Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][O:34][CH3:35].C(OCC)(=O)C>CN(C=O)C.O>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])[CH2:4][CH2:3]1
Reactant: COCCCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65 mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to it was added 1-bromo-3-methoxypropane (0.337 g, 2.20 mmol). The resulting mixture was stirred at rt for 72 h. LCMS indicated incomplete conversion, so additional 1-bromo-3-methoxypropane (0.337 g, 2.20 mmol) and cesium carbonate (0.538 g, 1.65 mmol) were added and the mixture was heated to 70° C. for 1 hour. Dilution with ethyl acetate (60 mL) and water (40 mL) followed by shaking gave a separation of phases. The organic phase was isolated, washed with water (2×30 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a residue. Purification by silica gel chromatography (gradient 100% DCM to 60:1 DCM:MeOH) gave the title compound as a yellow oil (0.522 g, 109% yield). LCMS: m/z 436 (M+H+), retention time 1.50 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.68-1.77 (m, 2H) 2.67 (t, J=6.26 Hz, 2H) 3.02 (br. s., 8H) 3.16 (s, 3H) 3.27 (t, J=5.80 Hz, 2H) 3.31-3.37 (m, 2H) 3.41 (t, J=6.26 Hz, 2H) 7.61-7.65 (m, 1H) 7.66-7.74 (m, 2H) 7.99-8.03 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N:21]=[C:22]=[O:23].S([O-])(O)(=O)=O.[K+]>ClCCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[NH:21][C:22]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)=[O:23]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(C=O)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCCl
Product: O=Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Yield: 57 %

Procedure:
A mixture of 484 mg of 3-aminobenzaldehyde (4 mmol) (polymerized form) and 290 μl of 2-fluoro-5-trifluoromethylphenyl isocyanate in 4 ml of DCE is treated in a CEM Discover microwave oven at 100° C. for 10 minutes (power 90). After cooling, the mixture is poured into 100 ml of saturated potassium hydrogen sulfate solution and extracted with twice 50 ml of ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. 740 mg of the expected aldehyde (yield=57%) are obtained in an LC/MS purity of 82%. The crude product is used directly for the following steps. ([M+H]+): 327. RT=4.28 min (acetonitrile/water gradient from 30% to 90%-Method B).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=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>[NH:29]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:31]=[N:30]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Temperature: 120 °C
Yield: 67.8 %

Procedure:
4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.20 g, 0.00061 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.00079 mol) were combined in DMF (5.0 mL, 0.064 mol) and then potassium carbonate (0.25 g, 0.0018 mol) in 1 mL water was added. The reaction was degassed with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.00007 mol) was added and in a sealed tube the reaction was heated to 120° C. oil bath. The reaction was heated for 30 minutes, allowed to cool and then taken up in ethyl acetate. The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated to give an oil. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.13 gm, 70%) as a crystalline white powder, LC/MS (M+H)+: 315, 1H NMR (DMSO-d6) δ 13.35 (bs, 1H), 8.59 (bs, 1H), 8.32 (d, 1H, J=8.5), 8.26 (bs, 1H), 7.76 (d, 1H, J=6.0), 7.45 (d, 1H, J=8.5), 7.01 (d, 1H, J=6.0), 5.73 (s, 2H), 3.61 (t, 2H), 0.92 (t, 2H), 0.0 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O>N1C=CC=CC=1>[CH3:17][C:16]1[CH:18]=[CH:19][C:13]([S:10]([O:1][CH2:2][C:3]2([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CO)COC(=O)N1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
To a chilled (0° C.) solution of 4-(hydroxymethyl)-4-methyloxazolidin-2-one (629 mg, 4.8 mmol) in anhydrous pyridine (4 ml) was added in portions tosyl chloride (1.05 g, 5.5 mmol). The solution was allowed to warm to ambient temperature and stirred under nitrogen for 48 hours. Water (12 mL) was added dropwise to the reaction mixture, and the resulting suspension was stirred at ambient temperature for 5 hours. The solids were isolated, and dried under vacuum to afford (4-methyl-2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate 1.17 g (86%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][C:26]=3[F:34])[CH:16]=2)=[O:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CO.C1COCC1>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:16]=[C:15]([C:13]([N:11]4[CH2:12][CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:10]4)=[O:14])[S:23][C:22]=23)=[C:26]([F:34])[CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of (3-(tert-butyldimethylsilyloxy)azetidin-1-yl)(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)methanone 273 (336 mg, 0.67 mmol) and NiCl2.6H2O (318 g, 1.34 mmol) in MeOH/THF (4.7 mL/4.7 mL) was added NaBH4 (101 g, 2.68 mmol) at 0° C. and the mixture stirred for 1 hr. The reaction mixture was added to an EDTA.4Na (1.1 g/100 mL) solution and extracted with EtOAc. The aqueous layer was filtered and extracted again with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (pure EtOAc) giving 274 as creamy foam (145.2 mg, 46% yield). MS (m/z): (M+1) 474.1 (100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:23])[C:10](Br)([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH3:11].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>CN(C=O)C>[CH3:7][O:8][C:9](=[O:23])[C:10]([O:32][C:26]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=1[F:24])([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH3:11]
Reactant: COC(=O)C(C)(Br)c1ccc(S(C)(=O)=O)cc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Oc1ccc(F)cc1F)c1ccc(S(C)(=O)=O)cc1
Temperature: 65 °C

Procedure:
Potassium carbonate (0.15 g, 1.08 mmol) was added to a mixture of 2-Bromo-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester and 2,4-difluorophenol in DMF (5 ml) and heated at 60-70° C. for 2-3 Hrs then cool the reaction mixture to RT and poured onto water (25 ml) which was then extracted with ethyl acetate (2×25 ml), organic layer was washed with water (2×25 ml), dried over sodium sulfate and solvent was removed under reduced pressure to get 2-(2,4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester as oil which was taken in a mixture of methanol (5 ml) and sodium hydroxide in water (0.04 g in 5 ml). This mixture was stirred at room temperature for overnight. Methanol was removed from the reaction mixture, acidified with 1N HCl, extracted with ethyl acetate (2×25 ml), washed with brine (20 ml), solvent was removed to get the desired product 2-(2,4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 3.45 (s, 3H), 6.71-6.75 (m, 1H), 6.81-6.93 (m, 2H), 7.86 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][S:26]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:36][CH:35]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(S(C)(=O)=O)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-Methanesulfonyl-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (CDCl3): δ 1.45–1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz, 1H) 2.44–3.02 (m, 7H), 3.91 (s, 3H), 3.94 (s, 3H), 6.88–7.85 (m, 7H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:49]([C:45]2[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH3:41])[CH:44]=2)(=[O:51])=[O:50])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran (5 mL) at 0° C., and 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) were added at the same temperature. The mixture was stirred at room temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a colorless oil (yield 551 mg, quantitative).
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:10])[C:5](=[CH:8]O)[C:6]#[N:7].P(Cl)(Cl)(Cl)(Cl)[Cl:12].O>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C:5](=[CH:8][Cl:12])[C:6]#[N:7]
Reactant: COC(=O)C(C#N)=CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C#N)=CCl
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a suspension of the sodium salt of methylhydroxymethylene-cyanoacetate (19.0 g, 127 mmol) in 200 mL of dichloromethane was added phosphorous pentachloride (26.5 g, 127 mmol) in one portion. The reaction mixture was allowed to exotherm to reflux temperature and then maintained at reflux with stirring for 4 hours. The resulting light yellow suspension was allowed to cool to 23° C. and then poured into 400 mL of cold water. The mixture stirred for 15 minutes and the phases were separated. The aqueous layer was extracted with 100 mL of dichloromethane and the combined organic layers were washed twice with water, dried over magnesium sulfate, and concentrated to 16.8 g of the title compound which was of sufficient purity for use in Example 1. 1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H), 7.58 (s, 0.35H), 8.04 (s, 0.65H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][C:12]([F:21])=[CH:11][C:10]=2[F:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[NH:30][C:29]=2[CH:36]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][C:12]([F:21])=[CH:11][C:10]=2[F:22])=[N:7][C:2]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[NH:30][C:29]=3[CH:36]=2)=[N:3][CH:4]=1
Reactant: Fc1cc(F)c(Nc2nc(Cl)ncc2Cl)c(N2CCOCC2)c1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cc(F)cc4N4CCOCC4)n3)cc2N1

Procedure:
8-[5-Chloro-4-(2,4-difluoro-6-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-6-morpholin-4-yl-phenyl)-amine and 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Title compound was isolated as a white solid (58 mg, 38%) HPLC 99% purity, LCMS 503.22 (M+H), HNMR (DMSO) 9.36 (s, 1H), 9.29 (s, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.97-6.93 (m, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.79 (d, J=10.8 Hz, 1H), 3.52 (m, 4H), 2.92 (m, 4H), 2.56 (m, 2H), 2.08-2.02 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][C:3]1[C:2]([NH:1][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[N:4]=1)#[N:22]
Reactant: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: N#Cc1cccc(Oc2ccc(NC(=O)Nc3ccccc3)c(Oc3cccc(C#N)c3)n2)c1

Procedure:
To 3,3′-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (3.0g, 8.7 mmol) dissolved in acetonitrile (100 mL) was added phenyl isocyanate (1.1 g, 9.5 mmol). After refluxing for 4 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/4) as eluent gave material which was crystallized from ethyl acetate/hexane to give N-[2,6-bis(3-cyano-phenoxy)pyridin-3-yl]-N′-phenylurea; NMR (CDCl3) 8.65 (d, 1), 7.4 (m, 8), 7.1-7.3 (m, 6), 6.8 (s, 1), 6.7 (d, 1) ppm;
Reaction SMILES: [C:1]([SiH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Mg].Cl[C:13](C)(CC)CC.Cl[SiH](Cl)Cl>>[CH2:7]([SiH:6]([CH2:9][CH3:10])[C:1]([CH3:3])([CH2:2][CH3:13])[CH2:4][CH3:5])[CH3:8]
Reactant: CCC(C)(Cl)CC
Reactant: CC[SiH](CC)C(C)(C)CC
Agent: Cl[SiH](Cl)Cl
Agent: [Mg]
Product: CC[SiH](CC)C(C)(CC)CC

Procedure:
The procedure of synthesizing Compound 34a was repeated, except that 3-methylpentan-3-ylmaganesium chloride THF solution (100 mL), which had been prepared from magnesium (2.43 g, 100 mmol) and 3-chloro-3-methylpentane (13.6 mL, 100 mmol); trichlorosilane (10.0 mL, 99.1 mmol); and ethylmagnesium chloride THF solution (0.93M, 200 mL, 190 mmol) were employed, whereby the Compound 38a was obtained as a colorless liquid (boiling point; 39 to 42 mmHg, 94 to 97° C. fraction, 8.86 g, 51%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH2:15]([NH2:18])[CH2:16][NH2:17].Cl>O>[NH2:17][CH2:16][CH2:15][NH:18][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: NCCN
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NCCNC(=S)Nc1ccccc1

Procedure:
A solution of phenyl isothiocyanate (500 mg) in abs. THF (6 ml) was added dropwise over 20 minutes under argon to a solution of ethylenediamine (5.56 g) in abs. THF (6 ml). Afterwards, the reaction mixture was added to water, acidified with 10% HCl and extracted with ethyl acetate. The aqueous phase was then basified with potassium carbonate and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Subsequently, co-evaporation with toluene was effected twice. 650 mg of the desired product remained.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32]([CH:34]1[C:46]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32]([CH:34]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[C:41]2[C:46]1=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C1c2ccccc2-c2ccccc21)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(C1c2ccccc2-c2ccccc21)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.238 g (0.384 mmol) of (2R*,4S*)-2-benzyl-1-(9-fluorenoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.066 g (1.54 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR70## is obtained (0.155 g, 79%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.36, FD-MS: M+ =523.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH2:17])[CH:8]=1)([CH3:6])[CH3:5].[F:19][C:20]1[CH:21]=[C:22]([C:26]2[N:31]=[C:30]([CH3:32])[C:29]([C:33](O)=[O:34])=[CH:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH:17][C:33]([C:29]2[C:30]([CH3:32])=[N:31][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[N:27][CH:28]=2)=[O:34])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: COC(=O)C(C)(C)c1cn(N)c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2ccc(F)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (0.85 mmol) and 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (217 mg, 0.935 mmol) in DMF (8.5 mL) is stirred at 40° C. for 0.5 h. The mixture is treated with DMTMM (246 mg, 0.89 mmol) and stirred at 60° C. for 1 h. The mixture is concentrated in vacuo, diluted with saturated aqueous Na2CO3 (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(5-fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-3-yl)-2-methyl-propionic acid methyl ester, which is used in the next step without further purification.
Reaction SMILES: FC1C=C(C2C=NC=C3C=2N=C(C(OCC)=O)C=C3)C=CC=1O.[OH:24][CH2:25][CH2:26][O:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1.[F:41][C:42]1[CH:43]=[C:44]([C:64]2[CH:65]=[N:66][CH:67]=[C:68]3[C:73]=2[N:72]=[C:71]([C:74]([NH2:76])=[O:75])[CH:70]=[CH:69]3)[CH:45]=[CH:46][C:47]=1OCCOCCOCCOC1CCCCO1.Cl.O1CCOCC1>O1CCOCC1>[C:74]([C:71]1[CH:70]=[CH:69][C:68]2[C:73](=[C:64]([C:44]3[CH:45]=[CH:46][C:47]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=4)=[C:42]([F:41])[CH:43]=3)[CH:65]=[N:66][CH:67]=2)[N:72]=1)(=[O:75])[NH2:76]
Reactant: NC(=O)c1ccc2cncc(-c3ccc(OCCOCCOCCOC4CCCCO4)c(F)c3)c2n1
Reactant: CC(C)(C)OC(=O)c1ccc(OCCO)cc1
Agent: CCOC(=O)c1ccc2cncc(-c3ccc(O)c(F)c3)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(OCCOc2ccc(-c3cncc4ccc(C(N)=O)nc34)cc2F)cc1
Reaction time: 8 h

Procedure:
Tert-butyl 4-{2-[4-(2-carbamoyl-1,6-naphthyridin-8-yl)-2-fluorophenoxy]ethoxy}benzoate (174 mg, 0.346 mmol) was synthesized from ethyl 8-(3-fluoro-4-hydroxyphenyl)-1,6-naphthyridine-2-carboxylate synthesized in Example 1 (1a) and tert-butyl 4-(2-hydroxyethoxy)benzoate synthesized in Reference Example 9 by the same methods as in Example 2 (2a) and (2b), and then dissolved in 1,4-dioxane (1.0 mL). To the resulting mixture, a 4M HCl/1,4-dioxane solution (8.0 mL) was added at 0° C., followed by stirring overnight.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]([CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:11])=O)=[CH:5][CH:4]=1)[CH3:2]>C(Cl)(=O)C>[CH2:1]([C:3]1[S:7][C:6]([CH:8]2[CH2:12][C:13](=[O:14])[O:15][C:9]2=[O:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(CC(=O)O)C(=O)O)s1
Solvent: CC(=O)Cl
Product: CCc1ccc(C2CC(=O)OC2=O)s1
Yield: 77.8 %

Procedure:
Ring formation of 20 g (0.088 mole) of (5-ethyl-2-thienyl)succinic acid by 90 cc of acetyl chloride, performed under the conditions of example 3, provided 14.4 g (yield=78%) of (5-ethyl-2-thienyl)succinic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH:19]5[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][CH:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:32]([F:35])([F:34])[F:33])[CH:4]=1>CC#N>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C:19]5[CH2:24][NH:23][CH2:22][CH2:21][C:20]=5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:32]([F:35])([F:33])[F:34])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)C2CN(C(=O)OC(C)(C)C)CCC2N4CCC3)c(C(F)(F)F)c1
Solvent: CC#N
Product: COc1ccc(-c2cc3c4c(c2)c2c(n4CCC3)CCNC2)c(C(F)(F)F)c1
Yield: 97 %

Procedure:
The title compound (0.60 g, 98%) was prepared by the general method of Example 312, step B from tert-butyl 2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.78 g, 1.6 mmol) as a white foam. 1H NMR (CDCl3, 300 MHz) δ2.20-2.30 (m, 2H), 2.79 (t, J=5.4 Hz, 2H), 2.90-3.20 (m, 3H), 3.30 (t, J=5.8 Hz, 2H), 3.91 (s, 3H), 3.98 (t, J=5.8 Hz, 2H), 4,12 (s, 2H), 6.84 (s, 1H), 7.07 (dd, J=2.5, 8.4 Hz, 1H), 7.18 (s, 1H), 7.25-7.35 (m, 2H) ppm. MS (ESI): 428 (base, M+CH3CN).