradient elution 0%-20% ethyl acetate in DCM, to give the desired material as a yellow foam (1.130 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13](O)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:19](=[O:22])([O-])[O-].[K+].[K+].[CH:25]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26]1>CC(CC)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:13]([O:22][CH:19]3[CH2:7][CH2:6][CH2:5][CH2:10]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: BrC1CCCC1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(O)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OC3CCCC3)c(OC3CCCC3)c2)cc1
Temperature: 40 °C
Yield: 92 %

Procedure:
4′-methanesulfonyl-biphenyl-3,4-diol (30 mg) and potassium carbonate (38 mg) were dissolved in methylethylketone. Afterward, cyclopentylbromide (51 mg) and tetrabutylammoniumiodide (2-3 mg) were added one after another and heated for 24 hours at 40° C. After filtering just potassium carbonate, the residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/1, v/v). As a result, the present compound (37 mg, productive yield 92%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCC1.ClC1C=C2C(/C(=C/C3C=CC=C(Cl)C=3)/C(=O)N2)=CC=1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: O=Cc1cccc(Cl)c1
Agent: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Temperature: 65 °C

Procedure:
To the mixture of 6-bromooxindole (16.2 g, 92 mmol) (Combi-block) and 3-chloro-benzaldehyde (12.9 g, 92 mmol) in methanol (109 mL) was added pyrrolidine (6.55 g, 92 mmol) dropwise. The mixture was then heated at 65° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 16.2 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[C:27](Cl)(=[O:29])[CH3:28].Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:27](=[O:29])[CH3:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4′-Fluoro-biphenyl (0.03 mol) was added to 1 M AlCl3 in nitrobenzene (40 mL, 0.04 mol) with chilling in an ice bath. Acetyl chloride (0.06 mol) was added dropwise and the mixture stirred overnight at room temperature. The dark solution was poured into a mixture of crushed ice (150 mL), water (25 mL) and HCl (50 mL). The aqueous phase was separated and the nitrobenzene removed by steam distillation to give a dark low melting solid. The solid was recrystallised from aqueous methanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.7, 115.9 (d, J 21.5), 127.1, 129.0 (d, J=7.8), 135.8, 136.0 (d, J 2.9), 144.7, 163.0 (d, J 248.0) and 197.8.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:19]([F:22])=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:16]([O:17][CH3:18])=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:6].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:23][C:3]1[C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:21][CH:20]=[C:19]([F:22])[C:4]=1[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:16]([O:17][CH3:18])=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:6]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc(N)c3F)cc12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)c4ccccc4)c3F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
3-Amino-2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.005 g, 0.0157 mmol) was taken up as a slurry in CHCl3 (1.0 mL). Three drops of pyridine were added, followed by the addition of benzenesulfonyl chloride (0.00600 mL, 0.0470 mmol). The slurry was stirred overnight at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(phenylsulfonamido)benzamide (5.7 mg, 79%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.59 (s, 1H), 11.01 (s, 1H), 10.39 (br s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.76-7.78 (m, 2H), 7.64-7.68 (m, 1H), 7.57-7.61 (m, 1H), 7.31-7.37 (m, 1H), 7.17-7.21 (m, 1H), 4.01 (s, 3H); m/z (APCI-neg) M−1=458.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:5]1[CH:4]=[CH:3][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH3:28])=[O:26])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 90 °C

Procedure:
5-Bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (5 g), methyl acrylate (1.4 ml), triethylamine (2. 1 ml), palladium acetate (0.070 g) and tri-orthotolyl phosphine (0.185 g) were combined in N,N-dimethylformamide (20 ml). The mixture was heated in a sealed tube under nitrogen at 90° C. for 24 h. After cooling, the reaction mixture was partitioned between dichloromethane and dilute hydrochloric acid, the mixed phases were filtered through celite and the phases separated. The organic layer was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue which was triturated with diethyl ether and filtered to yield the subtitled compound as an off white solid (4.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:19])[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][CH2:20][CH:18]([C:4]2[CH:3]=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:7]3[C:8]4[CH:9]=[N:10][CH:11]=[CH:12][C:13]=4[C:14]([CH3:17])([CH3:16])[O:15][C:6]=3[CH:5]=2)[CH3:19])=[CH:28][CH:27]=1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CS(=O)(=O)Cl
Product: CC(CCCc1ccc(F)cc1)c1cc(NS(C)(=O)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
The titled compound was prepared by reacting 10-amino-8-[5-(4-fluorophenyl)-2-pentyl]-5,5-dimethyl-5H-[1]benzopyrano[4,3-c]pyridine with methanesulfonyl chloride according to the method of Example 3. The crude product was filtered and recrystallized from acetonitrile; m.p. 208°-209°.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(C(F)(F)F)c1

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 0.705 ml of 3-(trifluoromethyl)aniline in place of the 2-fluoroaniline. 228 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(trifluoromethyl)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[N:32]([CH2:20][C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(=O)OC(C)(C)C)Nc2ccc(C#N)c(Cl)c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CN=[N+]=[N-])Nc1ccc(C#N)c(Cl)c1
Yield: 105.4 %

Procedure:
1,1-Dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{[(4-methylphenyl)sulfonyl]oxy}butanoate (35.0 g, 76 mmol) and sodium azide (9.83 g, 150 mmol) in DMF (150 mL) were stirred at 65° C. for 2.25 h. After cooling, the reaction was diluted with cold H2O (500 mL) and extracted with Et2O (3×). The combined organic extracts were washed with H2O (3×), treated with charcoal and dried (MgSO4), filtered and the solvent evaporated. The residue was dissolved in a small amount of Et2O and filtered through a short plug of silica gel. Evaporation of the filtrate afforded the titled compound (26.9 g, >100%) as an oil. 1H-NMR (CDCl3) δ: 1.46 (9H, s), 2.58 (2H, m), 3.56 (2H, d, J=5.2 Hz), 3.99 (1H, m), 6.54 (1H, d, J=8 Hz), 6.99 (1H, s), 7.43 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 336.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH2:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][C:22]#[CH:23].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:23]#[C:22][CH2:21][CH2:20][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: C#CCCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C#CCCNC(=O)OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
A solution of (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (28, 3.4 g, 10.0 mmol), benzyl but-3-ynylcarbamate (17, 2.0 g, 10 mmole), and triethylamine (20 mL) in anhydrous THF (60 mL) pre-cooled to −78° C. was degassed with argon. The mixture was warmed to room temperature and dichlorobis(triphenylphosphine)palladium(11) (PdCl2(PPh3)2 (702 mg, 1 mmole) and CuI (381 mg, 2 mmole) were added rapidly in one portion under argon. The mixture was heated at 60° C. for 4 h, then at room temperature for 48 h. The reaction mixture was filtered through a plug of diatomaceous earth and the filtrate was partitioned between EtOAc (500 mL) and 1 N HCl (200 mL). The aqueous layer was separated and back-extracted with EtOAc (300 mL). The combined organic extracts were washed with water (300 mL) and brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silical gel, 10:1 hexanes/EtOAc) to afford carbamate 29 (1.24 g, 37%) as a brown thick oil: 1H NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.39-7.29 (m, 6H), 7.13 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.7, 2.4 Hz, 1H), 5.17 (br s, 1H), 5.13 (s, 2H), 3.46 (q, J=6.3 Hz, 2H), 2.67 (t, J=6.3 Hz, 2H), 1.01 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:21][C:20]([CH2:22][O:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>C1COCC1>[NH4+:8].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:21][C:20]([CH2:22][O:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([O-:29])=[O:28])=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: N
Solvent: C1CCOC1
Product: O=C([O-])CCC(=O)OCc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Product: [NH4+]
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Compound 1 (170 mg, 0.4 mmle) in 10 mL THF was treated with NH3 at 25° C. After 30 mins, the precipitate formed in the reaction was filtered out to give Compound 17 in a yield of 90%.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25](CC(N)=O)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O[C:32]([C:34]([F:37])([F:36])[F:35])=O.N1CC(C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)C1.O(CC(F)(F)F)S(C(F)(F)F)(=O)=O>C(N(CC)CC)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:32][C:34]([F:37])([F:36])[F:35])[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Agent: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(F)(F)F)C3)ccc1-2

Procedure:
Following the procedure of 319, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235, trifluoroethyl triflate and triethylamine were reacted to give 422 isolated as a white solid (105 mg, 52%). LCMS: RT=12.34 min, [M+H]+=450. 1H NMR δ (ppm) (CDCl3): 8.32 (1H, d, J=8.18 Hz), 7.90 (1H, s), 7.10 (1H, dd, J=8.21, 1.86 Hz), 6.98 (1H, d, J=1.83 Hz), 5.93-5.84 (1H, m), 4.39 (2H, t, J=5.05 Hz), 3.90 (2H, t, J=7.29 Hz), 3.82-3.73 (1H, m), 3.42-3.33 (4H, m), 3.04 (2H, q, J=9.39 Hz), 1.61 (6H, d, J=6.63 Hz)