Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)C(O)=O)(C)(C)C.[C:29]([O:33][C@@H:34]([C:37]1[C:38]([C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([C:48]([F:51])([F:50])[F:49])[CH:41]=[CH:40]2)[CH2:35][OH:36])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C@@H:34]([C:37]1[C:38]([C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([C:48]([F:50])([F:49])[F:51])[CH:41]=[CH:40]2)[C:35]([OH:5])=[O:36])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1cc2nc(C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Product: Cc1cc2nc(C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)acetic acid (7J) was prepared following the procedure used to prepare compound 1L of Example 1 except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)ethanol (7I) was used instead of compound 1K. 1H-NMR 300 MHz, (CD3OD) δ 8.01 (s, 1H), 7.95 (d, 1H), 7.71 (d, 1H), 7.65-7.55 (m, 2H), 7.35 (d, 1H), 5.24 (s, 1H), 2.71 (s, 3H), 0.99 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C23H22ClF3NO3: 452.9. Found: 452.1, 454.1.
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([Cl:17])[N:9]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:17][C:10]1[N:9]=[C:8]([NH:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C)(C)CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
Add neopentylamine (18 mL, 150 mmol) to a suspension of 2,6-dichloro-3-nitropyridine (20 g, 103 mmol) and Na2CO3 (18.5 g, 175 mmol) in EtOH (1.6 mL/mmol) at RT and stir overnight. Concentrate and dilute the resultant slurry with water (100 mL) and slowly neutralize with concentrated HCl (approx. 40 mL) to pH=7. Cool the suspension at 0° C. for 1 h and collect solid by vacuum filtration. Wash the solid with ice water (4×50 mL) and air dry overnight. Recrystallize the material from EtOAc and hexanes to give the title compound as a yellow solid (21.23 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[OH:26])/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:16])[C:14]2[C:13](=[O:17])[N:12]([CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH3:22])[C:9]=2[N:8]=1.CI.[C:29](=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:18]([N:12]1[C:13](=[O:17])[C:14]2[N:15]([CH3:16])[C:7](/[CH:6]=[CH:5]/[C:4]3[CH:23]=[CH:24][C:25]([O:26][CH3:29])=[C:2]([OH:1])[CH:3]=3)=[N:8][C:9]=2[N:10]([CH2:21][CH3:22])[C:11]1=[O:20])[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CC)c1=O
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(O)c3)n2C)n(CC)c1=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 30.6 %

Procedure:
Compound 173 (400 mg, 1.12 mmol) obtained in Reference Example 112 was dissolved in 8 ml of dimethylformamide. To the solution were added 0.35 ml (5.62 mmol) of methyl iodide and 415 mg (5.62 mmol) of lithium carbonate, and the mixture was stirred at 80° C. for 3.5 hours. Water was added thereto to dissolve lithium carbonate, followed by addition of chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to give 127 mg (yield 76%) of Compound 174 as a pale brown powder. The obtained crude crystals were further recrystallized from ethanol.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([C:24](=[O:27])[CH2:25][F:26])[CH2:20][C:21]([OH:23])=O)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:28][NH:29][CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH3:28][N:29]([CH3:30])[C:21](=[O:23])[CH2:20][CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:24](=[O:27])[CH2:25][F:26]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(CC(=O)O)C(=O)CF
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(CC(=O)N(C)C)C(=O)CF
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To a solution of 3-(CBz-Val-amido)-5-fluoro-4-oxo-pentanoic acid (150 mg, 0.39 mmol) in THF (5 ml) was added a solution of 2.0 M dimethylamine in THF (0.2 ml, 0.4 mmol), EDCI (82.2 mg, 0.42 mmol) and HOBT (106 mg, 0.78 mmol) at 0° C. The resulting mixture was stirred for 2 h at 0° C., then was stirred at room temperature overnight. The solution was diluted with ethyl acetate (20 ml), washed with water (4×20 ml), and the organic layer was dried and evaporated. The residue was purified by chromatography over silica gel (hexane-EtOAc, 1:1 to pure EtOAc) to give 10 mg (6%) of the titled compound as a white solid. 1H NMR (DMSO-d6): 8.36-8.30 (m, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.33-7.29 (m, 5H), 5.45-5.09 (m, 2H), 5.03 (bs, 2H), 4.59-4.57 (m, 1H), 3.90-3.82 (m, 1H), 2.94 (bs, 3H), 2.84-2.73 (m, 4H), 1.97-1.93 (m, 1H), 1.25 (bs, 1H), 0.86-0.82 (m, 6H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.ClC([O-])=O>ClC(Cl)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:11]2([C:14]#[N:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:22][CH:21]=1
Reactant: N#CC1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])Cl
Solvent: CC(Cl)Cl
Product: N#CC1(Nc2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
To 1-Benzyl-4-(4-chloro-phenylamino)-piperidine-4-carbonitrile (163 mg, 0.5002 mmol) in dichloroethane (5 ml) was added 1-chloroethyl chloroformate (65μl, 0.600 mmol). The mixture was heated to reflux and stirred under N2. After 1 hour 15 minutes, an additional 86 μl (0.800 mmol) of the chloroformate was added to the reaction and stirred for an additional 2 hours at reflux. After cooling to room temperature the reaction was concentrated under reduced pressure. To this residue was added methanol (5 ml) and the reaction was heated at reflux for 2 hours. Next, the reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water. The organic layer was removed and sodium hydroxide (1N) was added to the aqueous layer until pH≈9. The aqueous layer was extracted with ethyl acetate 2 times and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (84 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Br:13]Br>Br.C(O)(=O)C>[BrH:13].[Br:13][CH2:9][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:12])=[CH:5][C:6]=1[CH3:11])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1c(C)cc(C)nc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)CBr)c(C)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2,4,6-trimethylpyridin-3-yl)ethanone (5.0 g, 30.6 mmol) in 33% HBr in acetic acid solution (10.2 mL) was added bromine (1.57 ml, 30.6 mmol) in acetic acid (10.2 mL) dropwisely. The reaction was stirred at 70° C. for 2.0 h. The solution was cooled to room temperature and washed with ether. The residue was dried under reduced pressure to give 2-bromo-1-(2,4,6-trimethylpyridin-3-yl)ethanone hydrobromide, which was used directly for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([O:33][CH3:34])[CH:27]=[C:28]4[C:32]=3[NH:31][N:30]=[CH:29]4)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([O:33][CH3:34])[CH:27]=[C:28]4[C:32]=3[NH:31][N:30]=[CH:29]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc(COCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2[nH]ncc2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(COCC2(c3ccc(F)cc3)CCNCC2)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-methoxy-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (20 mg, 0.041 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 1.5 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (95%). LC/MS (HPLC method 3): tR=2.387 min, 384.41(MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19])[CH:6]=[CH:5]2
Reactant: N#Cc1cccc(CBr)c1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(Cn2ccc3cc(F)ccc32)c1
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To a solution of 3 g (22.2 mmol) of 5-fluoroindole in 90 ml of dry DMF was added 8.28 g (23 mmol) NaH and 4.51 g (23 mmol) of 3-bromomethyl benzonitrile. The mixture was stirred overnight at and thereafter distributed between water and dihcloromethane. The water layer was extracted twice with dichloromethane, and the combined organic extracts were washed with brine, dried and evaporated. The oily residue was subjected to flash chromatography eluting with dichloromethane/hexane (1/1), to give 5.75 g (76%) of the subtitle product.
Reaction SMILES: [CH3:1][C:2]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.O1CCCC1>[Pd].C(O)C>[CH3:1][C:2]1([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1)O2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCc1ccccc1)O2
Reaction time: 4 h
Yield: 69 %

Procedure:
A mixture of 1.3 g (4.2 mmol) of 3,4-dihydro-2,5,7,8-tetramethyl-2-(2-phenylethynyl)-2H-1-benzopyran-6-ol (Example 1), 0.3 g of 5% palladium on carbon, 50 ml of tetrahydrofuran and 50 ml ethanol was hydrogenated at atmospheric pressure for 4 hours. The catalyst was filtered off and the filtrate was evaporated. Crystallization of the residue from hexane yielded 0.9 g (69 %) of colorless crystals with m.p. 96°-98°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]([CH2:23][CH3:24])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:18]([CH2:23][CH3:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CCC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 93 %

Procedure:
Methyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoate was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 180 mg (93% yield) of acid 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoic acid. MS found: (M+H)+=389.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].N1C=CN=C1.[CH2:10]([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[C:29]([F:31])[C:28]([NH2:32])=[C:27]([F:33])[CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)[CH2:11][CH3:12]>ClCCl>[F:31][C:29]1[CH:30]=[C:25]([CH:22]2[CH2:21][CH2:20][CH:19]([CH:16]3[CH2:17][CH2:18][CH:13]([CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15]3)[CH2:24][CH2:23]2)[CH:26]=[C:27]([F:33])[C:28]=1[N:32]=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CCCC1CCC(C2CCC(c3cc(F)c(N)c(F)c3)CC2)CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCC1CCC(C2CCC(c3cc(F)c(N=C=S)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.9 ml of thiophosgene are added dropwise over the course of 30 minutes at 15-25° C. to 18.4 g of imidazole in 150 ml of dichloromethane, and the mixture is stirred at RT for a further 2 hours. 15.8 g of 4-(4′-n-propylbicyclohexyl-4-yl)-2,6-difluorophenylamine (prepared as described in Examples 1a-1e) are subsequently added, and the mixture is stirred at RT for 24 hours. Conventional work-up gives 4′-(3,5-difluoro-4-isothiocyanatophenyl)-4-n-propylbicyclohexyl having the following properties: C 65 N 225.5 1; Δε 16.0; Δn 0.1990.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]2=[NH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15]OS(F)(=O)=O>C(Cl)Cl>[C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]2=[N:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C(=N)N(c2ccccc2)CC1=O
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: CN=C1N(C)C(=O)CN1c1ccccc1

Procedure:
3.78 g. of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, 40 ml. dry methylene chloride and 6 ml. of methylfluorosulfonate were mixed and stirred in a flash equipped with a drying tube at room temperature. After 20 hours the solid was filtered and the filtrate was stripped to dryness. The residue was treated with 30 ml. of water and extracted once with ether. The aqueous layer was separated and added slowly to 12 ml. of 5N NaOH with cooling and stirring. The white precipitate was filtered, washed with water and dried. Thin-layer chromatography showed a single spot (Rf 0.6, 5% EtOH·CH2Cl2). The yield was 2.75 g. (68%), m.p. 116°-118° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][C:13]([C:21]56[CH2:30][CH:25]7[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]7)[CH2:22]5)[CH2:28]6)([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:4][C:3]=1[C:31]1[CH:36]=[C:35]([C:37]23[CH2:46][CH:41]4[CH2:42][CH:43]([CH2:45][C:39]([C:47]56[CH2:56][CH:51]7[CH2:52][CH:53]([CH2:55][CH:49]([CH2:50]7)[CH2:48]5)[CH2:54]6)([CH2:40]4)[CH2:38]2)[CH2:44]3)[CH:34]=[C:33]([N+:57]([O-])=O)[C:32]=1[OH:60]>[Pd].CN(C)C=O>[OH:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][C:13]([C:21]56[CH2:22][CH:23]7[CH2:24][CH:25]([CH2:26][CH:27]([CH2:29]7)[CH2:28]5)[CH2:30]6)([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:4][C:3]=1[C:31]1[CH:36]=[C:35]([C:37]23[CH2:46][CH:41]4[CH2:42][CH:43]([CH2:45][C:39]([C:47]56[CH2:48][CH:49]7[CH2:55][CH:53]([CH2:52][CH:51]([CH2:50]7)[CH2:56]5)[CH2:54]6)([CH2:40]4)[CH2:38]2)[CH2:44]3)[CH:34]=[C:33]([NH2:57])[C:32]=1[OH:60]
Reactant: O=[N+]([O-])c1cc(C23CC4CC(C2)CC(C25CC6CC(CC(C6)C2)C5)(C4)C3)cc(-c2cc(C34CC5CC(C3)CC(C36CC7CC(CC(C7)C3)C6)(C5)C4)cc([N+](=O)[O-])c2O)c1O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cc(C23CC4CC(C2)CC(C25CC6CC(CC(C6)C2)C5)(C4)C3)cc(-c2cc(C34CC5CC(C3)CC(C36CC7CC(CC(C7)C3)C6)(C5)C4)cc(N)c2O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
Next, in a 300 mL recovery flask, the obtained 81.3 g of 2,2′-dihydroxy-3,3′-dinitro-5,5′-bis[3-(1-adamantyl)-(1-adamantyl)]-biphenyl (0.10 mol), 0.318 g of 10% palladium-activated carbon (0.30 mmol), 273 mL of N,N-dimethylformamide and a stirrer were charged and agitated at 25° C. for 24 hours under a hydrogen atmosphere. A reaction solution was filtered and then added to 1 L of ion-exchange water. Solid precipitate was collected by filtration, then agitated in 1 L of ion-exchange water for one hour and dried under reduced pressure, thus obtaining 69.3 g of 2,2′-dihydroxy-3,3′-diamino-5,5′-bis[3-(1-adamantyl)-(1-adamantyl)]-biphenyl (0.092 mol; the yield was 92.0%).
Reaction SMILES: IC.[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([NH:19][S:20]([CH:23]4[CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:16]=[N:17][CH:18]=3)[CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[O:26].[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][N:19]([C:15]1[CH:16]=[N:17][CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]3[O:6][C:5](=[O:26])[N:4]([CH3:3])[C:8]=3[CH:9]=2)[CH:14]=1)[S:20]([CH:23]1[CH2:25][CH2:24]1)(=[O:22])=[O:21]
Reactant: Cn1c(=O)oc2ccc(-c3cncc(NS(=O)(=O)C4CC4)c3)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1cncc(-c2ccc3oc(=O)n(C)c3c2)c1)S(=O)(=O)C1CC1
Reaction time: 4 h

Procedure:
Iodomethane (55.4 mg, 0.39 mmol) was added dropwise to a suspension of N-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)cyclopropanesulfonamide (104 mg, 0.3 mmol), potassium carbonate (207 mg, 1.5 mmol) in DMF (1.5 mL) at room temperature. The resulting mixture was stirred at this temperature for 4 h. The mixture was diluted with ethyl acetate (50 mL) and washed with water (2×50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with NaHCO3 solution and dried over anhydrous Na2SO4. After filteration and concentration, the residue was treated with ether then filterated to pale solid (30 mg). ESI-MS m/z: 3601 [M+1]+, Retention time 1.15 min; 1HNMR (MeOD, 400.342 MHz) δ 0.96-1.03 (m, 4H), 2.65-2.72 (m, 1H), 3.47 (s, 3H), 7.38 (d, J=8 Hz, 1H), 747 (dd J=8, 2 Hz, 1H), 7.52 (s, 1H), 8.18 (t J=2 Hz, 1H), 8.64 (d, J=2 Hz, 1H), 8.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C@H:24]1[OH:30].[C:31](OC(=O)C)(=[O:33])[CH3:32].CN(C1C=CC=CN=1)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C@H:24]1[O:30][C:31](=[O:33])[CH3:32]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1OC(C)=O
Temperature: 0 °C

Procedure:
To a solution of compound of example 106 (3.35 g, 7.79 mmol) in dry CHCl3 (25 mL) was added acetic anhydride (1.76 g, 17.43 mmol) at 25° C. with stirring, followed by the addition of dimethylaminopyridine (0.033 g, 1% w/w). The mixture was stirred for 0.5 h. It was poured into ice water (50 mL), basified using a saturated aqueous Na2CO3 solution and extracted using CHCl3 (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. The oil obtained was purified using a silica gel column and 0.1% MeOH+1% liquor NH3 in CHCl3 as eluant to get the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CC(O)=O>[CH2:3]1[C:2]2[NH:18][C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]=2[CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)NC1CCCC(=O)C1
Reactant: NNc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NC1CCc2c([nH]c3ccccc23)C1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A stirred solution of 140.9 g (0.909 mol) of N-(3-oxocyclohexyl)acetamide in 900 ml of glacial HOAc was heated at 85°-95° C. while 98.2 g (0.909 mol) of phenylhydrazine was added dropwise during 1 hr. After an additional 3 hr at 95°±5°, the hot solution was poured into 5 l. of H2O. When the initially formed gum had solidified, the product was filtered, washed with 2.5 l. of H2O, then 2 l. of Et2O to give 167.6 g (81%) of a grey solid, mp 203°-206°. Recrystallization was best effected by dissolving the crude solid in boiling Me2CO (1 g/25 ml) and boiling down to 1 g/10 ml. The resulting yellow solid (133.5 g, mp 208°-209°) was recrystallized again from Me2CO to yield 111.8 g of white solid, mp 208°-209°. To remove Me2CO occluded by the crystalline solid, the product was further recrystallized from EtOH, 86% recovery of white solid, mp 208°-209°.
Reaction SMILES: [NH2:1][C:2]1[N:19]=[CH:18][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)[C:4]=2[CH:3]=1.CCN(CC)CC.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].CO.CCOC(C)=O>C1COCC1.CN(C1C=CN=CC=1)C>[Br:17][C:13]1[CH:12]=[C:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:30])[CH:28]=[CH2:29])[N:19]=[CH:18][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.6 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]-pyrido[3,4-d]pyrimidine (J Med Chem, 1996;39:1823) (455 mg, 1.50 mmol) in dry THF (50 mL) at 0° C. under N2 was added Et3N (22.5 mmol, 1.61 mL), a catalytic amount of DMAP (45 mg) and acryloyl chloride (4.50 mmol, 366 μL). The reaction mixture was stirred for 1 hour and then additional acryloyl chloride (100 μL) was added and the reaction was allowed to warm to room temperature and stirred for another hour before being worked up as in the previous example, to give after column chromatography on silica gel eluting with MeOH/EtOAc (5:95), N-[4-[(3-bromophenyl)amino]pyrido-[3,4-d]pyrimidin-6-yl]acrylamide (20 mg, 37%) as a cream powder, mp (EtOAc/MeOH) 238-245° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][CH2:24][CH2:25][NH2:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The solution of 14.3 g (31.6 mmol) 5-benzyloxy-1-(3-tert-butoxycarbonylamino-propyl)-1H-indole-2-carboxylic acid ethyl ester in 140 mL dichloromethane was cooled to 0° C. and 70 mL (104.2 g, 914 mmol) trifluoroacetic acid was added. The cooling bath was removed and after stirring at room temperature for 1 h, the solution was neutralized with 1M aqueous sodium hydroxide solution and was extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to give the crude product as yellow oil (>100%). The compound was pure enough for the next step without further purification.