Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)=[O:3].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:33])=[C:23]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH3:32])[N:24]=2)=[CH:16][CH:15]=1>>[CH3:33][C:22]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:7]3[CH:8]=[CH:9][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=3)=[CH:15][CH:16]=2)=[N:24][C:23]=1[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH3:32]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: NC(=O)c1ccc(B(O)O)cc1
Product: Cc1oc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-aminocarbonyl phenyl boronic acid (236 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 17 mg (15%). MS (m/e) 390.3 (M+1)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(=O)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a solution of 4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexan-1-one (450 mg, 1.41 mmol, 1.00 equiv) in DCM (10 mL) was added methanesulfonyl chloride (242 mg, 2.11 mmol, 1.50 equiv) and triethylamine (430 mg, 4.25 mmol, 3.00 equiv) via syringe under nitrogen. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was diluted with 50 mL of DCM, washed with brine, dried over anhydrous sodium sulfate and evaporated to give 500 mg (89%) of [(3S)-12-[(4-oxocyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([NH:19][C:20](OCC)=O)[N:14]=1)[CH3:3]>O1CCCC1>[CH3:18][N:17]1[C:13]([NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:25]=[CH:26][CH:27]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=2)=[N:14][C:15]([NH:19][CH3:20])=[N:16]1
Reactant: CCOC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Solvent: C1CCOC1
Product: CNc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Yield: 33.8 %

Procedure:
A mixture of 5-[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino]-1-methyl-1H-1,2,4-triazole-3-carbamic acid, ethyl ester (0.35 g) lithium aluminium hydride (0.13 g) and tetrahydrofuran (10 ml) was heated under reflux for 48 h. The mixture was quenched with water (0.5 ml), filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica with methanol as the eluant to give the title compound as a pale yellow oil (0.1 g). TLC silica; methanol/0.88 ammonia 80:1, Rf 0.43. NMR (CDCl3) 2.78 t (1H); 3.0-3.3 m (3H); 5.47 t (1H); 5.95 t+brs (3H); 6.50 q (2H); 6.6 s (5H); 7.17 t (3H); 7.78 s (6H); 7.93 m (2H).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](O)=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.O>[C:1]1(=[O:22])[N:5]([CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([NH2:25])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.6 %

Procedure:
To a stirred solution of 2-phthalimido-3-phenylpropionic acid (2.95 g, 10.0 mmol) in tetrahydrofuran (25 mL) are added carbonyldiimidazole (1.62 g, 10.0 mmol) and a few crystals of 4-N,N-dimethylaminopyridine, followed by 15 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 45 minutes and 1 mL of concentrated ammonium hydroxide then is added. After 10 minutes, the reaction mixture is diluted with 50 mL water and the resulting slurry is partially concentrated to remove the tetrahydrofuran and filtered. The solid is washed with water and dried in vacuo (60° C.,<1 mm) to afford 2.46 g (84%) of 2-phthalimido-3-phenylpropionamide as a white powder: mp 224-226° C.; 1H NMR (DMSO-d6, 250 MHz)δ 7.79 (s, 4H, Ar), 7.71 (br s, 1H, CONH2), 7.32 (br s, 1H, CONH2), 7.20-7.02 (m. 5H, Ar), 5.06-4.98 (m, 1H), 3.56-3.25 (m, 2H); 13C NMR (DMSO-d6, 250 MHz) d: 169.6, 168.0, 137.1, 134.3, 131.2, 129.5, 128.1, 126.3, 122.9, 54.2, 33.7. Anal. Calculated for C17H14N2O3. Theoretical: C, 69.38; H, 4.79; N, 9.52. Found: C, 69.37; H, 4.73; N, 9.43.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C>[Si:22]([O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(-c2nc3ccc(O)cc3s2)cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2nc(-c3ccc(N)nc3)sc2c1
Yield: 76.6 %

Procedure:
A solution of 2-(6-aminopyridin-3-yl)-1,3-benzothiazol-6-ol (177 mg, 0.73 mmol), TBDMSCl (121 mg, 1.1 equiv) and imidazole (124 mg, 2.5 equiv) in DMF (2.0 ml) was stirred at ambient temperature for 2 h. The reaction mixture was then partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organics dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by silica gel chromatography, using a mixture of DCM and methanol (95:5) as eluent, to yield 200 mg of the title compound as a white solid. 1H NMR δ 8.56 (d, 1H) 7.96 (dd, 1H) 7.80 (d, 1H) 7.54 (d, 1H) 6.98 (dd, 1H) 6.67 (s, 2H) 6.56 (d, 1H) 0.97 (s, 9H) 0.22 (s, 6H); MS m/z (M+H) 358.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([OH:28])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CCc1cncc(Cl)c1)CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(CC(O)CCc1cncc(Cl)c1)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a stirred solution of 1-{[4-(4-chlorophenyl)piperazin-1-yl]sulfonyl}-4-(5-chloropyridin-3-yl)butan-2-one (228 mg, 0.51 mmol) in a mixed solvent system of CH2Cl2/MeOH (1:1, 5 mL) at RT was added solid sodium borohydride in one portion. The reaction was stirred for 40 minutes before being quenched with aqueous hydrochloric acid (1 M, 2 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried, (MgSO4), filtered and concentrated in vacuo. The crude product was then filtered through a plug of silica gel, eluting with 50% ethyl acetate in hexane to give the title compound (111 mg, 0.25 mmol).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].Br[CH2:18][CH2:19][O:20][CH3:21]>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:16])=[CH:13][CH:14]=2)[N:9]([CH2:18][CH2:19][O:20][CH3:21])[CH:8]=1)=[O:6]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1cc(C(=O)OC)c2ccc(Br)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Sodium hydride (60% in mineral oil, 87 mg, 2.2 mmol) is added to a solution of 6-bromo-1H-indole-3-carboxylic acid methyl ester (500 mg, 1.97 mmol) in DMF (5 mL) at room temperature and the mixture is stirred for 30 minutes. To the reaction mixture is added 1-bromo-2-methoxy-ethane (222 μL, 2.36 mmol). After one hour, sodium hydride (20 mg) is added. Thirty minutes later, 1-bromo-2-methoxy-ethane (60 μL) is added. The mixture is heated to 60° C. for one hour. The cooled mixture is quenched with a small amount of water and concentrated under reduced pressure. The residue is taken up in ethyl acetate and filtered. The filtrate is concentrated under reduced pressure and the resulting residue is purified by column chromatography (gradient: 10 to 60% ethyl acetate/heptane) followed by purification via radial chromatography (gradient: 0 to 1% MeOH/CH2Cl2) to provide the title compound (386 mg, 63%). ES/MS m/e 314.0 (M+2).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([Br:17])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccsc1C(=O)NCc1ccccc1
Solvent: CC#N
Product: Cc1cc(Br)sc1C(=O)NCc1ccccc1
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a stirred solution of N-benzyl-3-methylthiophene-2-carboxamide (0.74 g, 3.18 mmol) in acetonitrile (15 mL) was added N-bromosuccinimide (0.57 g, 3.18 mmol). The reaction mixture was stirred for 16 h, and then concentrated in vacuo. The residue was purified by column chromatography eluting with 5-35% ethyl acetate in hexane to afford the title compound as a colorless solid (0.69 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 6.87 (s, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 310.1 (M+1), 312.1 (M+1).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.O[CH:10]1[C:16]([OH:40])([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH2:15][CH2:14][NH:13][C:12](=[O:41])[CH2:11]1>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:40][C:16]1([C:17]2[S:18][C:19]([C:22]3[CH:27]=[C:26]([NH:28][C:29]4[N:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][N:30]=4)[CH:25]=[C:24]([CH3:39])[CH:23]=3)=[CH:20][N:21]=2)[CH:15]([OH:5])[CH2:14][NH:13][C:12](=[O:41])[CH2:11][CH2:10]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNC(=O)CC3O)s2)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC(=O)NCC3O)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
The 70:30 mixture of products from Step 1 (100 mg, 0.22 mmol) was dissolved in acetone (1 mL) and water (125 μL). Osmium tetroxide (4% in H2O, 548 μL, 0.09 mmol) and 4-methylmorpholine N-oxide (105 mg, 0.90 mmol) were added and the suspension was stirred for 1 h at room temperature. The reaction was quenched with 5% aqueous sodium thiosulfate and stirred for 15 minutes. The mixture was washed with ethyl acetate (3×), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a mixture of 4,5-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one and 5,6-dihydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one (70:30, 40 mg, 0.084 mmol 37% yield) as a brownish-yellow solid. MS ESI: [M+H]+ m/z 480.1. 1H NMR (600 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.80 (d, J=4.9, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.53-7.36 (m, 2H), 7.23 (d, J=4.9, 1H), 7.11 (s, 1H), 5.92 (s, 1H), 5.86 (s, 1H), 5.12-5.01 (m, 1H), 4.04-3.99 (m, 1H), 3.58-3.36 (m, 1H), 3.19-3.09 (m, 1H), 2.96-2.75 (m, 1H), 2.30 (s, 3H), 2.04-1.82 (m, 2H) rhSYK activity=+++
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1.C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1.CCOCC>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([B:17]([OH:18])[OH:16])=[CH:6][CH:7]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: COB(OC)OC
Reactant: CC(C)Cc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Cc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a suspension of 0.68 g (28.15 mmol) of magnesium turnings in 50 mL of tetrahydrofuran under argon, a crystal of iodine was added and a solution of 4-bromo-isobutylbenzene (6.0 g, 28.15 mmol) in 25 mL of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The mixture was refluxed for an additional 1 hour, cooled to room temperature and added in portions over 15 min to a solution of trimethylborate (2.93 g, 28.15 mmol) in 50 mL of ether at -78° C. under argon. After 30 min at -78° C., the solution was warmed to room temperature, stirred for 90 minutes and 10% aqueous hydrochloric acid (100 mL) was added. After 10 minutes, the solution was extracted with ether (3×100 mL) and the combined ether extracts were extracted with 1 M sodium hydroxide (3×100 mL). The aqueous extracts were acidified with dilute hydrochloric acid to pH 2 and extracted with ether (3×100 mL). The combined ether extracts were washed once with water (100 mL), dried and evaporated to afford 3.5 g of a white solid. Crystallization from ether/hexanes provided 2.3 g (46%) of compound A as a white solid in two crops, m.p. 134-135° C.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:21]=[CH:20][N:19]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[N:10]1([C:5]2[C:4](=[O:15])[N:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[N:21]=[CH:20][N:19]=3)[NH:7][CH:6]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: NNc1cc(N2CCCCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.5 g (26.3 mmol) of the compound from Example 42A and 6.1 g (31.5 mmol) of the compound from Example 8A are dissolved in 55 ml ethyl acetate and 1.2 g (10.5 mmol) p-toluenesulfonic acid are added. The mixture is heated to the reflux and is stirred at this temperature for 16 h. After cooling to RT, the precipitate is filtered off and washed with ethyl acetate. The solid is dissolved in 50 ml water and the solution is adjusted to pH 7 with 1 N hydrochloric acid. The precipitate is filtered off, washed with water and diisopropyl ether and finally dried over phosphorus pentoxide.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][NH2:36])[CH2:25]1>>[NH2:36][CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:26]1[CH2:27][CH2:28][N:24]([C:11]2[C:12]([C:14]([F:16])([F:15])[F:17])=[C:13]3[C:8]([C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:19])[CH2:25]1
Reactant: NCc1ccccc1C1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Product: NCc1ccccc1C1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C(F)(F)F)C1

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylic acid (1.00 g, 3.0 mmol) and 2-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:14][CH:11]1[CH2:10][C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: COC(=O)c1cc2c(s1)CC(C)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCc2cc(C(=O)O)sc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a solution of 704 mg of 6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester (obtained in step b) in a mixture of THF (5ml) and methanol (2 ml) were added 8.37 ml of 1N LiOH and the reaction mixture was stirred at RT for 16 h. Then the pH was adjusted to 2 by addition of 2N HCl and the suspension was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The remaining residue was then purified by crystallization from hot dichloromethane to give 574 mg (87%) of 6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid as brown solid. MS (ISP) 195.1 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:9]1[CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13][NH:8]1
Reactant: COc1ccccc1C1CC(OC)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1CC(OC)CCN1
Temperature: 20 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-2-(2-methoxyphenyl)-4-methoxypiperidine (864 mg, 2.67 mmol) in CH2Cl2 at 0° C. was added TFA (9.6 mL) and the resulting solution was stirred at 0-40° C. for 2 hours. TFA was removed in vacuo, and the residue was stirred with 40 mL of 1:1 mixture of CH2Cl2 and 1N NaOH for 20 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as a light brown oil (565 mg). 1H NMR (CDCl3, 400 MHz) δ: 3.82 (3H, s, OMe), 3.37 (3H, s, OMe).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
A stirred solution of 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (52 mg, 0.18 mmol), 5-fluoro-1,3-dihydro-indol-2-one (25 mg, 0.4 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.04 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered under reduced pressure. The resulting solid was washed with anhydrous ethanol (0.2 ml×5), purified by silica gel column chromatography with dichloromethane:methanol (15:1) as eluents to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 38%) as a yellow solid
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].[C:27]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])([CH3:30])([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>>[C:27]([C:31]1[CH:32]=[C:33]([NH:34][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:19])[CH:35]=[CH:36][CH:37]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (90 mg, 0.255 mmol), 3-tert-butylaniline (38 mg, 0.255 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43 mg, 0.280 mmol), and 1-hydroxy-7-azabenzotriazole (25 mg, 0.255 mmol) were combined in a round bottom flask and taken up in 5 ml dry of DMF. The reaction was stirred at ambient temperature for 12 hours and then poured into 10% HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified on silica gel. Elution with a gradient of 2-5% methanol-dichloromethane provided the title compound (100 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[S:23][CH:24]=[C:25]([CH:27]=O)[N:26]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][NH:1][C:2]3[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=3)[N:26]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CNc3ccc(F)nc3)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-amino-2-fluoropyridine (0.476 g, 4.2 mmol) was added to 4-(4-Formyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 2.8 mmol) in dry DCM (10 mL). Sodium triacetoxyborohydride (0.9 g, 4.2 mmol) was then added. The reaction was stirred for 3 hours at room temperature under N2. The organic layer was washed with 2M NaOH solution, water, brine, dried (MgSO4), and the solvent was removed in vacuo. The material was purified by silica gel chromatography (DCM/methanol: 10:1 v/v) to give the desired product. 1H NMR (CDCl3): δ 7.59-7.60 (1H, m), 7.06-7.10 (1H, m), 7.02 (1H, s), 6.76 (1H, dd, J=8.8, 3.6 Hz), 4.4 (2H, d), 4.20-4.31 (3H, m), 3.09-3.17 (1H, m), 2.8-2.95 (2H, m), 2.07-2.10 (2H, m), 1.77-1.47, (2H, m), 1.47 (9H, s).
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1)(=O)=O.[CH3:37][O-:38].[Na+]>CO.CC(O)=O>[CH3:37][O:38][C:5]1[N:6]=[C:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:8]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10][C:9]=2[N:25]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Yield: 90.5 %

Procedure:
A solution of [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 53; 44 mg, 0.08 mmol) and NaOMe (100 mg, 0.25 mmol) in MeOH (1.5 mL) was heated at 60° C. for 1 h. The mixture was cooled, acidified with HOAc (3 drops), and directly purified using Preparative HPLC (conditions as in Example 54) to give the title compound (35 mg, 89%). MS (ESI): mass calcd. for C22H19F6N5O, 483.15; m/z found, 484.8 [M+H]+. 1H NMR (CDCl3): 9.63 (s, 1H), 8.39 (d, J=3.3 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.06-7.02 (m, 1H), 3.88 (s, 3H), 3.50-3.44 (m, 4H), 3.26-3.22 (m, 2H), 3.11-3.07 (m, 2H).