Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=Cc1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.0 g (17.03 mmol) of methyl 4-methylcinnamate, 3.33 g (18.73 mmol) of N-bromosuccinimide and 60 mg of 2,2'-azobis(2-methylpropionitrile) in 75 ml of carbon tetrachloride was heated to reflux with a heat lamp and stirred rapidly for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to give the title compound as an oil which crystallized. NMR in CDCl3 (δ units): 3.80 (singlet, 3); 4.48 (singlet, 2); 6.44 and 7.67 (doublets, J=15 Hz, 1); 7.39, 7.49 (doublets, J=7 Hz, 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[O:9]1[CH2:13][CH2:12]OC1=O.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:12][CH2:13][OH:9])[CH:6]=1
Reactant: O=C1OCCO1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 4-bromo-1H-pyrazole in DMF was added sodium hydride at room temperature. The mixture was stirred for 30 minutes, [1,3]dioxolan-2-one was added, the mixture was stirred and slowly warmed to room temperature. The reaction was monitored by TLC. After the reaction was done, EtOAc was added, washed with saturated NaHCO3, water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel, eluants EtOAc and DCM 10%, to give 2-(4-Bromo-pyrazol-1-yl)-ethanol 0.22 g, yield 34%. 1H NMR (400 MHz, chloroform-D) δ ppm 7.49 (s, 1H) 7.46 (s, 1H) 4.18-4.23 (m, 2H) 3.93-3.98 (m, 2H) 3.09 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:16]([O-])=O)=[CH:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([NH2:16])=[N:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N)ncc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
2-Chloro-4-(4-methyl-6-nitropyridin-3-yloxy)pyridine was dissolved in THF (11.95 ml)/methanol (11.95 ml) and ammonium chloride (0.256 g, 4.78 mmol) was added, followed by zinc dust (0.313 g, 4.78 mmol). The mixture stirred at RT for 1.5 hours before it was filtered through Celite®. The filtrate was evaporated under reduced pressure to yield a magenta film which was partitioned between ethyl acetate/THF (4:1) and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to yield 5-(2-chloropyridin-4-yloxy)-4-methylpyridin-2-amine as a brown oil (0.116 g, 103%), which was used in the next step without purification. MS (ESI) m/z: 236.1 (M+H+).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@H:25]([C:36](O)=[O:37])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[C@H:25]([C:36]([NH:22][CH2:21][C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:23])=[O:37])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33]
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: NCC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1)N[N+](=O)[O-]
Reaction time: 4 h

Procedure:
353 g of tosylate of glycine benzyl ester (H-Gly-o-Bzl, Tosylate) are dissolved in 2 liters of DMF; 115 g of NEM then 353 g of Z-Arg(NO2)-OH and finally 500 g of BOP are added. The pH of the medium is adjusted to 7 with the aid of NEM and using pH indicating paper on samples of the reaction medium diluted with water. The reaction medium is stirred and the state of advance of the reaction followed by TLC. After 4 hrs., the reaction is complete and the medium evaporated to dryness in vacuo at 35°. The residue of evaporation is taken up in 2 liters of ethyl acetate and 2 liters of water. Under these conditions, a solid is obtained which is drained and washed successively in solid phase with a 5% aqueous solution of HKSO4 +K2SO4, with pure water, with a 5% aqueous solution of NaHCO3 and finally water.
Reaction SMILES: [CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][C:18](OCC)=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:25])[CH3:24])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:12][C:11]=3[CH:23]([CH3:24])[CH3:25])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(CCCO)cc21
Reaction time: 18 h
Yield: 19.5 %

Procedure:
A solution of ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate (0.18 g, 0.46 mmol) in anhydrous diethyl ether (15 ml) was stirred at room temperature under a nitrogen atmosphere. LiAlH4 (0.09 g, 2.4 mmol) was slowly added to the solution. The mixture was stirred for 18 hr, quenched with water and 5% HCl, extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography hexane/EtOAc (4:6) twice to give (31 mg) of the product (0.031 g, 20%). 1H NMR (300 MHz, CDCl3) δ 7.70 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.03 (m, 2H), 3.73 (m, 4H), 3.17 (m, 1H), 2.80 (m, 6H), 2.18 (m, 1H), 1.98 (m, 3H), 1.37 (d, 6H), 1.26 (br, 1H), 0.94 (t, 3H); ESI (+) MS m/e=346 (MH+), ESI (−) MS m/e=344 (MH−).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow solid (155 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C@@H:9]([NH:11][C:12](=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:10].N(CCO)(CCO)CCO.O>C1COCC1>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][NH:11][C@@H:9]([CH3:10])[CH2:8][OH:7])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(CC(=O)N[C@@H](C)CO)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: OCCN(CCO)CCO
Product: COc1ccc(CCN[C@@H](C)CO)cc1OC
Reaction time: 1.5 h
Yield: 34.7 %

Procedure:
To a suspension of 12.6 g (0.33 mole) lithium aluminum hydride (LAH) in 150 mL of dry THF under argon was added dropwise a suspension of 21.0 g (0.083 mole) (S)-N-(2-hydroxy-1-methylethyl)-3,4-dimethoxybenzeneacetamide in dry THF. The reaction mixture was heated under reflux for 4 hr. An additional 1.0 g of LAH was added and refluxed another 3 hr. An additional 3.0 g of LAH was added and the reaction was refluxed overnight. To the reaction was added 69 mL (0.48 mole) of triethanolamine over 1 hr. After stirring for 90 min, 16 ml of water was added and this was stirred overnight. An additional 12 ml of water was added. The solid that formed was filtered off and the filter cake was washed three times with ether and once with THF. The filtrate was washed with brine and dried (K2CO3). The solvent was removed in vacuo. The residue was dissolved in ether/acetonitrile, the undissolved solid was filtered off and the filtrate was evaporated in vacuo. The residue was treated with ethereal hydrogen chloride and the solid was collected. Three recrystallizations from acetonitrile gave 6.9 g of (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-propanol (38%) mp, 120°-123° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O>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].O>[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)=[CH:15][N:14]=1
Reactant: Brc1ccc2cnccc2c1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3cnccc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Yield: 8.3 %

Procedure:
(Some starting materials may be obtained from Kalexsyn, Kalamazoo, Mich.) A glass microwave reaction vessel was charged with 6-bromoisoquinoline (120 mg, 0.58 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (262 mg, 0.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (32 mg, 0.04 mmol), sodium carbonate (183 mg, 1.730 mmol), and dioxane-H2O (2:1, 3 mL). The reaction mixture was sealed and heated at 100° C. for 1 h. Water was added in, and the suspension was filtered, the solid was air-dry. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 2% to 5% MeOH in CH2Cl2 to provide N-(2-chloro-5-(isoquinolin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (20 mg, 8.4% yield) as a white solid. MS (ESI pos. ion) m/z: calc'd for C20H13ClFN3O2S:413.0; found: 414.0(MH+). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44(t,J=8.80 Hz, 2 H) 7.82-7.85 (m, 2 H) 7.93 (d, J=5.87 Hz, 1 H) 8.00 (dd, J=8.61, 1.37 Hz, 1 H) 8.16 (d, J=2.15 Hz, 1 H) 8.29 (d, J=8.61 Hz, 1 H) 8.33 (s, 1 H) 8.58 (d, J=5.67 Hz, 1 H) 8.75 (s, 1 H) 9.40 (s, 1 H) 10.58 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:50]([S:53]([CH2:56][CH2:57][NH2:58])(=[O:55])=[O:54])([CH3:52])[CH3:51]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([NH:58][CH2:57][CH2:56][S:53]([CH:50]([CH3:52])[CH3:51])(=[O:55])=[O:54])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34]
Reactant: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CC(C)S(=O)(=O)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)CCNC(=O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Yield: 33.9 %

Procedure:
Prepared according to Procedure I utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoic acid (0.22 g, 0.4 mmol), carbonyldiimidazole (0.58 g, 3.6 mmol), and iso-propanesulfonylethylamine (0.24 g, 1.6 mmol) in DMF to afford the title compound (0.088 g). Electrospray MS 649 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]=O.[Cl-].[CH2:14]([O:21][C:22]1[CH:47]=[CH:46][CH:45]=[CH:44][C:23]=1[CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]=[CH:24][C:23]1[CH:44]=[CH:45][CH:46]=[CH:47][C:22]=1[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccccc1CCC=O
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccccc1CCC=Cc1ccccc1OCc1ccccc1

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, the whole of the 3-(2-methoxyphenyl)propanal prepared as described above, 1.65 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 1.01 g of 1,8-diazabicyclo[5,4,0]undec-7-ene were reacted in 30 ml of acetonitrile. The crude product, extracted as described in Preparation 3, was purified by column chromatography through silica gel, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.98 g of benzyl 2-[4-(2-methoxyphenyl)-1-butenyl]phenyl ether as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](O[N:49]2N=N[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CCCCC1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid 0 (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added cyclohexanamine (9.0 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of cyclohexanamine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-50—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclohexylacetamide. (27 mg, 0.055 mmol, 39%).
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[C:12]([CH:13]=O)=[C:11]([OH:15])[C:10]([O:16][CH3:17])=[CH:9][CH:8]=1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:6][C:7]1[C:12]([CH:13]=[CH2:1])=[C:11]([OH:15])[C:10]([O:16][CH3:17])=[CH:9][CH:8]=1
Reactant: COc1ccc(F)c(C=O)c1O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=Cc1c(F)ccc(OC)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 50 g of methyltriphenylphosphonium bromide in 300 ml of toluene there was added 45 ml of n-butyllithium (2.55 M, hexane solution) while cooling on ice under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was allowed to stand. A 150 ml portion of the supernatant was added dropwise to a solution of 5.00 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No. 457628-15-8] in 90 ml of toluene while cooling on ice. After stirring the mixture at room temperature for 1 hour, saturated aqueous ammonium chloride was added to the reaction mixture. The organic layer was extracted with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 3-fluoro-6-methoxy-2-vinylphenol (4.33 g) as a solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[N:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][N:45]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccc(Br)nc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 6-bromo-3-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (107 mg, 21%) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[CH:36][C:35]=1[CH3:40].NN>CO.C1COCC1>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][C:35]=2[CH3:40])[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (196 mg, 0.34 mmol) in MeOH/THF (2 mL/0.5 mL) was added hydrazine (0.5 mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture was concentrated, and purified on silica (50% MeOH in CHCl3 (0.5% NH4OH) to give a free base of the title compound, which was dissolved in MeOH (2 mL), and treated with HCl (aq, 37%). After stirring overnight, the reaction solution was concentrated to give the title compound (107 mg, 51%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H)+. 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.96 (s, 1H), 7.90 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.43 (t, J=7.3 Hz, 1H), 4.66 (m, 1H), 3.91 (s, 3H), 3.33-3.14 (m, 4H), and 2.10 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1>>[NH2:22][CH2:21][CH2:20][C@H:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)[CH2:14][CH2:15]1)[CH3:23]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: C[C@H](CCN)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Using general procedure A with 4-(trifluoromethyl)aniline (0.19 mL, 1.51 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (302 mg, 1.82 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a pale blue solid (232 mg, 49% over 2 steps).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[C:6]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][O:14][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[C:10]([F:13])([F:11])[F:12])[C:3]([OH:25])=[O:2]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(F)(F)F)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
500 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoic acid methyl ester was dissolved in 10 ml of MeOH:water/3:1. 230 mg of lithium hydroxide monohydrate were added to the solution, and the reaction was stirred at RT for 16 h then at 50° C. for 2 h. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The solution was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C(N(CC)CC)C>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)Cl
Reactant: N#Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Product: CCCCC(=O)Oc1ccc(C#N)cc1

Procedure:
This compound was prepared by reacting 4-hydroxybenzonitrile with valeryl chloride in the presence of triethylamine to give 4-cyanophenyl valerate which was subjected to a Fries rearrangement with aluminium chloride to give 4-hydroxy-3-valerylbenzonitrile which was reduced with sodium borohydride to give the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][CH:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:9]([C:22]([O:24]C)=O)[CH2:8]1>C(OCC)C.[Cl-].[NH4+].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[OH:24][C:22]1([CH:9]2[CH2:8][CH:7]([O:6][CH3:5])[CH2:11][N:10]2[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:2][CH2:1]1
Reactant: COC(=O)C1CC(OC)CN1C(=O)OCc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: CCOCC
Product: COC1CC(C2(O)CC2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3M solution of ethylmagnesium bromide (1.43 mL, 4.30 mmol) was added over a period of 40-60 minutes under stirring to a room temperature solution of 1-benzyl 2-methyl 4-methoxypyrrolidine-1,2-dicarboxylate (420 mg, 1.43 mmol) and titanium (IV) isopropoxide (0.086 mL, 0.286 mmol) in diethyl ether. The mixture was stirred for 1 hour at room temperature. The reaction was cooled to 0° C., treated with a few drops of saturated aqueous ammonium chloride, filtered through celite, and washed with diethyl ether. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford benzyl 2-(1-hydroxycyclopropyl)-4-methoxypyrrolidine-1-carboxylate. MS ESI calc'd. for C16H21Na4 [M+H]+ 292. found 292.