Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([OH:16])([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CN(C)C=O.[H-].[Na+].CI>C1C=CC=CC=1>[OH:16][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]1
Reactant: COC1(OC)CCC(O)(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 21.65 g. (0.085 mole) of 4-hydroxy-4-(p-fluorophenyl)cyclohexanone dimethyl ketal (prepared as in Example 25) in 80 ml. of dimethylformamide and 320 ml. of benzene, 3.56 g. of 57% sodium hydride is added. Following about 1 hour of stirring at room temperature, 35 ml. of methyl iodide is added and the mixture heated at reflux. After about 4 hours of heating an additional 10 ml. of methyl iodide is added. At the end of about 18 hours of heating, the suspension, after cooling, is washed with water and brine. The organic layer is evaporated to dryness and the gum remaining dissolved in 400 ml. of acetone, then 40 ml. of 2.5N hydrochloric acid added. At the end of about 4 hours, most of the solvent is removed under vacuum. The residue is extracted with ether and the organic layer washed with aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residual gum is chromatographed on a 2 l. column of Florisil (synthetic magnesium silicate), with elution by 2 l. of Skellysolve B, 2 l. of 95% Skellysolve B:5% acetone and 4 l. of 70% Skellysolve B:30% acetone. Crystalline fractions of first the product, then 6.87 g. (49%) of 4-hydroxy-4-(p-fluorophenyl)-cyclohexanone, melting at 108° to 114° C., are obtained. The product is recrystallized from petroleum ether to give 7.76 g. (41%) of 4-methoxy-4-(p-fluorophenyl)cyclohexanone, melting at 60° to 69° C. The analytical sample melts at 68° to 70° C.
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH:13]([OH:14])[CH2:12][CH2:11][CH2:10][NH:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1([CH2:6][CH:8]2[CH:13]([OH:14])[CH2:12][CH2:11][CH2:10][NH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C1NCCCC1O)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCNC1CN1CCCC1
Yield: 65.1 %

Procedure:
By reducing 5 g (0.025 moles) of 2-(pyrrolidin-1-yl)carbonyl-3-hydroxy piperidine, with 1.2 g (0.025 moles) of LiAlH4 in 100 ml of dry THF, using an alkaline work-up, 3 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:27][N:26]=[N:25][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:27][N:26]=[N:25][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:10])=[O:11])=[C:4]([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[OH:36])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2C(O)c2ccccc2Cl)cc1OC
Yield: 97.5 %

Procedure:
To 0.95 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3,4-dimethoxy-N-(1H-tetrazol-5-ylmethyl)benzenesulfonamide dissolved in 40 ml of ethanol is added 0.38 g of sodium borohydride, and the mixture is refluxed for 18 hours. The solvents are evaporated off and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 0.93 g of the expected product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])[CH:6]=[CH:7][CH:8]=1.[C:33]([O:36][CH:37]([CH:53]([O:57][C:58](=[O:60])[CH3:59])[C:54](Cl)=[O:55])[CH:38]([O:49][C:50](=[O:52])[CH3:51])[CH:39]([O:45][C:46](=[O:48])[CH3:47])[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:35])[CH3:34]>C(Cl)Cl.C(N(CC)CC)C.C(OCC)(=O)C>[C:58]([O:57][CH:53]([C:54](=[O:55])[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:10](=[O:32])[CH:11]([CH2:21][CH2:22][CH:23]([OH:24])[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:12]2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH:4]=1)[CH:37]([O:36][C:33](=[O:35])[CH3:34])[CH:38]([O:49][C:50](=[O:52])[CH3:51])[CH:39]([O:45][C:46](=[O:48])[CH3:47])[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:60])[CH3:59]
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2cccc(CN)c2)cc1
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2cccc(CNC(=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
112 mg (0.24 mmol) of 1-(3-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-methoxyphenyl)azetidin-2-one are dissolved in 5 ml of methylene chloride and 0.5 ml of triethylamine. At 0° C., 0.5 g of 2,3,4-triacetoxy-1-(acetoxychlorocarbonylmethyl)butyl acetate are added, and the mixture is allowed to thaw to room temperature. After 30 minutes, the mixture is diluted with ethyl acetate and then filtered through silica gel. The solvent is distilled off and the residue is purified by flash chromatography. The product is obtained as an amorphous solid:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Si](C)(C)C)[C:3]=1[CH:4]=[O:5].[Br:14]Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:14][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: C[Si](C)(C)c1cccc(O)c1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1c(O)cccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-6-trimethylsilylbenzaldehyde (8.1 g) in carbon tetrachloride (160 ml) was added bromine (2.15 ml) dropwise at 0° C., and the mixture was stirred at room temperature overnight. To the mixture was added aqueous sodium hydrogencarbonate solution, and the layers were separated. The aqueous layer was extracted with dichloromethane and the organic layers were combined, washed with sodium thiosulfate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and toluene (4:1) to afford 6-bromo-2-hydroxybenzaldehyde (4.74 g).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[C:8]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)=[N:7][C:6]=2[N:5]([CH3:25])[C:3]1=[O:4]>CN(C=O)C.[H][H].[Pd]>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[C:8]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)=[N:7][C:6]=2[N:5]([CH3:25])[C:3]1=[O:4]
Reactant: [H][H]
Reactant: Cn1c(=O)c2c(nc(C=Cc3cccc([N+](=O)[O-])c3)n2C)n(C)c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(CCc3cccc(N)c3)n2C)n(C)c1=O

Procedure:
Compound 54 was made from 21b with H2 /Pd 50 psi in DMF for 3 h. mp 158°-160° C. 1H NMR DMSO-d6 d 2.82 (t, 2H J=8 Hz); 2.96 (t, 2H J=8 Hz); 3.20 (s, 3H N--CH3); 3.42 (s, 3H N--CH3); 3.69 (s, 3H N7 --CH3); 4.95 (s, 2H --NH2); 6.34-6.39 (3H, H-2 H-4 H-6); 6.90 (t, 1H J=8 Hz, H-5). MS (CI/NH3) m/e 314 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[O:19])[CH:13]=[CH:12][C:5]=1[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7].[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39]Cl.O>CN(C=O)C>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][O:3][C:4]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[O:19])[CH:13]=[CH:12][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:6]=[CH:5][CH:4]=[CH:15][CH:11]=1)=[O:7]
Reactant: COCCOCCl
Reactant: C=CCOC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1cc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)ccc1C(=O)OCc1ccccc1

Procedure:
1.65 g (55 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a flask. A solution of 23.6 g (50 mmol) of allyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl methoxy)benzoate in 200 ml of DMF is added dropwise and the mixture is stirred until evolution of gas has ceased. 6.3 ml (55 mmol) of 2-methoxy ethoxymethyl chloride are then added dropwise and the reaction mixture is stirred for 2 hours. It is poured into water and extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane/ethyl ether (98:2). After evaporation of the solvents, 19.2 g (69%) of the expected ester are collected in the form of a slightly yellow oil.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=[CH:35][N:34]=1>O1CCCC1>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:11](=[O:10])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:35][N:34]=1
Reactant: NCCCCc1cncc2ccccc12
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCc2cncc3ccccc23)c2ccc(OC)cc2)cc1
Yield: 29.6 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.841 g) and 4-isoquinolinebutanamine (0.39 g) in tetrahydrofuran (8 mL) was stirred for 17 hours at room temperature and was worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate-hexane; 3:1) and then was crystallized from ethyl acetate-ether to provide 0.284 g of (E)-N-[4-(4-isoquinolinyl)butyl]-5.5-bis(4-methoxyphenyl)-2,4-pentadienamide, mp 91°-93° C.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Temperature: 70 °C
Yield: 100 %

Procedure:
To a mixture of ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (24 mg, 0.10 mmol, preparation: See, U.S. Pat. No. 6,670,357, especially example 61, the disclosure of which is hererin incorporated by reference), 2-fluoro-4-nitrophenol (20 mg, 0.125 mmol) and K2CO3 (28 mg, 0.20 mmol) was added DMF (0.5 mL). The reaction was heated at 70° C. for 20 minutes, cooled to room temperature and 2 mL of water was added. The mixture was filtered, the solid was washed with water, and dried to give the title compound (36 mg, 100%) as a light yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]([F:29])([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)[C:9](OC)=[O:10]>C(Cl)Cl>[F:7][C:8]([F:29])([C:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:25])([F:27])[F:26])=[CH:18][CH:19]=1)=[O:28])[C:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10]
Reactant: COC(=O)C(F)(F)C(=O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
Piperidine (175 μL, 1.763 mmol) was slowly added to Intermediate 103A (500 mg, 1.470 mmol) at rt. The reaction was stirred at rt for 3 h. The reaction was diluted with CH2Cl2, loaded onto a 12 g SiO2 column and eluted with EtOAc in hexanes. Fractions containing the product were combined and evaporated to dryness to provide the product (520 mg, 81%) as a clear oil. LCMS Anal. Calc'd for C18H20F5NO3 393.14, found [M+H] 394.2. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=9.1 Hz, 2H), 6.98-6.91 (m, 2H), 4.10 (t, J=5.9 Hz, 2H), 3.61-3.56 (m, 2H), 3.54-3.50 (m, 2H), 2.39-2.26 (m, 2H), 2.14-2.05 (m, 2H), 1.69-1.61 (m, 2H), 1.60-1.51 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31][CH2:32]C7C=CC=CC=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1.BrC[C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=1>>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31][CH2:32][C:44]7[CH:53]=[CH:52][C:51]8[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=8)[N:45]=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: COc1c(OCc2ccccc2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12
Reactant: BrCc1ccc2ccccc2n1
Product: COc1c(OCc2ccc3ccccc3n2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12

Procedure:
Synthesized according to the method of example 10 using 7-(2-methyl-1H-benzimidazol-6-yl)-4-{8-(methyloxy)-7-[(phenylmethyl)oxy]quinazolin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) in step 1 and 2-bromomethylquinoline in step 2. 1H NMR (400 MHz, d6-DMSO): 8.64 (s, 1H), 8.47 (d, 1H), 8.03 (m, 4H), 7.83 (m, 4H), 7.73 (d, 1H), 7.63 (m, 3H), 7.02 (d, 1H), 5.64 (s, 2H), 5.43 (br s, 3H) 4.62 (br s, 2H), 4.51 (br s, 2H), 4.01 (s, 1H), 2.80 (s, 3H); MS (EI) for C36H30N6O3: 595 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]([N:7]2[CH:6]([CH3:22])[C:5]3[C:9](=[CH:10][C:2]([C:32]4[CH:31]=[N:30][N:29]([CH:24]5[CH2:25][CH2:26][CH2:27][CH2:28][O:23]5)[CH:33]=4)=[CH:3][CH:4]=3)[C:8]2=[O:11])[CH3:13])=[CH:15][CH:16]=1
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2C)cc1
Reactant: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2C)cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Combine 6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (64 g, 177 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67 g, 295 mmol), potassium carbonate (70 g, 506 mmol), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (9 g, 11 mmol), dioxane (800 mL), and water (212 mL) under nitrogen and heat to 70-75° C. for 16 hours. Add 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15 g, 54 mmol) and heat to 80-85° C. for 2 hours. Concentrate under reduced pressure to 200 mL, add ethyl acetate (500 mL) and water (500 mL), stir for 30 minutes, and filter the solids. Combine the solids and the organic layer and evaporate under reduced pressure. Dissolve the residue in dichloromethane and filter through a pad of silica gel. Wash the silica gel pad with dichloromethane/ethyl acetate (1:0) and then (2:1) and evaporate to dryness under reduced pressure. Slurry the solid in a 2:1 mixture of petroleum ether/ethyl acetate (600 mL) for 30 minutes at 25-30° C. and filter to collect the solid to give the title compound as an off-white solid (68 g, 89%). ES/MS m/z: 432 (M+H).
Reaction SMILES: [F:1][C:2]1[C:14]([C:15]#[N:16])=[CH:13][C:5]2[NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH2:17]([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:25][CH2:26]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:28]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:25][CH2:26][N:6]1[C:5]2[CH:13]=[C:14]([C:15]#[N:16])[C:2]([F:1])=[CH:3][C:4]=2[O:9][C:8]([CH3:11])([CH3:10])[C:7]1=[O:12])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)Oc2cc(F)c(C#N)cc2NC1=O
Reactant: BrCCN(Cc1ccccc1)Cc1ccccc1
Product: CC1(C)Oc2cc(F)c(C#N)cc2N(CCN(Cc2ccccc2)Cc2ccccc2)C1=O

Procedure:
Using 7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile and N,N-dibenzyl-2-bromoethanamine, the title compound was obtained in a similar manner to Reference Example 3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH3:24][C:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 120 °C
Yield: 13.9 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 75 mg, 0.349 mmol), 4-chloro-6-(1,1-dimethylethyl)pyrimidine (Intermediate 10, 89 mg, 0.523 mmol) and DIPEA (0.122 mL, 0.697 mmol) were added together in N-methyl-2-pyrrolidone (2 mL) and the resulting mixture was heated at 120° C. for 2 hours and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (17 mg);
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:43])[C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N+:36]=5[O-:42])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:43])[C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N+:36]=5[O-:42])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])cc2)CCN3)cc1
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 146.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) and isobutylaldehyde (0.15 ml) were dissolved in 1,2-dichloroethane (80 ml), and to the solution, triacetoxy sodium borohydride (0.27 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. To the mixture, isobutylaldehyde (1 ml) and triacetoxy sodium borohydride (1.3 g) were further added, and the mixture was stirred overnight at room temperature. The mixture was washed with sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 2) (0.2 g) as yellow amorphous.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccc(F)cc2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (50 mg, 0.24 mmol) in THF (2 mL) at −78° C. was added 1.0 M 4-fluorophenylmagnesium bromide in THF (0.5 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[C:28](Cl)[N:27]=[C:26]([NH2:31])[N:25]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[C:28]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[N:27]=[C:26]([NH2:31])[N:25]=1)[CH3:20]
Reactant: CCOC(=O)Cc1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Product: CCOC(=O)Cc1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1

Procedure:
The title compound is synthesized analogously to example 25 from 220 mg (0.908 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XIX) and 195 mg (0.908 mmol) of ethyl(2-amino-6-chloropyrimidin-4-yl)acetate (from example LXIX).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[C:9]([F:18])=[N:8]2)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[O:25]=[C:26]1[N:30]([CH2:31][C:32]([OH:34])=[O:33])[C:29](=[O:35])[CH2:28][S:27]1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:28]4/[C:29](=[O:35])[N:30]([CH2:31][C:32]([OH:34])=[O:33])[C:26](=[O:25])[S:27]/4)=[CH:13][CH:14]=3)[C:9]([F:18])=[N:8]2)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(c1)c(F)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C(O)CN1C(=O)CSC1=O
Product: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(F)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from 1-(4-chloro-2-trifluoromethyl-benzyl)-3-fluoro-1H-indazole-5-carbaldehyde (from Example 368) and (2,4-dioxothiazolidin-3-yl)acetic acid following General Procedure F.