Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.I[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]2[CH2:20][C:21]([O:23][CH3:24])=[O:22].CNC1C=CC(I)=CC=1.C1(C)C=CC=CC=1>C(N(CC)CC)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.O>[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]2[CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)Cc1cc(=O)n(C)c2ccc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CNc1ccc(I)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(=O)n(C)c2ccc(C#N)cc12
Temperature: 25 °C

Procedure:
1.1 ml of trimethylsilyl cyanide (8.4 mmol) followed by 0.15 g (0.13 mmol) of tetrakistriphenylphosphinepalladium are added to a solution of 0.50 g (1.4 mmol) of methyl 6-iodo-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetate (prepared from N-methyl-4-iodoaniline according to the method described in Example 1) in 6 ml of anhydrous triethylamine. The reaction medium is then heated to reflux for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the medium is poured into 60 ml of toluene and 60 ml of water. The organic phase is washed with water and the initial aqueous phase is re-extracted with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under vacuum. The residue is purified by flash chromatography on silica, eluting with a methanol/dichloromethane (5:95) mixture.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]=[CH2:20])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:25][S:26]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])(=[O:28])=[O:27].[CH3:37][S:38]([OH:40])=[O:39].[Na]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][CH2:20][S:38]([CH3:37])(=[O:40])=[O:39])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:25][S:26]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])(=[O:27])=[O:28]
Reactant: C=Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1
Reactant: CS(=O)O
Agent: [Na]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(CCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 251 using N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(2-ethenyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (0.135 g, 0.247 mmol) and methane sulfinic acid, sodium salt (0.126 g, 1.234 mmol), the title compound was obtained as a solid (127 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.72 (s, 1H), 8.54 (d, J=5.49 Hz, 1H), 7.52 (m, 3H), 7.44 (m, 2H), 6.48 (d, J=5.49 Hz, 1H), 3.54 (m, 2H), 3.28 (m, 2H), 3.04 (s, 3H), 1.42 (s, 9H); MS (ESI): 627 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([OH:31])[C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH:26]([OH:31])[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(O)C(=O)O)cc2)c1-c1ccc(F)cc1
Yield: 61.7 %

Procedure:
A mixture of methyl 3-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]-2-hydroxypropionate (1.34 g), a 2N aqueous sodium hydroxide solution (10 ml) and methanol (20 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution (100 ml). The precipitated solids were collected by filtration, washed with water and dried to give 3-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]-2-hydroxypropionic acid (800 mg, 62%) as colorless crystals.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[OH:15])[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(#N)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:15][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([CH3:12])=[CH:11][C:6]=1[CH:2]([OH:1])[CH:3]([CH3:5])[CH3:4])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(O)c(C(O)C(C)C)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)c(C)cc1C(O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the above prepared 2-(1-hydroxy-2-methyl-propyl)-5-methoxy-4-methyl-phenol (2.45 g, 11.65 mmol) in 22 mL acetonitrile were successively added Cs2CO3 (4.56 g, 1.2 eq.) and ethyl bromoacetate (1.35 mL, 1.05 eq.) and the mixture vigorously stirred at ambient temperature for 3 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), gave 3.34 g of the title compound as colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([OH:25])=[C:19]2[CH:18]=[N:17]1)(=[O:9])=[O:8].[H-].[Na+].O[C@@H:29]([CH2:40][O:41][CH:42]([CH3:44])[CH3:43])[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1)=[O:31]>C1COCC1>[CH:42]([O:41][CH2:40][C@H:29]([O:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:7]([CH3:6])(=[O:9])=[O:8])[N:17]=[CH:18][C:19]=12)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1)=[O:31])([CH3:44])[CH3:43]
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC(C)C)nc1
Reactant: CS(=O)(=O)c1ccccc1-n1ncc2c(O)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccccc2S(C)(=O)=O)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 47.4 %

Procedure:
Phosphorus oxychloride (1.864 ml, 20.00 mmol) was added to 1-(2-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate N1) (0.290 g, 1 mmol), at ambient temperature. The resulting mixture was stirred at 100° C. for 4 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was evaporated. The residue was dissolved in DCM (30 mL). MP-Carbonate was added and the mixture stirred for 30 minutes then evaporated. The residue was dissolved in THF (5 mL). Sodium hydride (55.9 mg, 1.40 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (238 mg, 1.00 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes and then the THF solution prepared above was added. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was concentrated, diluted with water (10 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (25 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluent to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(2-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (242 mg, 47.5%, 81% ee). 1H NMR (400 MHz, DMSO-d6) δ 1.12 (6H, dd), 2.24 (3H, s), 3.38 (3H, s), 3.72-3.80 (1H, m), 3.96-4.05 (2H, m), 5.87-5.91 (1H, m), 7.58 (1H, dd), 7.77 (1H, dd), 7.86-7.92 (2H, m), 7.94-7.99 (1H, m), 8.16-8.21 (2H, m), 8.53 (1H, s), 8.60 (1H, s), 10.82 (1H, s); m/z (ESI+) (M+H)+=511; HPLC tR=2.07 min.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:44][S:45](Cl)(=[O:47])=[O:46].CCOC(C)=O>C(Cl)Cl.O>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:22][CH2:21]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:5]=2[N:4]=1
Reactant: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A stirred mixture of 297 mg (0.57 mmol) of N-[3-({2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine and 1 g of powdered K2CO3 in CH2Cl2 was cooled to 0° C. and 0.4 g of methanesulphonyl chloride was added. The mixture was allowed to warm to room temperature, and after 2 hrs it was diluted with water and the organic layer was separated and dried. Chromatography on alumina, eluting first with CH2Cl2/EtOAc (1:1) and then with EtOAc gave 200 mg (59% yield) of N-[3-({2-(difluoromethyl)-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-yl}oxy)propyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.84 (dd, J=8.4. 0.6 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 4.32 (t, J=6.8 Hz, 2H), 4.02 (m, 4H), 3.88 (m, 4H), 3.78 (m, 4H), 3.33 (m, 4H), 2.81 (s, 3H), 2.54 (t, J=7.2 Hz, 2H), 2.28 (s, 6H), 2.14 (pentet, J=7.0 Hz, 2H); Hydrochloride: mp (EtOH) 243-247° C.; Anal. Calcd. for C25H36ClF2N9O4S.1.5H2O: C, 45.6; H, 6.0; Cl, 5.4; N, 19.1. Found: C, 45.5; H, 6.1; Cl, 5.2; N, 19.2%.
Reaction SMILES: [N+:1]([C:4]12[CH2:19][C:18]([CH3:23])([C:20](O)=[O:21])[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:32]>C(Cl)Cl.Cl>[N+:1]([C:4]12[CH2:19][C:18]([CH3:23])([C:20]([F:32])=[O:21])[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reactant: Fc1nc(F)nc(F)n1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C(=O)F)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 9-nitro-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid (hereafter called Core C) (500 mg, 1.6 mmol) and pyridine (0.25 mL, 3.0 mmol) in 10 mL of DCM was added a solution of cyanuric fluoride (400 mg, 3.0 mmol) dropwise. After stirring 30 min, the reaction was diluted with 1N HCl, and extracted 2×DCM. The DCM extracts were dried over MgSO4. The solution was filtered, concentrated by rotary evaporator to give 482 mg (98%) of 9-nitro-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid fluoride Core D. MS found: (M+H)+=312.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Cl:13][C:14]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:15]=1[O:16][CH2:17][CH2:18][CH2:19]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:13][C:14]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:15]=1[O:16][CH2:17][CH2:18][CH2:19][O:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: Oc1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-n3cncn3)cc2)c(Cl)c1

Procedure:
125 mg of 4-[1,2,4]triazol-1-yl-phenol, 212 mg of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester and 207 mg of potassium carbonate are stirred for 24 hours at 50° C. in 4 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.9).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (573 mg, 82%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1)=[O:18]>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)[C:17]([O:16][CH3:15])=[O:18]
Reactant: COC(=O)c1ccc(B(O)O)c(C)c1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc3[nH]ncc23)c(C)c1
Temperature: 140 °C

Procedure:
To a microwave vial was added a mixture 4-bromo-6-(trifluoromethyl)-1H-indazole (0.478 g, 1.804 mmol), (4-(methoxycarbonyl)-2-methylphenyl)boronic acid (0.35 g, 1.804 mmol) and PdCl2(dppf) (0.066 g, 0.090 mmol) in dioxane (10 mL) and aqueous saturated NaHCO3 (3 mL). The resulting light yellow suspension was heated at 140° C. for 60 minutes in a microwave reactor. The reaction mixture was subsequently concentrated and the residue was diluted with EtOAc and washed with water. The volatiles were removed via rotary evaporation to give the title compound, which was used without further purification (0.53 g). ESI-MS m/z [M+H]+ calc'd for C17H13F3N2O2, 335.1. found 335.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][O:19][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C:17]#[N:18])[C:7]3=4.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][O:19][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][CH2:17][NH2:18])[C:7]3=4
Reactant: N#CCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: CO
Solvent: C1CCOC1
Product: NCCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 82 °C
Yield: 27.9 %

Procedure:
To a mixture of 2-[(8chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile (0.2838 g, 0.757 mmol) in dry THF (10 mL) is added borane-methylsulfide complex (0.22 mL, 2.27 mmol). The mixture is refluxed under an argon atmosphere at 82° C. for 18 h. The mixture is then cooled, to rt and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added and again removed. The residue is dissolved in methanol (10 mL), CH2Cl2 (5 mL), and conc. HCl (3 mL) and heated at 60° C. for 1 h. The mixture is neutralized with aqueous potassium carbonate and partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate and concentrated. Column chromatography (50 g silica gel) using CH3OH/CH2Cl2 (4/96) as eluent gave 0.080g (28%) of 2-[(8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine; mp 127-128° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([NH:13][C:14](=[O:21])[CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Br)=[CH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1([C:44](=[O:46])[CH3:45])[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]([NH:13][C:14](=[O:21])[CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][N:40]2[CH2:41][CH2:42][CH2:43][N:37]([C:44](=[O:46])[CH3:45])[CH2:38][CH2:39]2)=[CH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCCNCC1
Reactant: COc1ccc(-c2cc(NC(=O)C(C)CCCBr)n(C(=O)OC(C)(C)C)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(NC(=O)C(C)CCCN3CCCN(C(C)=O)CC3)n(C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
5-(5-Bromo-2-methyl-pentanoylamino)-3-(4-methoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (280.0 mg, 0.6 mmol, 1.0 eq) was dissolved in DCM (3 mL). Triethylamine (80 μL, 0.6 mmol, 1.0 eq) and 1-[1,4]-diazepan-1-yl-ethanone (158 μL, 170.0 mg, 1.2 mmol, 2.0 eq) were added and the mixture was stirred at room temperature for 24 hours, then at 50° C. for 16 hours. NaHCO3 saturated solution was added and the organic layer separated and collected. Evaporation of the solvent gave a crude product purified using SiO2 column (elution DCM, DCM:MeOH 99:1 to 96:4) obtaining the title product (181.3 mg, yield 54%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH2:13][CH3:14])=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH2:13][CH3:14])=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:3][CH2:2]1
Reactant: CCOc1cc(-c2ccccc2F)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2ccccc2F)c(C2CC2)cc1C=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Manganese dioxide (1.61 g) was added to a toluene (10 mL) solution of (2-cyclopropyl-5-ethoxy-2′-fluorobiphenyl-4-yl)methanol (1.06 g), and the mixture was stirred at 60° C. for 1 hour. Manganese dioxide (0.965 g) was further added to the reaction mixture, and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (955 mg).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13].CO>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COc1cccc(CNS(C)(=O)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)NCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.6 %

Procedure:
A solution of BBr3 (1.0 M in CH2Cl2, 111 mL, 111 mmol) was slowly added to a solution of N-(3-methoxy-benzyl)-methanesulfonamide (12.000 g, 55.7 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction was warmed to room temperature and was stirred for 4 h. Methanol (100 mL) was cautiously added and the solution was concentrated in vacuo. Flash chromatography (1:1 hexanes:EtOAc) provided N-(3-hydroxy-benzyl)-methanesulfonamide (11.50 g). 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 6.84 (m, 2H), 6.77 (m, 1H), 4.83 (bs, 1H), 4.24 (s, 2H), 2.86 (s, 3H); MS 201 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C@H:29]([NH2:31])[CH3:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C@@H:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCC[C@@H](C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCC[C@@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-4-methoxybutan-2-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.82 Hz, 3 H) 1.67-1.77 (m, 1 H) 1.77-1.89 (m, 1 H) 2.44 (s, 3 H) 3.39 (t, J=6.57 Hz, 2 H) 4.05-4.20 (m, 1 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.17 (br. s., 1 H) 8.43 (d, J=7.07 Hz, 3H) 8.87-8.95 (m, 1 H) 12.98-13.34 (m, 1 H); ESI-MS m/z [M+H]+ 406.2.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>O.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[O:21])=[CH:15][N:16]=1)=[CH:8]2)[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:24]
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3ncc(CCC(=O)N4CCOCC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (0.30 g), 1H-1,2,3-benzotriazol-1-ol (0.11 g) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.15 g) at room temperature. The mixture was stirred at room temperature for 2 hr, and morpholine (0.30 g) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were collected by filtration and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.24 g, yield 69%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 160-161° C.