Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:19])=[C:12]([S:15](Cl)(=[O:17])=[O:16])[CH:13]=2)[C:8]([CH3:21])([CH3:20])[CH2:7]1)(=[O:5])[CH3:4]>C1COCC1>[CH3:1][NH:2][S:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH3:21])([CH3:20])[CH2:7][N:6]2[C:3](=[O:5])[CH3:4])=[CH:10][C:11]=1[Br:19])(=[O:17])=[O:16]
Reactant: CN
Reactant: CC(=O)N1CC(C)(C)c2cc(Br)c(S(=O)(=O)Cl)cc21
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc2c(cc1Br)C(C)(C)CN2C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
Methylamine (2 M solution in THF, 2.4 mL, 4.9 mmol) was added to a solution of 1-acetyl-5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (300 mg, 0.82 mmol) in THF (10 mL). The solution was stirred at room temperature for 30 minutes then the solvent was removed in vacuo and the residue partitioned between water and EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (271 mg) as a yellow solid. 1H NMR (CDCl3): 8.93 (1H, s), 7.44 (1H, s), 5.07 (1H, s), 3.88 (2H, s), 2.68 (3H, d), 2.25 (3H, s), 1.48-1.22 (6H, s).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39].C(O)C.[ClH:50]>O1CCCC1>[ClH:50].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH2:24][N:44]1[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N1CCN(Cc2cc(C(C)(C)C)cc(-c3ccc(C(F)(F)F)nc3)c2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
Sodium triacetoxyborohydride (0.41 g, 2.0 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and 1-acetylpiperazine (0.24 mL, 1.8 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a colorless oil which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was then concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and solid was filtered off to afford 1-(4-(5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzyl)piperazin-1-yl)ethanone hydrochloride (0.32 g, 61% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13]O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:3]1[C:2]([CH3:1])=[N:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1nn(-c2ccccc2)nc1CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn(-c2ccccc2)nc1CBr
Temperature: 120 °C
Yield: 91.5 %

Procedure:
To a solution of (5-Methyl-2-phenyl-2H-[1,2,3]triazol-4-yl)-methanol (0.25 g, 1.30 mmol) in 10 ml of toluene was added PBr3 (0.53 g, 1.90 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.30 g, 90%) as a yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1.S(Cl)([Cl:47])=O>C(Cl)Cl>[Cl:47][CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(CO)c12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(CCl)c12
Temperature: 50 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
A solution of (R)-1-(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (800 mg, 1.371 mmol, see Example 109) and thionyl chloride (0.110 ml, 1.508 mmol) in DCM (15 ml) was allowed to stir at 50° C. for 18 h. Removed the solvent by reduced pressure and the residue was purified on silical gel 0-100% EtOAc/Hexane and yielded (R)-1-(4-(chloromethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (402 mg, 0.668 mmol, 49% yield). MS: [M+H]+ m/z 602.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]#[N:12].[CH3:13][O:14]CCl>[N+](C)([O-])=O.ClCCl.ClCCl>[C:11]([C:7]1[N:6]([CH3:5])[CH:10]=[C:9]([CH:13]=[O:14])[CH:8]=1)#[N:12]
Reactant: Cn1cccc1C#N
Reactant: COCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: Cn1cc(C=O)cc1C#N
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Aluminum trichloride (24.24 g, 180.86 mmol) was dissolved in nitromethane/dichloromethane (1/1, 320 ml), the solution was cooled to −20° C., and 1-methylpyrrole-2-carbonitrile (8 g, 75.36 mmol) was added. α,α-Dichlorodimethyl ether (10.4 g, 90.43 mmol), dissolved in dichloromethane (42 ml), was subsequently added dropwise. After stirring for 4 h at 0° C., the batch was poured onto ice (200 g). The aqueous phase was extracted with diethyl ether. The combined organic phases were washed until neutral with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution. After drying over sodium sulfate, the solvent was removed in a rotary evaporator. The crude product was employed in the reactions below without further purification.
Reaction SMILES: [CH2:1]([O:9][N:10]=[C:11]([C:17](=[O:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:23])(=O)=O>C(O)(=O)C>[CH2:1]([O:9][N:10]=[C:11]([C:17](=[O:19])[CH2:18][Cl:23])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCCCCCCCON=C(C(=O)CCl)C(=O)OCC
Yield: 90.9 %

Procedure:
Ethyl 2-n-octyloxyimino-3-oxobutyrate (syn isomer, 165.5 g.), sulfuryl chloride (84.7 g.) and acetic acid (165 ml.) were treated in a similar manner to that of Example F-(2) to give ethyl 2-n-octyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 169.6 g.), oil.
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:6][NH2:7])=[O:5])#[N:2].[F:14][C:15]([F:26])([F:25])[C:16](=O)[CH2:17][C:18](=O)[C:19]([F:22])([F:21])[F:20]>>[C:8]1([C:3]2[C:4]([OH:5])=[N:6][N:7]3[C:18]([C:19]([F:20])([F:22])[F:21])=[CH:17][C:16]([C:15]([F:14])([F:25])[F:26])=[N:2][C:1]=23)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CC(C(=O)NN)c1ccccc1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Product: Oc1nn2c(C(F)(F)F)cc(C(F)(F)F)nc2c1-c1ccccc1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 28.1 %

Procedure:
2-Cyano-2-phenylacetohydrazide [Int-1A] (1.00 g, 5.13 mmol, 1.0 eq) and 1,1,1,5,5,5-hexafluoropentane-2,4-dione (1.07 g, 5.13 mmol, 1.0 eq) were dissolved in 16.6 mL acidic acid and stirred for 3.5 h at 60° C. The reaction mixture was allowed to stir at rt overnight. The precipitate was isolated by filtration. The solid was washed with hexane and dried to give 500 mg (27% yield) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH:17]2[CH2:20][N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:18]2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([O:39][C@@H:40]3[CH2:44][CH2:43][O:42][CH2:41]3)=[CH:35][CH:34]=2)O1>>[CH3:15][C@@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:5]2[N:4]=[C:3]([O:16][CH:17]3[CH2:20][N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:18]3)[C:2]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C@@H:40]4[CH2:44][CH2:43][O:42][CH2:41]4)=[CH:35][CH:34]=3)=[CH:7][N:6]=2)[CH2:10][CH2:11]1
Reactant: CC1(C)OB(c2ccc(O[C@@H]3CCOC3)cc2)OC1(C)C
Reactant: CS(=O)(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Product: CS(=O)(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(O[C@@H]3CCOC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 3, 5-bromo-N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-amine was reacted with (R)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolane to provide the title compound (18 mg, 45% yield). 1H NMR (CDCl3, 400 MHz) 8.12 (s, 1H), 7.38 (m, 2H), 6.91 (m, 2H), 5.34 (m, 1H), 5.20 (sb, 1H), 4.95 (m, 1H), 4.31 (m, 2H), 4.09-3.92 (m, 6H), 2.90 (s, 3H), 2.22 (m, 2H), 1.80-1.57 (m, 6H), 1.23 (m, 2H), 0.94 (d, 3H). MS (ESI) m/z: Calc. 502.2 (M+). Found: 503.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([O:22][C:23](=[O:37])[CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=1)=[O:27])([CH3:21])([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[C:18]([O:22][C:23](=[O:37])[CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][N:36]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:34])=[CH:31][CH:32]=1)=[O:27])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCC(=O)OC(C)(C)C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (49 mg, 0.17 mmol) in isopropanol (2.0 mL) was heated with tert-butyl{[5-(hydrazinocarbonyl)thiophene-2-carbonyl]amino}acetate (44 mg, 0.15 mmol) prepared in Reference Synthetic Example 8 and 3 mg of p-toluenesulfonic acid monohydrate at 100° C. for 8 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, methanol and chloroform and dried to give 69 mg of the desired product (yield 83%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[CH3:2].[F:24][C:25]([F:45])([F:44])[C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]([NH:20][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:25]([F:45])([F:44])[F:24])[O:33][N:32]=2)=[O:36])[CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCOc1cc2c(Oc3cccc(N)c3)ncnc2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
To a stirred solution of 3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)aniline (100 mg, 0.322 mmol) and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (151 mg, 0.482 mmol) in anhydrous THF (5 mL), was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture was stirred at rt for 15 h. Concentration in vacuo followed by purification via silica gel column chromatography (eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate), afforded 1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (48 mg, 28%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (brs, 1H), 9.01 (s, 1H), 8.55 (s, 1H), 7.54-7.59 (m, 2H), 7.37-7.43 (m, 2H), 7.26 (m, 1H), 6.98 (m, 1H), 6.87 (s, 1H), 4.24 (q, J=7 Hz, 2H), 4.00 (s, 3H), 1.53 (s, 6H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 532 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:37])([C:33]([F:36])([F:35])[F:34])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[C:29]([NH2:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[N:16]=2)([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][C:8]1[C@:9]([CH3:37])([C:33]([F:36])([F:34])[F:35])[O:10][CH2:11][C@:12]([C:15]2[N:16]=[C:17]([NH:21][C:22]([C:24]3[C:29]([NH2:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ncc(C#N)cc3N)n2)CO[C@@]1(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(c2cccc(NC(=O)c3ncc(C#N)cc3N)n2)CO[C@@](C)(C(F)(F)F)C(N)=N1
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a solution of ((2R,5R)-5-{6-[(3-amino-5-cyano-pyridine-2-carbonyl)-amino]-pyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (71 mg, 0.133 mmol) in DCM (3 ml) was added TFA (1 ml). After stirring for 1.5 h the mixture was poured onto 10% aq. Na2CO3 and extracted three times with DCM. The combined organic layers were dried with K2CO3, filtered and evaporated. The title compound (46 mg) was obtained after chromatography on silica gel (hexanes/15-25% (EtOAc/EtOH 9:1)) as a yellow solid. HPLC: RtH3=3.027 min; ESIMS: 434 [(M+H)+]; 1H-NMR (600 MHz, DMSO-d6): 10.23 (s, 1H), 8.25 (s, 1H), 8.06 (d, 1H), 7.85 (t, 1H), 7.69 (s, 1H), 7.36-7.27 (m, broad, 3H), 6.12-6.00, (s, broad, 2H), 3.94 (d, 1H), 3.76 (d, 1H), 1.42 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21]([O:23]C)=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([F:41])[CH:40]=1)[NH2:37].C[Al](C)C>>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21](=[O:23])[NH:37][C:36]1[CH:35]=[C:34]([F:33])[CH:40]=[C:39]([F:41])[CH:38]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Agent: C[Al](C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Yield: 45.8 %

Procedure:
(S)-Methyl 1-(4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanamido)-3-bromo-1H-pyrrole-2-carboxylate (4 g, 7.84 mmol) was treated with 3,5-difluoroaniline (5.06 g, 39.19 mmol) and trimethyl aluminium (2 M in toluene, 19.6 mL, 39.18 mmol) according to the method of Preparation 10a. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 2.18 g (41% yield) of the title compound as a white solid. Purity 88%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O-])=O.[H][H]>C1COCC1.[Ni]>[N:9]1([CH2:8][CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:17]=[CH:16][CH:15]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(CCN2CCCCC2)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc(CCN2CCCCC2)c1

Procedure:
To a solution of 0.2 g (0.85 mmol, 1.0 eq.) of 1-(3-nitrophenethyl)piperidine (I-25) in 15 mL of THF was added ˜30 mg of Raney Nickel. The reaction mixture was stirred under 1 atm. of hydrogen at room temperature for 16 h. The reaction mixture was then filtered through Celite® and the solvent was removed in vacuo to provide 3-(2-(piperidin-1-yl)ethyl)benzenamine (I-26).
Reaction SMILES: [Mg].CN(C)P(N(C)C)(N(C)C)=O.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Cl.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+]>>[CH3:23][Si:22]([CH3:25])([CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Clc1ccccc1Cl
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[Si](C)(C)c1ccccc1[Si](C)(C)C
Temperature: 70 °C
Yield: 54.13 %

Procedure:
Magnesium (9.72 g, 400 mmol), hexamethylphosphoramide (HMPA) (80 mL, 460 mmol), 1,2-dichlorobenzene (14.76 g, 100 mmol), and a catalytic amount of 12 were combined in a 500 mL round bottomed flask and heated to 70° C. with stirring. Chlorotrimethylsilane was added dropwise to the solution at 70° C. The solution was stirred for an additional 30 minutes and then heated to 100° C. for 48 h. After cooling, the reaction mixture was poured over ice and NaHCO3. The Mg and precipitate were filtered off and the filtrate was extracted with ether (3×, 200 mL). The organic phase was washed with water (2×, 400 mL) and brine (1×, 400 mL) and dried with Na2SO4 and concentrated. The product was distilled under reduced pressure at 128-133° C. to yield a light yellow oil (12.0426 g, 54.13%). 1H NMR (300 MHz, CDCl3) δ 7.85 (dd, 2H, J=3.4 Hz, J=5.5 Hz, ArH), 7.49 (dd, 2H, J=3.4 Hz, J=5.5 Hz, ArH), 0.55 (s, 18H, CH3); 13C NMR (300 MHz, CDCl3) δ 145.98, 135.17, 127.76, 1.96
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[S:11][C:10]([NH:12][C:13](=[O:31])[C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[C:16]([O:27][CH:28]([CH3:30])[CH3:29])[CH:15]=2)=[N:9][CH:8]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[S:11][C:10]([NH:12][C:13](=[O:31])[C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[C:16]([O:27][CH:28]([CH3:29])[CH3:30])[CH:15]=2)=[N:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Yield: 90 %

Procedure:
3-[2-(3-Isopropoxy-5-phenoxybenzoylamino)-thiazol-5-yl]-propionic acid ethyl ester was prepared in 90% yield from the reduction of 3-[2-(3-isopropoxy-5-phenoxybenzoylamino)-thiazol-5-yl]-acrylic acid ethyl ester in methanol (10 mL) using hydrogen (60 psi) over Pd/C (200 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])=[O:14])[N:3]=2)=[CH:24][CH:23]=1
Reactant: C[C@H](NC(=O)c1nc(Br)c2ccccc2c1O)C(=O)O
Reactant: Sc1ccc(Cl)cc1
Product: C[C@H](NC(=O)c1nc(Sc2ccc(Cl)cc2)c2ccccc2c1O)C(=O)O
Temperature: 210 °C
Yield: 6.1 %

Procedure:
To a solution of 250 mg of (S)-2-{[1-bromo-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid in 0.7 ml of 1-methyl-2-pryrrolidinone was added 433 mg of 4-chloro-benzenethiol. The solution was heated at 210° C. for 30 min. using a CEM Discover microwave reactor. The solution was concentrated under vacuum. The resultant residue was crystallized from methanol to yield 18 mg of a tan solid; MS (−): m/z 401.10 (M−1)
Reaction SMILES: N[C:2]1C=C(NCCOC)C(C#N)=CN=1.[C:15]([C:17]1[C:18]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[CH:19][C:20]([NH:23][C:24]([N:26]2[C:35]3[C:30](=[CH:31][C:32]([CH2:41][N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][C:43]4=[O:49])=[C:33]([CH:36](OC)[O:37]C)[N:34]=3)[CH2:29][CH2:28][CH2:27]2)=[O:25])=[N:21][CH:22]=1)#[N:16]>>[C:15]([C:17]1[C:18]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[CH:19][C:20]([NH:23][C:24]([N:26]2[C:35]3[C:30](=[CH:31][C:32]([CH2:41][N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][C:43]4=[O:49])=[C:33]([CH:36]=[O:37])[N:34]=3)[CH2:29][CH2:28][C@@H:27]2[CH3:2])=[O:25])=[N:21][CH:22]=1)#[N:16]
Reactant: COCCNc1cc(N)ncc1C#N
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Product: COCCNc1cc(NC(=O)N2c3nc(C=O)c(CN4CCN(C)CC4=O)cc3CC[C@@H]2C)ncc1C#N

Procedure:
From intermediates 75 and 268, coupled and deprotected in an analogous manner to intermediate 80 and Example 201. The title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[NH2:24]>>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]=2[CH3:1])=[O:18])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH2:30][CH2:29]1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Br)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(Br)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 60.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (1.7 g) and 3-bromo-4-(4-morpholinopiperidin-1-yl)aniline (2.0 g), the title compound (2.1 g) was obtained, melting point: 220–230° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:10]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C(=O)O
Reactant: Cc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1cccc(COC(=O)C(C)C)c1
Yield: 59.8 %

Procedure:
25 g (0.2 mol) of 3-methylbenzyl alcohol (Aldrich), 18 g (0.2 mol) of isobutyric acid and 0.6 g of p-toluenesulfonic acid are heated in a 500 ml three-necked flask apparatus with a water separator until the water is completely separated. Washing is then firstly performed with diluted sodium hydrogencarbonate solution and thereafter with water. After removing the toluene by distillation, the residue is distilled using a bulb tube distillation oven. 23 g of product (60% of theoretical) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].Br[CH:11]([CH2:21][CH3:22])[C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]#[C:17][CH3:18])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([CH2:21][CH3:22])[C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]#[C:17][CH3:18])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Reactant: Oc1cnc(Cl)c(Cl)c1
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cnc(Cl)c(Cl)c1

Procedure:
5,6-Dichloropyridin-3-ol was reacted with 2-bromo-N-(4methylpent-2-yn-4-yl)butyramide in a similar procedure to that described in Example 10, Stage 2 to give 2-(5,6-dichloro-3-pyridyloxy)-N-(4methylpent-2-yn-4-yl)butyramide, gum.