Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:19]O>>[CH3:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:19])=[O:10]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C
Temperature: 55 °C

Procedure:
Sulfuric acid (6 ml, 113 mmol) was added to drop wise to a solution of the 2-methyl-4-nitrobenzoic acid (5 g, 27.6 mmol) in MeOH (138 ml) at RT. After the addition was complete the mixture was heated to 55° C. overnight. The volatiles were removed in vacuum and the residue partitioned between EtOAc (100 ml) and water (100 ml). The layers were separated and aqueous phase extracted with EtOAc (2×100 ml). The organic fractions were combined, washed with saturated sodium bicarbonate (aqueous, 100 ml), brine, dried over Na2SO4, filtered and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CC(=O)c3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-bromoacetophenone as described for compound 8. Purified by chromatography [ethyl acetate: petroleum ether (60-80° C.)/1:3]. Crystallized from diethyl ether. M.p. 133-135° C.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[BH4-].[Na+]>>[CH3:35][N:2]([CH3:1])[C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([CH2:16][CH3:17])([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]([OH:33])[C:29]([CH3:31])([CH3:32])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)[CH2:18][CH3:19])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)N(C)C)cc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)N(C)C)cc2c1
Yield: 60.1 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid dimethylamide (215 mg, 0.451 mmol) is reduced with NaBH4 (34 mg, 0.901 mmol) analogous to Example 3 to give the title product (130 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][C:29]#[N:30]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][C:29]#[N:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: N#CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 3-chloropropionitrile (65 mg, 0.73 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (5% methanol/chloroform) to give the subject compound (72 mg, yield 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[N:23]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=2)[N:23]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)Oc1ccc(-c2cccc(CCl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2cccc(-c3ccc(OC(F)(F)F)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
A solution of 39 mg (0.17 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 2-Chloromethyl-6-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 65 mg (77%) of the title compound as white powder.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])([CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])(O)[CH:10]=1)O)([O-])=O.[H][H]>C(O)C.[Pd]>[C:23]([O:22][CH2:21][CH2:20][O:19][C:5]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:10][C:4]=1[NH2:1])(=[O:25])[CH3:24]
Reactant: [H][H]
Reactant: CC(=O)OCCOC1(O)C=CC(O)(OCCOC(C)=O)C([N+](=O)[O-])=C1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCCOc1ccc(OCCOC(C)=O)c(N)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
2-Nitro-1,4-bis-(2-acetoxyethoxy)hydroquinone (115 g) was dissolved in ethanol at 50° C. and reduced with hydrogen in the presence of palladium catalyst (2 g, 5% Pd/C). When uptake of hydrogen ceased the solution was screened to remove the catalyst and the filtrates allowed to cool to room temperature. The crystalline solid was isolated by filtration and dried under vacuum to give 90 g of product.
Reaction SMILES: CCCCCC.[H-].[Na+].[C:9]([CH2:11]P(=O)(OCC)OCC)#[N:10].[CH2:20]1[C:29](=O)[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1>C1COCC1.O>[C:21]1([CH2:11][C:9]#[N:10])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH2:29][CH:20]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC1=CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a mechanically stirred mixture of hexane washed sodium hydride (8.98 g, 0.187 mol, 50%/mineral oil) in THF (400 mL) was added diethyl cyanomethylphosphonate (33.13 g, 0.187 mol) dropwise. The reaction was stirred at room temperature for 1/2 hour. β-Tetralone (24.8 g, 0.170 mol) in THF (100 mL) was added dropwise at 0° C., and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with water (600 mL) and extracted with ether (3×400 mL). The organic phase was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give an orange oil. Distillation from bulb to bulb under high vacuum yielded 22.65 g (79%) of product as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[Br:1][C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 16.3) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.96 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=480.2 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1>>[C:1]1([S:7]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]([C:27]3[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=3)=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc(Br)ccc1CS(=O)(=O)c1ccccc1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)c1cc(-c2ccnn2C)ccc1CS(=O)(=O)c1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Example 37, starting from methyl 2-(benzenesulphonylmethyl)-5-bromobenzoate (Intermediate 63) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)O1>>[CH3:8][N:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:3][C:4]1=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cn1ccc(I)cc1=O
Product: Cn1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-iodo-1-methylpyridin-2(1H)-one and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Frontier, Cat. No. P1164). LCMS (M+H)+: m/z=291.1.
Reaction SMILES: Br[C:2]1(Br)[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.CS(C)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C)C1C=CC=CC=1>O>[NH:22]([C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: CC1CCC(Br)(Br)c2ncc(C(=O)O)c(=O)n21
Solvent: CN(C)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC1CC=C(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Reaction time: 72 h
Yield: 55.8 %

Procedure:
1.83 g. (0.005 moles) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved in 5 ml. of dimethyl sulfoxide. To the solution 0.5 ml. (0.0055 moles) of aniline and 1.3 ml. (0.01 moles) of N,N-dimethylaniline are added. The reaction mixture is allowed to stand for three days, whereupon it is poured onto 20 ml. of water. The crystals are filtered off, washed with a small amount of water, dried and recrystallized from acetonitrile. 0.83 g. (55.8%) of 9-anilino-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are obtained, melting at 169° to 170° C.
Reaction SMILES: Cl[C:2]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3].[NH3:29]>O.CCOCC>[C:2]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[NH2:29]
Reactant: N
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)Cl)OC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(N)=O)OC(C)=O

Procedure:
Ethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate (8.38 g.; 0.02 mole) is added with stirring to a 28% solution of ammonia in water (concentrated ammonium hydroxide) (75 ml.). The amide forms at once and separates as a semi-solid. It is dissolved in ether, washed with water and dried over sodium sulfate. The ether is removed under vacuum to give the title compound as a semi-solid, yield 6.8 g. The product is purified by column chromatography on silica gel with 2% methanol in chloroform as eluant; pmr (CDCl3)δ 0.88 (3H,t), 2.02 (3H,s CH3COO), 4.12 (2H,q), 4.85 (1H,m HCO), 5.98 (2H,s NH2).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][O:47][CH:48]([F:50])[F:49])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C@@H:10]1[CH2:51][O:52]CC1C=CC=CC=1)C1C=CC=CC=1.CO.O1CCCC1>[Pd].ClC1C=CC=CC=1Cl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:51][OH:52])[O:11]2)=[CH:32][C:33]=1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][O:47][CH:48]([F:50])[F:49])=[CH:41][CH:40]=1
Reactant: FC(F)OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(CCOC(F)F)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-(2-(difluoromethoxy)ethyl)benzyl)phenyl)tetrahydro-2H-pyran (intermediate BM) was taken up in a mixture of 4:1 methanol:tetrahydrofuran (0.5 mL) and 9.6 μL of 1,2-dichlorobenzene was added followed by palladium on charcoal (10%, 5 mg). The mixture was stirred at room temperature under a hydrogen balloon for 30 min. The mixture was passed through a short Celite® pad to remove the catalyst, and the pad was washed with methanol (1 mL). Solvent was evaporated and the product was purified by TLC using 8:1 dichloromethane:methanol to obtain compound BN (2.5 mg, yield 64%). 1H NMR (300 MHz, CDCl3): δ 7-33-7.11 (m, 7H), 6.30 (t, JC-F=75.6 Hz, 1H), 4.13 (d, J=9 Hz, 1H), 4.04 (m, 4 H), 3.86-3.80 (m, 3H), 3.64 (t, J=4.5, 6.6 Hz, 2H), 3.47-3.41 (m, 2H), 2.90 (t, J=6.9, 7.2 Hz, 2H); LC-ESI-MS (m/z): 457 (M−H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:27][CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(-c2ccncc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 28 using 5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1) and 4-pyridineboronic acid to afford a yellow solid. UPLC-MS (condition 1) tR=1.62 min, m/z=445.0 [M+H]+, m/z=443.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.85 (dd, J=8.68, 4.28 Hz, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.24 (dd, J=11.25, 4.16 Hz, 2H) 3.40-3.53 (m, 1H) 4.21 (br. s, 1H) 4.87 (br. s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.45 (d, J=5.87 Hz, 2H) 7.86 (d, J=9.29 Hz, 2H) 8.07 (d, J=2.45 Hz, 1H) 8.65 (d, J=5.14 Hz, 2H) 8.78 (d, J=2.20 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1C=CC=C(C)C=1C.CC1C(C)=CC=CC=1[O:29]CCCC(O)=O.COC(=O)CCC(O)=O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][C:15]([O:16][CH3:17])=[O:29]
Reactant: Cc1cccc(OCCCC(=O)O)c1C
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Agent: COC(=O)CCC(=O)O
Product: COC(=O)CCC(=O)N1CCCc2c(Br)cccc21

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that 4-(2,3-dimethylphenoxy)butanoic acid was replaced by 4-methoxy-4-oxobutanoic acid. LCMS, [M+Na]+=349.9. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.0 Hz, 1H), 7.25 (br. s, 1H), 7.03 (t, J=8.1 Hz, 1H), 3.80-3.73 (m, 2H), 3.68 (d, J=11.0 Hz, 2H), 3.66 (s, 3H), 2.81 (t, J=6.9 Hz, 2H), 2.78-2.72 (m, 2H), 2.71-2.63 (m, 2H), 1.99 (dd, J=12.5, 6.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([F:41])=[CH:4][C:5]2[C:10]3[C:11]4[C:38](=[O:39])[NH:37][C:36](=[O:40])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:29][C@H:28]([CH2:30][OH:31])[C:27]([F:33])([F:32])[C@H:25](O)[C@H:23]6[OH:24])[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:34])=[C:16]([F:35])[CH:15]=5.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[C:3]([F:41])=[CH:4][C:5]2[C:10]3[C:11]4[C:38](=[O:39])[NH:37][C:36](=[O:40])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:29][C@@H:28]7[CH2:30][O:31][C@@H:25]([C:27]7([F:33])[F:32])[C@H:23]6[OH:24])[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:34])=[C:16]([F:35])[CH:15]=5
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C(F)(F)[C@H](O)[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@@H]2CO[C@H]([C@H]1O)C2(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
To a solution of 2,3,9,10-tetrafluoro-12-(4-deoxy-4,4-difluoro-β-D-glucopyranosyl)-6,7,12,13-tetrahydro(5H)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (0.035 g, 0.060 mmol) in 4 mL of dry THF was added triphenylphosphine (0.048 g, 0.18 mmol) and DIAD (0.035 mL, 0.18 mmol), at room temperature under Ar. The resulting reddish-orange solution was stirred at room temperature for 18 h and then it was partitioned with ethyl acetate-water. The organic phase was separated, washed (brine), dried (Na2SO4) and evaporated to give a yellow gum. This residue was purified by prep. tlc (20×20 cm×0.5 mm SiO2/THF-hexane, 1:1) and the major fraction was repurified by prep. hplc to give the title compound (0.009 g, 29%) as a yellow solid: 1H NMR (acetone-d6, 400 MHz) δ 10.67 (s, 1H), 9.83 (s, 1H), 8.88 (m, 1H), 8.73 (m, 1H), 7.56 (m, 2H), 6.44 (m, 1H), 4.91 (m, 2H), 4.47 (d, J=10.0 Hz, 1H), 4.41(d, J=11.0 Hz, 1H), 4.27 (m, 1H); MS (ESI−) m/e 560 (M−H)−; HPLC: 91.1% (320 nm).
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]([CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:26]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:3])[CH2:23][CH3:24])=[CH:15][N:14]=2)=[CH:17][CH:18]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCBr
Reactant: CC[C@H](C)CCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ncc(CCCCC[C@@H](C)CC)cn2)cc1
Temperature: 0 °C

Procedure:
Pour 0.33 g of sodium hydride (about 50% oil suspension), 3 ml of dry N,N-dimethylformamide into a 30 ml three-mouth flask equipped with a cooling tube, thermometer, dripping funnel, and calcium chloride tube. Next, slowly drip 1.71 g of optically active (s)-4-[5-(6-methyl octyl)-2-pyrimidinyl]phenol which is dissolved in 6 ml of dry N,N-dimethylformamide, into the flask at room temperature. Furthermore, after reacting it for 30 minutes, add 1.10 g of 1-bromoctane, allow to react for 7 hours at 90° C. After the reaction, pour the mixture into ice water, then extract the product with ethyl acetate. The organic layer is thoroughly washed with water, dried, the organic solvent is evaporated and removed, and then the impure product is obtained. This impure product is refined with silica gel chromatography, and recrystallized to obtain 1.3 g of optically active (s)-2-[4-n-octyloxyphenyl]-5-[6-methyloctyl]pyrimidine.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[NH:16][CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:19]=1[C:20]([NH2:22])=[O:21]>O1CCCC1.C(OCC)(=O)C>[C:8]([NH:14][C:15]1[NH:16][CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reaction time: 16 h
Yield: 86.3 %

Procedure:
0.227 cm3 (1.62 mmol) of triethylamine and 0.085 cm3 (0.81 mmol) of butyryl chloride are added, at a temperature close to 25° C., to a solution of 0.20 g (0.81 mmol) of 2-amino-4-(4-nitro-phenyl)-1H-pyrrole-3-carboxamide in 25 cm3 of tetrahydrofuran. After stirring for 16 hours at this temperature, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 60 cm3 of ethyl acetate and then washed with three times 20 cm3 of water. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.221 g of 2-butyrylamino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in the form of a brown powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 0.94 (t, J=7.5 Hz, 3H); 1.63 (m, 2H); 2.36 (t, J=7.5 Hz, 2H); from 6.20 to 8.50 (very broad m, 2H); 6.79 (d, J=3.0 Hz, 1H); 7.64 (d, J=9.0 Hz, 2H); 8.18 (d, J=9.0 Hz, 2H); 10.3 (broad s, 1H); 11.6 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[O:20])=[C:17]([O:35][CH3:36])[CH:16]=2)[N:10]=1.[C:37]([Cu])#[N:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:37]#[N:38])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[O:20])=[C:17]([O:35][CH3:36])[CH:16]=2)[N:10]=1
Reactant: N#C[Cu]
Reactant: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: COc1cc(-n2nc(-c3c(Cl)cccc3C#N)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by following the procedure as described for Example-62 by using 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methoxybenzamide (Intermediate-43, 0.130 g, 0.21 mmol), DMF (4 mL) and CuCN (0.020 g, 0.23 mmol) to afford 0.030 g of crude product which was further purified by column chromatography in basic alumina eluting with 50% methanol:DCM and few drops of 10% ammonia to afford 0.030 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 3.94 (s, 3H), 7.52 (t, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.81 (m, 3H), 8.05-8.12 (m, 3H), 8.26 (s, 1H), 10.40 (s, III), 13.01 (br s, 1H); MS (m/z): 532.12 (M+H)+.