Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:24])=[C:11]([NH:13][C:14]([C:16]3[S:20][C:19](B(O)O)=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH3:32]>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:24])=[C:11]([NH:13][C:14]([C:16]3[S:20][C:19]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:31]=4[CH3:32])=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccncc1Br
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(B(O)O)s1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cnccc2C)s1

Procedure:
The title compound was prepared by coupling 5-(5-(cyclopropylcarbamoyl)-2-methylphenylcarbamoyl)thiophen-2-ylboronic acid (Example 210, Step A) with commercially available 3-bromo-4-methylpyridine using the method described in Step B of Example 136 to afford a white solid after purification by reverse phase preparative HPLC (Example 212). HPLC Ret time=1.99 min. LCMS [M+H]+ 392.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[NH:25][C:26]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[CH:27][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([C:26]4[NH:25][C:24]([C:23]([F:37])([F:36])[F:22])=[N:28][CH:27]=4)=[CH:30][CH:31]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2cnc(C(F)(F)F)[nH]2)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2cnc(C(F)(F)F)[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
67 mg (0.22 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 49 mg (0.22 mmol) of 4-[2-(trifluoromethyl)-1H-imidazol-5-yl]aniline (Example 1.3B) were reacted according to General Method 1. Yield: 26 mg (22% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.C[O:19][C:20]([CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:25]3[CH2:26][CH2:27][CH:22]([C:20]([OH:21])=[O:19])[CH2:23][CH2:24]3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Reactant: COC(=O)C1CCC(=O)CC1
Product: O=C(O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole prepared in Example 3 and 4-oxo-cyclohexane-1-carboxylic acid methyl ester were reacted according to the same procedures as Step B of Example 1 and Example 30 sequentially to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:23]=[C:22]([N:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:4]=1[C:5]([C:7]1[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:8]=1[C:9](O)=[O:10])=[O:6].[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1.C(OC(=O)C)(=O)C>CCCCCC>[CH3:37][N:36]([CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH3:39])[CH3:28])[CH:35]=[CH:34][C:33]=1[C:5]1([C:4]2[CH:20]=[CH:21][C:22]([N:24]([CH3:26])[CH3:25])=[CH:23][C:3]=2[N:2]([CH3:27])[CH3:1])[C:7]2[C:8](=[C:12]([Cl:19])[C:13]([Cl:18])=[C:14]([Cl:17])[C:15]=2[Cl:16])[C:9](=[O:10])[O:6]1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(N(C)C)c1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(C)C)c1

Procedure:
A mixture of most of the 2-(2,4-bis(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid from part A of this example, N,N,N',N'-tetramethyl-m-phenylenediamine (0.82 g. plus 0.4 g.) and acetic anhydride was heated under reflux. Concentration of a toluene extract of the resulting product gave a tar, which was slurried in hexane, affording 3,3-bis(2,4-bis(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=Y2 =Y4 =(CH3)2N, Z4 =Z5 =Z6 =Z7 =Cl) (m.p. 195°-197° C.).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]1=[O:25].[C:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)#[N:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Cu]I>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:10]([C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH:11]=[CH:12][CH:13]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[C:3]1=[O:25]
Reactant: N#Cc1ccc(I)cc1
Reactant: Cc1c(-c2ccc[nH]2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2cccn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 31.8 %

Procedure:
A solution of 3,6-dimethyl-5(1H-pyrrol-2-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 201) (20.0 mg), 4-cyanoiodobenzene (39.4 mg), copper(I) iodide (1.0 mg), cyclohexyldiamine (0.6 mg) and potassium phosphate (36.4 mg) in 1,4-dioxane (2.0 ml) was stirred with heating under reflux for fifteen hours. Thereto were added 4-cyanoiodobenzene (39.4 mg), copper(I) iodide (1.0 mg), cyclohexyldiamine (0.6 mg) and potassium phosphate (36.4 mg) and the resulting mixture was stirred with heating under reflux for four hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and further purified by silica gel column chromatography (eluent: hexane/acetone/methanol) to afford 4-[2-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrrol-1-yl]benzonitrile (8.2 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.[F:17][C:18]([F:33])([F:32])[S:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+]([O-])=O)=[CH:25][CH:24]=1)(=[O:21])=[O:20].O>CN(C=O)C>[F:17][C:18]([F:33])([F:32])[S:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]2[C:25](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:24]=1[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)(=[O:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Oc1ccc2ccccc2c1C1NCCc2ccccc21)C(F)(F)F
Reaction time: 3 h

Procedure:
Powdered K2CO3 (2.30 g, 17 mmol) was added to a solution of 1 (2.30 g, 8.4 mmol) and 4-nitrophenyl trifluoromethanesulfonate (2.28 g, 8.4 mmol) in DMF (70 mL). After 3 hours, the mixture was poured into water (300 mL) and extracted with CH2Cl2 (250 mL, 3 times). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to provide crude 2 as an oil which was purified by column chromatography on silica gel (5:1 hexanes/EtOAc). The fractions containing the product (Rf=0.50, 5:1 hexanes/EtOAc) were collected and concentrated under reduced pressure to yield the title product 2 (3.15 g, 92% yield) as an oil. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.18 (d, J=8.8 Hz, 1H), 7.92-7.83 (m, 2H), 7.46-7.11 (m, 5H), 6.92 (t, J=7.2 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.97 (s, 1H), 3.54-3.28 (m, 3H), 2.94 (d, J=14.8, 1H), 2.31 (s, 1H); 13C NMR (CDCl3, 75 MHz, ppm): δ 146.03, 137.81, 134.57, 133.68, 131.97, 131.48, 131.02, 129.22, 128.45, 128.07, 126.71, 126.59, 126.32, 126.11, 120.75, 118.98, 116.51, 55.86, 44.96, 29.67.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:13])[CH3:2].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][CH:15]1[O:12][C:8]2=[CH:7][C:6]3[CH2:5][C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:11]=3[CH:10]=[C:9]2[CH2:16]1
Reactant: C=CCBr
Reactant: CCN1C(=O)Cc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1C(=O)Cc2cc3c(cc21)CC(C)O3
Yield: 45 %

Procedure:
A mixture of 17.7 g. (0.1 mole) of 1-ethyl-5-hydroxyoxindole, 8.66 ml. (0.1 mole) of allyl bromide and 13.8 g. (0.1 mole) of potassium carbonate in 500 ml. of acetone was heated at reflux for 3 hours. The reaction was cooled, filtered and concentrated. The residue was purified by chromatographing on 550 g. of silica gel using diethyl ether-hexane (1:1, v:v) as the eluent to give 9.8 g. (45% yield) of the desired compound.
Reaction SMILES: COC([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16])=O.[CH3:17][Si](I)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]([CH3:17])[C:7]1=[O:16]
Reactant: C[Si](C)(C)I
Reactant: COC(=O)NC1C(=O)NCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1Cc2ccccc2C(N)C1=O

Procedure:
Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50–80° C. for 3 hrs and then cooled and poured into a seperatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 and then with 5% NaHSO3. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50–87%.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][O:37][CH2:38][CH2:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH2:39][CH2:38][O:37][CH3:36])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 55.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 99, 1 g, 2 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (1.2 g, 5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (140 mg, 0.2 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-{1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-1H-pyrrolo[2,3-b]pyridine (0.6 g, 57%) as a white solid: LC/MS m/e calcd for C27H27FN2O5S2 [M+H]+ 543.65, observed 543.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH:25]=O)[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH3-]C#N.[Na+]>CC(O)=O.CO>[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH2:25][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=CC1CCCCN(C(=O)OCc2ccccc2)C1
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCCCC(CNc2ccccc2)C1
Reaction time: 0.33 h

Procedure:
Aniline (0.126 mL, 1.38 mmol) was added to a solution of 3-formyl-azepane-1-carboxylic acid benzyl ester (147) (0.300 g, 1.15 mmol) in 5% HOAc in MeOH (11.5 mL). The reaction was stirred for approx. 20 minutes, then NaBH3CN (0.2164 g, 3.44 mmol) was slowly added and the reaction was stirred at room temperature overnight. The reaction was then concentrated in vacuo and EtOAc and a few drops of 10% NaOH were added. The organic was washed with saturated NaCl (aq), dried with NaSO4, concentrated in vacuo, to give crude 3-phenylaminomethyl-azepane-1-carboxylic acid benzyl ester (148). Compound 148 was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1>O=P(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
To a solution of 0.64 g (2.75 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 20 mL POCl3 was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring for 3 hours in a heat flux condition. The solution was cooled to room temperature and dissolved in distilled water. After the adjustment of pH to 8-10 with ammonia, extraction was conducted using ethyl acetate. The organic layer was dried over magnesium sulfate and vacuum concentrated. The residue thus obtained was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.61 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 65%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.O[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:31]=1)[C:27]#[N:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:27]([C:26]1[CH:25]=[C:24]([CH:31]=[C:30]([O:32][C:33]([F:34])([F:36])[F:35])[CH:29]=1)[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:28]
Reactant: N#Cc1cc(CO)cc(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3cc(C#N)cc(OC(F)(F)F)c3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
To an ice-cooled solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (131 mg, 0.456 mmol), 3-(hydroxymethyl)-5-(trifluoromethoxy)benzonitrile (114 mg, 0.524 mmol) and triphenylphosphine (179 mg, 0.684 mmol) in THF (3 mL) was added diisopropyl diazene-1,2-dicarboxylate (0.135 mL, 0.684 mmol) dropwise. After stirring at 0° C. for 15 min, the cooling bath was removed and the mixture was stirred at 23° C. for 3 h and then concentrated. The residue was purified by preparative TLC to provide the title compound as a yellow solid (50 mg). LCMS m/z=487.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][O:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:4][CH:3]=1.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1OCCC=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCCc1ccc(F)cc1

Procedure:
71.5 g (0.23 mol) of N-(4-(4-fluorophenyl)-3-butenyloxy)-phthalimide (prepared according to German Laid-Open Application DOS 3,838,310) were dissolved in 300 ml of tetrahydrofuran, 2 g of palladium on active carbon (10% strength) were added and hydrogenation was carried out under slightly superatmospheric pressure until 1.2 times the theoretical amount of hydrogen had been consumed.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.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>[NH2:20][C:4]1[N:3]=[C:2]([C:25]2[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:23]([C:22]([F:21])([F:37])[F:36])[CH:24]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 30 %

Procedure:
A solution of 2-iodo adenosine (1.00 g, 2.53 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (784 mg, 3.04 mmol), cesium carbonate (1.81 g, 6.08 mmol) and Pd(PPh3)4 (293 mg, 0.25 mmol) in toluene (2.4 mL) and ethanol (4.8 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 30 s) for 40 min in 2 batches and the crude reaction mixtures were combined. The solvents were then removed in vacuo and the residue dissolved in EtOAc (200 mL) and washed with sat. aq. NaHCO3 (100 mL) and brine (100 mL). Purification by flash column chromatography (normal phase, ICN silica, 50 g, 18-32μ, gradient 5-25% ethanol in DCM, residue dry loaded, product eluted in 25% ethanol) afforded (2R,3R,4S,5R)-2-{6-amino-2-[3,5-bis(trifluoromethyl)phenyl]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 11 as an off-white glass (364 mg, 30%).
Reaction SMILES: N[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S:10]([NH2:14])([NH2:13])(=[O:12])=[O:11].C1CCN2C(=NCCC2)CC1>O>[NH:13]1[C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]([NH2:5])=[N:14][S:10]1(=[O:12])=[O:11]
Reactant: NS(N)(=O)=O
Reactant: N#Cc1cccnc1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: NC1=NS(=O)(=O)Nc2ncccc21
Temperature: 160 °C

Procedure:
A stirred mixture of 2-aminonicotinonitrile (238 mg, 2.0 mmol), sulfamide (192 mg, 2.0 mmol), and 1 mL of DBU was heated at 160° C. under nitrogen overnight. After it was cooled down to room temperature, the reaction mixture was diluted with water, and extracted three times with EtOAc. The aqueous layer was dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with 15% MeOH in dichloromethane to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.87 (t, J=5.6 Hz, 1H), 7.95 (brs, 2H), 8.22 (d, J=5.2 Hz, 1H), 8.39-8.37 (m, 1H), 12.58 (brs, 1H). MS 199 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:14]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(N)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
A solution of 10 mL (95.4 mMol) 1,2-diamino-2-methylpropane and 20 mL (144 mMol) triethylamine in 300 mL dichloromethane was cooled to 0° C. To this solution was added a solution of 26 gm (93.3 mMol) (triphenyl)methyl chloride in 50 mL dichloromethane. The resulting mixture was stirred at room temperature for about 18 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate containing from 0–10% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 16.0 gm (52%) of the desired compound as a white solid.
Reaction SMILES: COC([C:5]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]2)[CH2:7][C:6]=1[OH:16])=O.[Na+].[Cl-].O>CS(C)=O>[CH2:7]1[C:8]2([CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]2)[CH2:9][CH2:10][CH2:5][C:6]1=[O:16]
Reactant: COC(=O)C1=C(O)CC2(C=CCCC2)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCCC2(C=CCCC2)C1
Temperature: 160 °C
Yield: 95 %

Procedure:
To a solution of the relevant 2-hydroxy-spiro[5.5]undecan-2,7-diene-3-carboxylic acid methyl ester isomer (9) or (9′) (19.0 g, 85.0 mmol) in DMSO (66 mL) was added NaCl (5.5 g, 93.5 mmol) and H2O (4.6 mL, 255 mmol). The reaction mixture was heated at 160° C. for 6 hours then cooled and poured into H2O (100 mL). The aqueous layer was extracted with Et2O (5×) and the combined organic layers dried over anhydrous MgSO4. The solvent was removed in vacuo and the resulting residue purified over silica (n-pentane/Et2O, 95:5) to afford 13.3 g (95% yield) of the desired product as a colorless oil which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.[Br:19]Br.ClCCl>C1C=CC=CC=1>[Br:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[O:10]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1Cl)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
Part B: To a solution of 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone (2.82 gram, 9.42 mmol) in benzene (25 mL) is added bromine (0.48 mL, 1.49 gram, 9.31 mmol) and the resulting solution is stirred at room temperature for two hours. Dichloromethane is added and the resulting solution is washed with aqueous NaHCO3 solution. The organic layer is dried over MgSO4, filtered and evaporated in vacuo to give 3.55 gram (quantitative yield) of 2-bromo-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone as a yellow oil (purity˜95% according to HPLC analysis). 1H-NMR (200 MHz, CDCl3): δ 7.00-7.50 (m, 7H), 6.16 (s, 1H).