Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].[N+:29](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([NH2:29])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 23.8 %

Procedure:
A mixture of 6 g (0.02 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-carboxylate and 5.6 g (0.04 mol) of potassium carbonate in 80 ml of dimethylformamide is heated for 30 minutes at 60° C. and left to cool, 8.5 g (0.042 mol) of 2,4-dinitrophenylhydroxylamine are added, the mixture is kept for 24 hours at room temperature and poured into 200 ml of a water/ice mixture, and the precipitate formed is filtered off, washed with water, dried in a desiccator and recrystallized from dimethylformamide to give 1.5 g of a solid melting at 276°-279° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.Cl[S:39][N:40]([CH:46]([CH3:48])[CH3:47])[C:41](=[O:45])[O:42][CH2:43][CH3:44]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:39][N:40]([CH:46]([CH3:48])[CH3:47])[C:41]([O:42][CH2:43][CH3:44])=[O:45])=[O:19])[CH2:6]2)=[O:4]
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Reactant: CCOC(=O)N(SCl)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of the title compound of Step B (2.0 g, 4.8 mmol) in 50 ml methylene chloride cooled to 0° C. was added triethylamine (1.0 g, 0.01 mol) and ethyl (chlorosulfenyl)(1-methylethyl)carbamate from Step D (1.4 g, 7.7 mmol). The mixture was allowed to warm to room temperature and stirred for one hour. The crude mixture was purified by silica column chromatography using ether-hexane (1:2) as eluent. The title compound (2.38 g) was obtained in about 90% purity (mp: 130°-134°). Extraction of the product with ether-hexane (2:1) gave 1.8 g of a highly pure material mp: 139°-140° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)(C)(C)C.C(N(CC)C(C)C)(C)C.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:33][C:34](=[O:35])[NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred slurry of (4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester (500 mg, 2.19 mmol) and N,N-diisopropylethylamine (382 μL, 2.63 mmol) in DCM (8 mL) at 0° C. under N2 was added benzylchloroformate (311 μL, 2.41 mmol) dropwise via syringe. After 30 min the reaction was allowed to warm to room temperature and stirred for a further 2 h before diluting with DCM (50 mL). The solution was washed successively with 1 N HCl, sat. NaHCO3 and brine before drying over Na2SO4. Residual chloroformate was removed by chromatography using a 12 g ISCO combi-flash cartridge (silica gel, 90:10 to 50:50 hexane/EtOAc) to afford the di-protected intermediate which was treated directly with DCM (2 mL) and TFA (2 mL). After 1 h the volatiles were removed in vacuo and the residue partitioned between sat. NaHCO3 and EtOAc. Concentration of the organic layer in vacuo afforded (4-amino-cyclohexylmethyl)-carbamic acid benzyl ester (517 mg, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[C:30]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].[H-].[Na+]>C1COCC1.C1C=CC=CC=1>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([NH:38][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:11][C:12]=3[CH:13]=2)=[O:25])=[CH:39][CH:40]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(C(C)(C)C)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 10.7 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.276 mmol), benzene (4 mL), thionyl chloride (5.0 mL), 4-tert-butylaniline (0.123 g, 0.828 mmol), THF (5.0 mL) and 60% NaH (0.033 g, 0.825 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.28 (s, 9H), 2.65 (s, 3H), 6.54 (s, 1H), 7.37 (d, J=7.8 Hz, 3H), 7.60-7.68 (m, 4H), 9.43 (s, 1H), 9.93 (s, 1H), 11.56 (s, 1H); MS [M+H]+: 508.57.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[P:20]([O-:38])([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].O[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([N:47]1[C:51](=[O:52])[C:50]([C:53]2[C:61]3[C:56](=[CH:57][C:58]([N+:62]([O-:64])=[O:63])=[CH:59][CH:60]=3)[N:55]([CH3:65])[CH:54]=2)=[C:49]([C:66]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[N:68]([CH3:75])[CH:67]=2)[C:48]1=[O:76])=[O:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:75][N:68]1[C:69]2[C:74](=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:66]([C:49]2[C:48](=[O:76])[N:47]([C:45]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][O:21][P:20](=[O:38])([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:46])[C:51](=[O:52])[C:50]=2[C:53]2[C:61]3[C:56](=[CH:57][C:58]([N+:62]([O-:64])=[O:63])=[CH:59][CH:60]=3)[N:55]([CH3:65])[CH:54]=2)=[CH:67]1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(C(=O)NCCCCO)C2=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(C(=O)NCCCCOP(=O)(OCc3ccccc3)OCc3ccccc3)C2=O)c2ccccc21
Temperature: -78 °C
Yield: 82.8 %

Procedure:
Triphenylphosphine (0.86 g, 3.29 mmol) and Dibenzyl phosphate (0.91 g, 3.29 mmol) were added to a solution of 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrole-1-carboxylic acid (4-hydroxybutyl)-amide (prepared as in example 23, 1.41 g, 2.74 mmol) in THF (50 mL). The mixture was cooled to −78° C. Diethyl azodicarboxylate (0.52 mL, 3.29 mmol) was added dropwise over 5 min. The cooling bath was removed and after 2 h, the mixture was evaporated. Chromatography of the residue over silica gel using 2:1 EtOAc/hexane then EtOAc gave phosphoric acid dibenzyl ester 4-{[3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrole-1-carbonyl]-amino}butyl ester (1.76 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([F:22])([F:20])[F:21])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccc2cc(OCc3ccccc3)ccc21)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Cn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 0 °C
Yield: 82.4 %

Procedure:
A solution of Example 78A (1.98 g, 6.20 mmol) in THF (20 mL) at 0° C. was treated dropwise with 1M BH3 THF in THF (11.2 mL, 11.2 mmol), heated at reflux for 16 hours, cooled to 0° C., treated 6M HCl (approximately 1 mL), diluted with ethyl acetate (60 mL), washed with 10% NaHCO3 (30 mL) and brine (30 mL), dried (MgSO4), filtered, and concentrated to provide 1.56 g of the desired compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:16]12[C:25](=[O:26])[O:24][C:22](=[O:23])[C:17]=1[CH2:18][CH2:19][CH2:20][CH2:21]2>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:25]([C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:22]([OH:24])=[O:23])=[O:26])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Product: O=C(O)C1=C(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
Using as starting materials, 2.3 g of 3,5-bistrifluoromethyl aniline and 1.5 g of 1-cyclohexene-1,2-dicarboxylic anhydride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li:9]CCCC.[N-]=C=O.[NH4+].[Cl-]>C1C=CC=CC=1.C1COCC1.CCOCC.O>[Li:9][C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1
Reactant: C#Cc1ccccc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [N-]=C=O
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: [Li]C1(C#C)C=CC=CC1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
Acyl azide 338 (7 mg, 0.0114 mmol) in benzene (1 mL) was stirred at 80° C. for 6 h, after which the solvent was removed and the residue dissolved in THF. In a separate flask, a 0.19 M solution of 1-lithio-phenylacetylene was prepared by deprotonation of phenylacetylene (in THF) with n-BuLi (0.88 equiv.) at −78° C. To this solution (0.2 mL, 0.19 M) in THF was added the isocyanate in THF (0.5 mL) at −78° C. After stirring at −78° C. for 50 min, saturated NH4Cl (3 mL) and water (0.6 mL) were added and the resulting mixture was diluted with Et2O (45 mL), the layers separated, and the organic layer washed with brine, dried over MgSO4, filtered and concentrated. Filtration over silicagel (14% EtOAc in hexanes) provided a crude product (6 mg) which was treated with 370 μL of a solution HF pyridine in THF at RT. After stirring for 48 h at RT, the reaction was quenched with a phosphate buffer (pH 7.0; 10 mL), extracted with EtOAc (3×15 mL), dried over MgSO4 and concentrated. Purification by EC (silicagel, 33% EtOAc in hexanes) gave 2 mg of compound 349 (56%). 349: [α]D=−42 (c 0.1, MeOH); IR 2927, 1652, 1605, 1500, 1451, 1294, 1218, 1123; 1H-NMR (400 MHz, CD3OD) δ 7.58 (2H, app. dt, J=1.6, 6.8 Hz), 7.40-7.52 (3H, m), 7.14 (1H, app.t, J=8.0 Hz), 6.82 (1H, d, J=14.0 Hz), 6.74 (1H, d, J=8.4 Hz), 6.66 (1H, d, J=7.2 Hz), 5.51 (1H, ddd, J=7.6, 7.6, 14.4 Hz), 5.26-5.44 (3H, m), 4.14 (1H, dd, J=3.6, 9.2 Hz), 3.58 (1H, dd, J=8.4, 16.4 Hz), 3.38 (1H, br), 2.36-2.50 (2H, m), 2.29 (1H, br.d, J=14.4 Hz), 1.84-1.94 (1H, m), 1.72-1.84 (3H, m), 0.88 (3H, d, J=6.8 Hz); MS (ES) m/z (%): 460.22 ([M+H]+, 100) HRMS (FAB) Calcd for C28H29NO5Li (MLi+): 466.2206. Found: 466:2204.
Reaction SMILES: [Br:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:25].[C:26](OC(=O)C)(=[O:28])[CH3:27].O>N1C=CC=CC=1>[C:26]([O:25][C@@H:3]1[C@@H:2]([Br:1])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]3[C@@]2(C)C[C@@H]1Br
Reaction time: 8 h

Procedure:
2β-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (750 mg.) in pyridine (2 ml.) was treated with acetic anhydride (1 ml.) and the mixture was allowed to stand at room temperature overnight. It was then poured into water to give a white solid (720 mg.) which was recrystallised from methanol to give the title compound (471 mg.) as white crystals, m.p. 154°-156°, [α]D + 128.5°.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16].B1(B2OCC(C)(C)CO2)OCC(C)(C)C[O:23]1.CC([O-])=O.[K+].C[N+]1([O-])CCOCC1.S(=O)(O)[O-].[Na+]>C1COCC1.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]>[Cl:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:2]([OH:23])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: O=C1C(Cc2c(Cl)cccc2Br)CCN1C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(O)cccc2Cl)CCN1C1CCCCC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 26.8 %

Procedure:
Charge a flask with 3-(2-bromo-6-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 56) (210 mg, 0.57 mmol), bis(neopentyl glycolato)diboron (150 mg, 0.68 mmol), KOAc (200 mg, 2.0 mmol) and Pd(dppf)Cl2 (23 mg, 0.03 mmol) and purge with nitrogen. Add DMSO (5 mL) and plunge into an 80° C. oil bath and stir under nitrogen for 24 hours. Cool to room temperature and pour into water. Extract with ether. Dry over sodium sulfate, filter and concentrate. Dissolve residue in 1N NaOH (10 mL) and stir at room temperature overnight. Extract water with ether and acidify the aqueous layer with HCl. Extract with ether, dry over sodium sulfate, filter and concentrate. Dissolve residue in THF (5 mL) and add N-methyl morpholine N-oxide (200 mg, 1.7 mmol) and heat to reflux for 6 hours. Cool to room temperature and pour into saturated aqueous sodium bisulfite. Extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify over silica gel (3:1 to 1:1 hexanes:ethyl acetate). Triturate the recovered material with 2:1 hexanes:ethyl acetate to afford 47 mg (27%) of the title compound as a white solid. Mass spectrum (apci) m/z=308.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:6][C:5]([CH3:14])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:3]=1.[CH2:28](B(O)O)[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:28]([C:2]1[C:7]([O:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:6][C:5]([CH3:14])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:3]=1)[CH3:29]
Reactant: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1Cl
Reactant: CCB(O)O
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: [Na+]
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(C)cc1OC(CC)CC
Temperature: 25 °C

Procedure:
Pd(PPh3)4 (12 mg, 0.01 mmol) is added to a solution of compound 45 (41 mg, 0.1 mmol) in toluene (0.6 ml), followed by ethylboronic acid (73 mg, 1 mmol) and Na2CO3 (1M, 0.2 ml, 0.2 mmol). The resulting mixture is heated to reflux overnight, and then cooled to room temperature. The toluene layer is separated. The aqueous layer is extracted with EtOAc. The combined organic layers are combined, washed with water, brine, dried, filtered and evaporated. The crude product is purified by chromatography (eluted with 6% EtOAc in hexane) to give the product as a white crystalline solid. 1H NMR (CDCl3) δ 1.00 (t, J=7.6 Hz, 6H), 1.23 (t, J=7.6 Hz, 3H), 1.73 (m, 4H), 2.09 (s, 3H), 2.84 (q, J=7.6 Hz, 2H), 3.87 (s, 3H), 4.16 (m, 1H), 6.78 (s, 1H), 6.89 (dd, 1H), 6.92 (s, 1H), 7.27 (d, J=8.4 Hz, 1H). LCMS 398.34 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])([CH3:4])([CH3:3])[CH3:2].C(O)=[O:29]>C(Cl)Cl.O.[NH4+].[OH-].S([O-])([O-])(=O)=O.[Hg+2]>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: O=CO
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccc(Cl)cc1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of {3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester (9.2 g, 23 mmol) in CH2Cl2 (100 mL) containing formic acid (9.18 mL) was cooled to 0° C. Mercury(II) sulphate (2.1 g, 7.1 mmol) was added and the reaction stirred for 2 h at 0° C. The mixture was diluted with H2O (20 mL) and NH4OH (20 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic portions were washed with H2O, dried over MgSO4, filtered and the solvents evaporated in vacuo to afford [3-[4-chloro-2-(2-fluorobenzoyl)-phenyl]-3-oxopropyl]-carbamic acid tert-butyl ester 8.9 g (95%) as a brown solid. This material (8.9 g, 22 mmol) was dissolved in HCl (4N in dioxane, 185 mL) and stirred at room temperature for 30 min. The solution was then evaporated in vacuo. The residue was dissolved in CH2Cl2 (250 mL) and diisopropylethylamine amine (18 mL) was added. The solution was stirred at room temperature for 2 h. The solution was evaporated in vacuo and the residue purified by column chromatography (silica gel, 10 to 50% EtOAc/hexanes) to provide 4k (2.9 g, 46%) as a brown solid MS m/z=288 (M+H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([CH3:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[C:34]2[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=2[N:36]=[CH:37][N:38]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[C:34]4[CH:41]=[CH:40][NH:39][C:35]=4[N:36]=[CH:37][N:38]=3)=[O:5])=[N:7][CH:8]=[C:9]([CH3:30])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: COCN(c1cc(C)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)c2ncnc3[nH]ccc23)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
Prepared from 200 mg (0.42 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-5-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide, 202 mg (0.50 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.25 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 2 mL methanol and 2 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([C:16](O)=[O:17])[C:5]=2[CH:4]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][OH:17])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)c1ccccc1-2
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CO)c1ccccc1-2
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A solution of 2-methoxy-9-fluorenecarboxylic acid (2.2 g, 9.2 mmol) in 100 mL of THF at 0° C. was charged with 1M THF solution of BH3 -THF complex (20 mL, 20 mmol). The reaction mixture was stirred overnight then quenched with 10 mL of 10% acetic acid in methanol an diluted with 100 mL of water. The layers were separated, the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined extracts were dried over magnesium sulfate and evaporated. The residue was crystallized from methanol-water to afford 1.87 g (87.0%) of product.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:11]([O:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1sccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1sccc1OCc1ccccc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A mixture of methyl 3-hydroxy-2-thiophenecarboxylate (5.00 g, 31.61 mmol), benzyl bromide (3.76 mL, 31.61 mmol), and K2CO3 (4.81 g, 34.77 g) in acetone (50 mL) was stirred at reflux for 1.5 hrs. After cooled to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=15/1 to 9/1) to give methyl 3-(benzyloxy)-2-thiophenecarboxylate as a pale yellow oil (7.91 g, yield: quant.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([NH2:14])=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl.[CH3:20][C:21](N(C)C)=O>>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:14]=[C:20]([CH3:21])[N:8]2[CH2:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)CNc1nc(Cl)ncc1N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2cnc(Cl)nc2n1CC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4.2 g of 2-chloro-N4-(2,2-dimethyl-propyl)-pyrimidine-4,5-diamine in 40 ml of DMA was added 1.6 ml of POCl3. The solution was stirred at 100° C. for 2 hours, cooled and extracted with ethyl acetate and saturated NaHCO3 solution. The organic phases were dried over sodium sulfate and evaporated to dryness yielding 2-chloro-9-(2,2-dimethyl-propyl)-8-methyl-9H-purine as a brown oil.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH3:13][C:14]1([CH3:31])[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[C:21]1([CH:29]=[O:30])[CH2:26][CH2:25][C:24]([CH3:27])=[CH:23][CH:22]1[CH3:28]>C1(C)C=CC=CC=1>[CH3:31][C:14]1([CH3:13])[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[C:21]1([CH2:29][OH:30])[CH2:26][CH2:25][C:24]([CH3:27])=[CH:23][CH:22]1[CH3:28]
Reactant: CC1=CC(C)C(C=O)(C2C3CCC(C3)C2(C)C)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=CC(C)C(CO)(C2C3CCC(C3)C2(C)C)CC1
Temperature: 21.200000762939453 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
A 3-L reaction flask equipped with a stirrer, a thermometer, a reflux condenser, a heating mantle, and an addition funnel was charged with Vitride (1112 g, 3.5 mol) and toluene (1 Kg). The resulting mixture was stirred at 21.2° C. The Diels-Alder product containing 1-(3,3-dimethyl-bicyclo[2.2.1]hept-2-yl)-2,4-dimethyl-cyclohex-3-enecarbaldehyde (778.5 g, 2.59 mol, synthesized as above in EXAMPLE XI) was added over about 4 hours. The temperature was allowed to rise to 35° C. The reaction mass was aged for 1 hour. The excessive Vitride reagent was quenched with ethyl acetate (125 g), followed by sodium hydroxide (30%, 3 Kg). The temperature was allowed to rise to 40° C. and stirred for another 0.5 hours. The organic phase was washed with hot water (1 L) twice and distilled to yield the crude product [1-(3,3-dimethyl-bicyclo[2.2.1]hept-2-yl)-2,4-dimethyl-cyclohex-3-enyl]-methanol (829.5 g).