Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:49])[CH:6]([O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][NH:26][C:27]([C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][C:30]=3[CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])[CH:21]=2)[C:16]=1[C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CO>[CH2:38]([C:30]1[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:29]=1[C:27]([NH:26][CH2:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)=[C:15]([O:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:49])=[O:4])[CH:24]=[CH:23]2)=[O:28])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(Cl)cc3)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(Cl)cc3)c(OC(Cc3ccccc3)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1 N NaOH (300 μL, 0.30 mmol) was added under nitrogen to a solution of 2-[6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-chloro-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (182 mg, 0.28 mmol), prepared in the previous step, in 30 mL of methanol plus 2.5 mL of water at room temperature. After the addition the reaction was stirred at room temperature overnight. If starting material remains additional 1 N NaOH is added until the reaction is complete. A total of 900 μL of 1 N NaOH was added. The reaction was acidified by the addition of 1.6 mL of 1 N HCl and then concentrated under reduced pressure. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (166 mg, 94%) as a white solid, mp 169-172° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC)(=O)CCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH2:37][CH3:38])[C:33]([O:35][CH3:36])=[O:34]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH2:37]([CH:32]([CH2:31][CH2:30][CH2:29][CH2:28][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:33]([O:35][CH3:36])=[O:34])[CH3:38]
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Reactant: CCC(CCCCBr)C(=O)OC
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCCC(=O)OC
Product: CCC(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)OC
Temperature: 100 °C
Reaction time: 40 h

Procedure:
The procedure in Example 5 is followed but using 4,6-diphenyl-2-pyridinone (2.8 g) (prepared by analogy with the method described in Patent EP 108 592 from methyl butanoate), methyl 6-bromo-2-ethylhexanoate (5.4 g), silver carbonate (1.6 g) and dimethylformamide (100 cc). The reaction mixture is heated at 100° C. for 31 hours then at 120° C. for 40 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1). (yellow oil)
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)=[CH2:2].[C:12]1([CH3:27])[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.NC(N)=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][C:23]2[CH:24]=[CH:25][C:20]([C:19]#[C:18][C:15]3[CH:16]=[CH:17][C:12]([CH3:27])=[CH:13][CH:14]=3)=[CH:21][CH:22]=2)=[O:10])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: C=CC1CCC(C(=O)O)CC1
Reactant: Cc1ccc(C#Cc2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: NC(N)=O
Solvent: Cc1ccccc1
Product: C=CC1CCC(C(=O)Oc2ccc(C#Cc3ccc(C)cc3)cc2)CC1
Temperature: 25 °C

Procedure:
5.0 g of 4-vinylcyclohexanecarboxylic acid, 6.7 g of 4-p-tolylethynylphenol, 4.0 g of 4-(dimethylamino)pyridine and 250 ml of toluene were mixed at RT, 7.3 g of DCC in 50 ml of toluene were added, and the mixture was stirred vigorously overnight at RT, during which the urea formed precipitated. 1 g of oxalic acid was then added, and the mixture was stirred at RT for a further hour in order to destroy the excess DCC. The conventional work-up gave 4-p-tolylethynylphenyl 4-vinylcyclohexanecarboxylate in the form of colorless crystals.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])(OCC)=O)C.[CH2:18]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[I:31])[CH:26]=O)[CH2:19][CH2:20][CH3:21].O>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:22][C:23]1[CH:24]=[C:25](/[CH:26]=[C:13](\[O:12][CH3:11])/[C:14]([O:16][CH3:17])=[O:15])[CH:28]=[CH:29][C:30]=1[I:31])[CH2:19][CH2:20][CH3:21].[CH2:18]([O:22][C:23]1[CH:24]=[C:25](/[CH:26]=[C:13](/[O:12][CH3:11])\[C:14]([O-:16])=[O:15])[CH:28]=[CH:29][C:30]=1[I:31])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1cc(C=O)ccc1I
Reactant: CCOP(=O)(COCC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCOc1cc(/C=C(/OC)C(=O)[O-])ccc1I
Product: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1I
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33 %

Procedure:
0.7 g (16.5 mmol) of sodium hydride are added portionwise to a solution at 0° C. of 3.9 g (16.5 mmol) of methyl (diethoxyphosphoryl)methoxyacetate in 45 mL of tetrahydrofuran. The reaction mixture is stirred for 45 minutes at room temperature, followed by dropwise addition of 3.4 g (11.8 mmol) of 3-butoxy-4-iodobenzaldehyde (prepared as described in Example 19g) in 30 mL of tetrahydrofuran. The reaction is slightly exothermic and the reaction mixture is maintained at a temperature of 25-27° C. with an ice bath. When the temperature has stabilized, the reaction mixture is stirred for 20 hours at room temperature. The reaction is worked up by addition of 60 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 98/2 heptane/ethyl acetate mixture. 1.5 g (33%) of the isomer methyl (Z)-3-(3-butoxy-4-iodophenyl)-2-methoxyacrylate are obtained in the form of a yellow solid and 1.0 g of the isomer (E)-3-(3-butoxy-4-iodophenyl)-2-methoxyacrylate are obtained in the form of a pale yellow oil.
Reaction SMILES: O[CH:2]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][C:12]=1[C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[CH:3]([N+:8]([O-:10])=[O:9])[CH2:4][CH2:5][CH2:6][CH3:7].C(OC(=O)C)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:8]([C:3]([CH2:4][CH2:5][CH2:6][CH3:7])=[CH:2][C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][C:12]=1[C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])([O-:10])=[O:9]
Reactant: CCCCC(C(O)c1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of tert-butyl 4-(1-hydroxy-2-nitrohexyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (632 mg, 1.31 mmol) in THF (3 mL) was added acetic anhydride (0.136 mL, 1.44 mmol) and a crystal of DMAP (−5 mg). After stirring at room temperature for 30 min, the reaction mixture was concentrated in vacuo. The residue was suspended in DCM (3.0 mL) and DMAP (192 mg, 1.57 mmol) was added. After stirring at room temperature overnight, the reaction mixture was diluted with DCM and washed with brine. The aqueous layer was back-extracted with DCM and the pooled organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-25% EtOAc/hexanes) to give the title compound (485 mg, 80%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.12-8.09 (m, 1H), 8.01-8.00 (m, 1H), 7.97 (s, 0.5H), 7.81 (s, 0.5H), 7.46 (d, J=8 Hz, 0.5H), 7.39 (d, J=8 Hz, 0.5H), 7.24-6.79 (m, 4H), 4.94 (s, 1H), 4.31 (s, 1H), 3.47 (t, J=6 Hz, 1H), 3.00-2.47 (m, 5H), 1.65-1.31 (m, 4H), 1.63 (s, 9H), 0.95-0.86 (m, 3H); MS(ESI+) m/z 465.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:27]=[C:28]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38]([OH:40])=O)[CH:29]=[CH:30][CH:31]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:38]([C:33]1[N:34]=[C:35]([CH3:37])[S:36][C:32]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)=[O:40]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2cccc(F)c2)s1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-(3-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) 348 (M+H).
Reaction SMILES: C[O-].CO.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]Cl)[CH2:22][CH2:21]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[C:12]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][O:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:22][CH2:21]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: O=C(c1ccccc1)N1CCC(CCl)CC1
Agent: C[O-]
Solvent: CO
Solvent: CCOCC
Product: O=C(c1ccccc1)N1CCC(COc2ccccc2)CC1
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a mixture of 28 ml of 30% sdium methanolate solution and 50 ml of methanol are added 14.1 g (0.15 mole) of phenol. The reaction mixture is evaporated in a vacuum and the residue is taken up in 120 ml of N,N-dimethyl formamide, 35.5 g (0.15 mole) of N-benzoyl-4chloromethylpiperidine are added thereto and the reaction mixture is stirred for 12 hours at 60°-70° C. After cooling, the reaction mixture is mixed with diethyl ether, washed with water and dilute aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and evaporated in a vacuum. The oily residue is triturated with diethyl ether/ligroin. There are obtained 23.0 g of N-benzoyl-4-phenoxymethylpiperidine (52% of theory); m.p. 95°-96° C.
Reaction SMILES: O[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[N:5]=[N:4]1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:12][C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:2][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:4]=[N:5][C:6]=2[CH:11]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc2c(c1)nnn2CO
Solvent: CCO
Product: Cc1ccc2c(c1)nnn2CNc1ccccc1

Procedure:
5.0 g (0.03 mol) of 1-hydroxymethyl-5-methylbenzotriazole and 2.9 g (0.03 mol) of aniline were suspended in ethanol and refluxed for 1 hour. The insoluble substance was removed by filtration while it was still hot and the filtrate was cooled to obtain crude crystals. By recrystallization of the crude crystals from ethanol 4.2 g of the desired compound having a melting point of 149° to 152° C. was obtained.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:16][CH2:15]1.O>C(O)C>[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH2:19]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Hydrazine monohydrate (0.272 ml, 5.61 mmol) was added to a solution of 2-{2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl}isoindoline-1,3-dione (compound of Reference Example 66; 0.745 g, 1.87 mmol) in ethanol (5 ml), and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.170 g, 34%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)([CH2:6][CH2:7][CH3:8])[C:3](O)=[O:4].Cl.[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32]N.O.O[N:38]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:1][C:2]([CH2:6][CH2:7][CH3:8])([C:3]([NH2:38])=[O:4])[C:9]([N:10]([C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)[CH2:32][CH2:31][C:30]([F:35])([F:34])[F:29])=[O:27]
Reactant: NCCC(F)(F)F
Reactant: On1nnc2ccccc21
Reactant: CCCC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(O)(C(N)=O)C(=O)N(CCC(F)(F)F)[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A solution of 70.0 mg (0.19 mmol) 2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid and 31.3 mg (0.21 mmol) 3,3,3-trifluoropropylamine hydrochloride in 3 ml tetrahydrofuran were cooled to 0° C. and 28.2 mg (0.21 mmol) 1-hydroxy-benzotriazole hydrate, 103 μl (0.61 mmol) diisopropylethylamine and 40.1 mg (0.21 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 90:10 to 50:50) yielded 50.0 mg (57%) (R/S)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-propyl-N-(3,3,3-trifluoro-propyl)-malonamide: MS (m/e): 464.0 (M+H)+.
Reaction SMILES: [N+:1]1([O-])NC=C2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.C[N:12]([CH:14]=O)[CH3:13].CS([Cl:20])(=O)=O>>[Cl:20][C:6]1[CH:5]=[CH:14][N:12]=[C:13]2[NH:1][CH:9]=[CH:8][C:7]=12
Reactant: [O-][n+]1[nH]cc2ccccc21
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)Cl
Product: Clc1ccnc2[nH]ccc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to a procedure described WO03/082289 A1. A solution of azaindole N-oxide (6.82 g, 51.0 mmol) in DMF (36.0 ml, 470 mmol) was heated to 50° C. Methanesulfonyl chloride (11.0 ml, 137 mmol) was added to the heated solution at such a rate as to maintain the reaction temperature at 65 to 75° C. The resulting mixture was heated at 68-77° C. until the reaction was judged complete by RPLC. The total reaction time was 4 h. The reaction was cooled to rt and quenched with water (10 mL). The mixture was cooled to 5° C. 10 N NaOH solution was added to raise the pH of the solution to 7. The resulting slurry was warmed to rt, agitated for 1 h, and then filtered to collect the product. The product was washed with additional water and dried under vacuum. Rusty solid, 4-chloro-1H-pyrrolo[2,3-b]pyridine was collected. 1H NMR (Bruker, 400 MHz, DMSO-d6) 12.0 (br s, 1H), 8.19 (d, J=5.4 Hz, 1H), 7.60 (t, J=3.0 Hz, 1H), 7.20 (d, J=5.0 Hz, 1H), 6.52 (d, J=3.0 Hz, 1H).
Reaction SMILES: [OH:1][C@@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].C(Cl)Cl.ClC(Cl)(Cl)C(=N)O[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.F[C:28](F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:17]([O:1][C@@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:28][C@:2]([O:1][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](O)C(C)C
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(=O)[C@@H](OCc1ccccc1)C(C)C
Product: COC(=O)[C@@](C)(OCc1ccccc1)C(C)C
Temperature: 0 °C
Yield: 288 %

Procedure:
To a flame-dried 50 mL flask was added methyl(S)-2-hydroxy-3-methylbutyrate (330 mg, 2.5 mmol), anhydrous CH2Cl2 (1.5 mL), cyclohexane (3 mL). The reaction flask was cooled to 0° C., and benzyl 2,2,2-trichloroacetimidate (0.464 mL, 2.5 mmol) was added with stirring. To the resulting solution was added trifluoromethanesulfonic acid (0.044 mL, 0.5 mmol). After addition was completed, the reaction was warmed to room temperature and was stirred for 17 hrs. The reaction was monitored by 1H NMR, and most of SM was consumed. The reaction mixture was filtered, and collected solid was rinsed with cyclohexane (2×10 mL). The filtrate was washed with saturated NaHCO3 (5 mL), water (2×5 ml), brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude oil was purified by flash chromatography eluting with EtOAc-Hexanes (0.5:99.5) to afford the desired compound methyl (S)-methyl-2-benzyloxy-3-methylbutanoate (319 mg, 1.44 mmol, 57% yield). 1H NMR (300 MHz, CDCl3): consistent with proposed structure.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:12]2[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH3:22])[N:20]=2)[C:15]([NH2:17])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH:7]1([C:12]2[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH3:22])[N:20]=2)[C:15]#[N:17])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cc(C(N)=O)cc(C2CCCC2)n1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cc(C#N)cc(C2CCCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Pyridine (8.86 g, 91.3 mmol) is added to a solution of 2-cyclopentyl-6-methoxy-isonicotinamide (3.35 g, 15.2 mmol) in DCM (100 mL). The mixture is cooled to 0° C. before trifluoroacetic acid anhydride (9.58 g, 45.6 mmol) is added portionwise. The mixture is stirred at 0° C. for 1 h before it is diluted with DCM (100 mL) and washed with sat. aq. NaHCO3 solution (100 mL) and brine (100 mL). The separated org. phase is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-cyclopentyl-6-methoxy-isonicotinonitrile (2.09 g) as a pale yellow oil; LC-MS**: tR=0.80 min, [M+1]+=not detectable; 1H NMR (D6-DMSO): δ 1.61-1.82 (m, 6H), 1.94-2.03 (m, 2H), 3.16 (quint, J=7.8 Hz, 1H), 3.89 (s, 3H), 7.15 (s, 1H), 7.28 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:39][CH2:40][CH2:41][O:42][CH3:43]>COCCOC.CO.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([C:9]2[N:8]=[C:7]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[N:27]=[CH:26]4)[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:39][CH2:40][CH2:41][O:42][CH3:43])[CH:5]=3)[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc([N+](=O)[O-])c3)nc2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(N)c3)nc2cc1OC
Reaction time: 12 h

Procedure:
A mixture of tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.560 g, 0.95 mmol) and 10% Pd/C (ca. 0.1 g) in DME (100 mL) and MeOH (100 mL) was hydrogenated under a balloon of H2 at RT for 12 h. The mixture was filtered through a pad of Celite® and concentrated in vacuo to give tert-butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate as an off white solid (0.510 g, 0.92 mmol, 97%). HPLC retention time 5.62 mins.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:26])[N:15]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:11]([C:27]([O:29]CC)=O)[N:10]=2)[CH2:4][CH2:3]1.[NH2:32]C1C(C(OCC)=O)=NC(N[C@H]2CC[C@@H](O)CC2)=NC=1NC1C=CC=CC=1OC>ClCCl>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:26])[N:15]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:11]([C:27]([NH2:32])=[O:29])[N:10]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@@H](O)CC3)nc21

Procedure:
Ethyl 2-(cis-4-hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(cis-4-hydroxycyclohexylamino)-6-(2-methoxyphenyl-amino)pyrimidine-4-carboxylate (0.272 g, 0.678 mmol) and 1,1′-1,1′-carbonyldiimidazole (1.09 g, 6.78 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F. A mixture of the title compound and the imidazole ester were formed and were taken on without further purification. MS (ESI) m/z 399 [M+1]+ (title compound), 522 [M+1]+ (imidazole urea).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=C(C#N)[CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:27]([C:26]([OH:29])=[O:28])[CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C#N)cc1S2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Temperature: 25 °C

Procedure:
Add 8.5 g. of the nitrile of Example 33 to a mixture of 220 ml. of acetic acid (glacial) and 220 ml. of 50% sulfuric acid. Heat the mixture at reflux under a nitrogen atmosphere overnight. Cool to room temperature and separate the solids by filtration. Recrystallize from acetic acid to obtain the title product. (m.p. 230°-232° C.)
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Br:1][C:2]1[C:15]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:2]3[CH:15]=[CH:6][CH:5]=[CH:4][CH:3]=3)([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Br)cccc21
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: OC1(c2ccccc2)c2ccccc2C(O)(c2ccccc2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.37 g (32.4 mmol) of 1-bromoanthraquinone was put into a 500 mL three neck-flask, and the atmosphere of the flask was substituted with nitrogen. 150 mL of tetrahydrofuran (abbreviation: THF) was added to the flask, and then 34.0 mL (71.3 mmol) of phenyllithium (2.1 mol/L dibutyl ether solution) was added in one portion. The solution was stirred for 24 hours at room temperature. After the reaction was completed, the reaction solution was washed with water, and the aqueous layer was extracted with ethyl acetate. The extracted part was combined with the organic layer, and then dried with magnesium sulfate. After drying, the mixture was subjected to suction filtration, and the filtrate was concentrated, resulting in 14.4 g of 1-bromo-9,10-diphenyl-9,10-dihydroanthracene-9,10-diol as a brown, oily compound in 100% yield.