Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]1=[O:18].C(N(C(C)C)CC)(C)C.[N:29]([CH2:32][C:33]([O:35]CC)=[O:34])=[C:30]=[O:31]>ClCCl>[OH:11][C:10]1[N:5]([CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:6](=[O:18])[N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:12])[C:9]=1[C:30]([NH:29][CH2:32][C:33]([OH:35])=[O:34])=[O:31]
Reactant: CC(C)CCN1C(=O)CC(=O)N(CCC(C)C)C1=O
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(CCC(C)C)c1=O
Reaction time: 5 h

Procedure:
-{[6-Hydroxy-1,3-bis(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A mixture of 1,3-bis(3-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (1.2 g, 4.47 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles) was stirred in dichloromethane (30 mL) and treated with ethyl isocyanatoacetate (501 uL, 4.47 mmoles). The mixture was stirred for 5 hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken up in ethanol-6 molar sodium hydroxide and stirred overnight. The mixture was acidified and extracted into ethyl acetate (×2). The extracts were washed with 1 molar hydrochloric acid evaporated, dried and evaporated. The title compound was recrystallized from acetic acid (430 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br. s, 1 H), 10.11 (s, 1 H), 4.09-4.16 (m, 2 H), 3.77-3.86 (m, 4 H), 1.51-1.62 (dt, J=13.29, 6.59, 6.59, 6.59, 6.59 Hz, 2 H), 1.42 (q, J=7.07 Hz, 4 H), 0.91 (d, J=6.57 Hz, 12 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([CH:28]3[CH2:31][CH:30]([C:32]([O:34]CC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:38])[CH:10]=1)#[N:2].[OH-].[Na+].Cl.[CH3:42][Mg]Br>O1CCCC1.C(O)C>[C:32]([CH:30]1[CH2:29][CH:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:38])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:31]1)(=[O:34])[CH3:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CC(C(=O)OCC)C2)c2ncnn12
Reactant: C[Mg]Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CC(C(C)=O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of ethyl 3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate (4.0 g), tetrahydrofuran (40 mL), ethanol (40 mL) and 1 M aqueous sodium hydroxide solution (40 mL) was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was mixed with N,O-dimethylhydroxyamine hydrochloride (1.1 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.2 g), 1-hydroxybenzotriazole (1.6 g), triethylamine (3.3 mL) and N,N-dimethylformaldehyde (40 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (40 mL), methylmagnesium bromide (23 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 2 hr. Methylmagnesium bromide (11 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.8 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:13][CH2:14][CH:15]=[O:16])[CH3:12]>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH:15]=[O:16])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH3:12]
Reactant: COc1nnc(N=C=O)s1
Reactant: CCNCC=O
Solvent: c1ccccc1
Product: CCN(CC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido] acetaldehyde.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 40.8 %

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole (1.8 g), sodium azide (0.98 g) and ammonium chloride (0.80 g) was stirred in DMF (6 ml) at 110° C. for 5 days, while supplementing sodium azide (1.6 g), ammonium chloride (1.3 g) and DMF (5 ml) to the reaction system. To the reaction mixture were added water and ethyl acetate, and precipitating crystals were collected by filtration. The organic layer of the filtrate was washed with water, dried and concentrated under reduced pressure to give crude crystals. These crystals were combined with the crystals obtained previously, this was followed by recrystallization from ethyl acetate - methanol to afford colorless prisms (0.82 g, 41%), m.p. 235-236° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:34]3[CH:39]=[CH:38][C:37]([C@@H:40]([CH3:43])[CH2:41][OH:42])=[CH:36][CH:35]=3)[C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1C=C(C=CC=1)CNC(=O)C(NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2)C1C=CC(CC(O)CC)=CC=1>>[NH2:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:21](=[O:22])[CH:20]([NH:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([N:8]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[N:10][CH:11]=[CH:12]2)[C:34]1[CH:35]=[CH:36][C:37]([C@@H:40]([CH3:43])[CH2:41][OH:42])=[CH:38][CH:39]=1
Reactant: C[C@@H](CO)c1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc([N+](=O)[O-])c2)cc1
Agent: CCC(O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc(N)c2)cc1
Product: C[C@@H](CO)c1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc(N)c2)cc1

Procedure:
76H (145 mg, 88%) was obtained from 76G (172 mg, 0.25 mmol) using a procedure similar to that used in the preparation of 70G. MS (ESI) m/z 656.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].CN(C)C=O.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:7]1[C:2]([Cl:1])=[C:3]([C:16]#[N:17])[C:4](=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(Cl)ccn(-c2ccccc2Cl)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)c(Br)cn(-c2ccccc2Cl)c1=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of 4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D of Example (16.4 g) and N,N-dimethylformamide (124 mL) was added N-bromosuccinimide (16.5 g) at 60° C., and the mixture was stirred for 40 hr. The reaction mixture was cooled to room temperature, and poured into water. The resulting solid was collected by filtration, and washed with water to give the title compound (20.9 g).
Reaction SMILES: [N:1]1([C:6]2([Li])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:16](Cl)([Cl:19])([CH3:18])[CH3:17]>C1COCC1>[Cl:19][Si:16]([CH3:18])([CH3:17])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:7]1
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1(N2CCCC2)C=Cc2ccccc21
Solvent: C1CCOC1
Product: C[Si](C)(Cl)C1C=C(N2CCCC2)c2ccccc21
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of (1-(1-pyrrolidinyl)-1H-indenyl)lithium (2.0) g. 10.46 mmol) in 25 mL of THF was added within 30 minutes to a 50 mL THF solution containing SiMe2Cl2 (8.1 g, 62.76 mmol). After the addition was complete the reaction mixture was stirred overnight. The solvent was then removed under reduced pressure. The residue was extracted with hexane and the solution was filtered. The solvent was then removed under reduced pressure leaving 2.40 g of product. Yield 82 percent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[OH:10][CH2:11][CH2:12][O:13][CH2:14][C:15](N)=[NH:16].CC(C)=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:12][CH2:11][OH:10])[N:16]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COCCO
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1nc(COCCO)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 16.0 g (0.133 mole) of 3-amino-2-pyrazinecarbonitrile and the above solution of 2-(2-hydroxyethoxy)acetamidine in absolute ethanol. Refluxing time: 2 hours 30 minutes. Yld: 20.5 g (70%), m.p. 149°-151° C. (ethanol). An analytical sample was obtained by recrystallization from a mixture of acetone and ethanol. M.p. 159°-161° C.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[CH:5]1.CI.[C:24](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:24])=[O:14])[C:7]=2[CH:6]=[CH:5]1
Reactant: O=C(O)c1cccc2c1ccn2CC(O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc2c1ccn2CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
There were dissolved, in 80 ml of dimethylformamide, 5.39 g of 1-(2-hydroxy-2-phenylethyl)indole-4-carboxylic acid prepared in Example 319 and 3.05 g of methyl iodide, followed by further addition of 2.91 g of potassium carbonate and stirring at room temperature for 30 minutes. The reaction system was poured into 300 ml of a 10% ammonium chloride aqueous solution and extracted with ethyl acetate (100 ml×3). The resulting organic phase was washed, in order, with a 10% citric acid aqueous solution and a saturated common salt solution, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give 5.14 g of methyl 1-(2-hydroxy-2-phenylethyl)indole-4-carboxylate as a yellow oily substance. The yield thereof was found to be 91%.
Reaction SMILES: C(OC(C1C(CO)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C.[C:28]([O:31][CH2:32][CH:33]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH:34]1[C:51]([OH:53])=[O:52])(=[O:30])[CH3:29]>>[C:28]([O:31][CH2:32][CH:33]1[CH2:39][CH:38]=[CH:37][CH2:36][N:35]([S:40]([C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)(=[O:42])=[O:41])[CH:34]1[C:51]([OH:53])=[O:52])(=[O:30])[CH3:29]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)O)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(CO)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)O)cc1

Procedure:
3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid was synthesized from 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert butyl ester in the same manner as the procedures used for the preparation of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid: MS (M-H)- =382.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:15]=[N:16][CH:17]=3)[CH:10]=2)[N:5](C2CCCCO2)[N:4]=1)=O.[S].[N:30]1[CH:35]=[C:34]([NH2:36])[C:33]([NH2:37])=[C:32]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:31]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:32]2[C:33]3[N:37]=[C:1]([C:3]4[C:11]5[C:6](=[N:7][CH:8]=[C:9]([C:12]6[CH:13]=[C:14]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:15]=[N:16][CH:17]=6)[CH:10]=5)[NH:5][N:4]=4)[NH:36][C:34]=3[CH:35]=[N:30][CH:31]=2)[CH:39]=1
Reactant: Nc1cncc(-c2cccnc2)c1N
Reactant: CCC(=O)Nc1cncc(-c2cnc3c(c2)c(C=O)nn3C2CCCCO2)c1
Agent: CC[SiH](CC)CC
Agent: [S]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Nc1cncc(-c2cnc3[nH]nc(-c4nc5c(-c6cccnc6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide (LX) (1 eq), sulfur (1 eq) and 3,3′-bipyridine-4,5-diamine (XLVIII) (1 eq) in DMF was heated overnight at 140° C. under argon. The solution was cooled and the DMF was distilled under vacuum. The residue was taken in DCM. Triethylsilane (2.5 eq) followed by TFA (30% by volume) was added to the solution and stirred for 2 h at room temperature until TLC showed disappearance of starting material. The solvent was removed under vacuum. Water was added to the residue, sonicated briefly and basified with 5 N NH4OH solution. The solids formed were filtered, washed with cold water and dried at room temperature. The solids were triturated with DCM followed by MeOH to get N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide (47) as a brown solid (49% yield). 1H NMR (DMSO-d6, 400 MHz): δ 1.67 (t, J=6 Hz, 3H), 2.45 (q, J=6 Hz, 2H), 7.62 (m, 1H), 8.50 (s, 1H), 8.62 (m, 1H), 8.72 (s, 1H), 8.77 (m, 3H), 8.91 (m, 1H), 8.99 (m, 2H), 9.41 (s, 1H), 10.31 (s, 1H), 13.95 (s, 1H), 14.62 (s, 1H). ESIMS found C25H19N9O m/z 462.50 (M+H).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]2)=[O:22])[C:6](=[O:37])[N:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[C:4]=1[CH3:48])#[N:2]>Cl.O1CCOCC1>[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:21]([N:7]2[C@H:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=3[S:17]([CH3:20])(=[O:19])=[O:18])[C:3]([C:1]#[N:2])=[C:4]([CH3:48])[N:5]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:46])([F:47])[F:45])[CH:39]=3)[C:6]2=[O:37])=[O:22])[CH2:24]1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCC[C@@H](N)C2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl [(3R)-1-{[(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]carbonyl}piperidin-3-yl]carbamate (Example 12A; 56.0 mg, 0.082 mmol) was dissolved in a 4 N solution of hydrogen chloride in dioxane (2.15 ml) and stirred at RT for 60 min. The contents of the flask was then concentrated under reduced pressure, and the residue was taken up in dichloromethane (15 ml) and 2 N aqueous sodium hydroxide solution (15 ml). After extraction, the organic phase was separated off, dried over sodium sulfate and concentrated under reduced pressure. This gave 47 mg (96% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[C:25]([NH:29][C:30]([C:32]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)C>[C:25]([NH:29][C:30]([C:32]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)NC(=O)C1(c2ccccc2)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (19 mg, 0.051 mmol, 1 eq.) in 2 mL of ethanol was added N-tert-butyl-4-phenylpiperidine-4-carboxamide (13.2 mg, 0.051 mmol, 1 eq.) and triethylamine (0.02 mL, 0.15 mmol, 3 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 22 mg (72%) of N-tert-butyl-1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidine-4-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.32 (m, 9 H) 2.17 (s, 2 H) 2.39-2.58 (m, 2 H) 4.07 (s, 2 H) 5.01 (s, 2 H) 7.10-7.44 (m, 12 H) 7.51 (d, J=6.59 Hz, 1 H) 8.37 (s, 1 H), [M+H]+ 599.7.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(C(O)C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)C(F)(F)F)cc1

Procedure:
2.88 g (0.015 mol) of 2,2,2-trifluoro-1-(4-methylphenyl)ethanol and 0.26 g (0.0007 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 125 ml of methylene chloride at room temperature. 9.3 ml (0.018 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 10 minutes with vigorous stirring and the mixture is stirred for a further 4 hours at room temperature. The reaction mixture is added to 100 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.4 mbar, 60°-70° C. bath temperature), 0.84 g (30% of theory) of 4-trifluoroacetyltoluene are obtained. nD20 : 1.4675.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:19]C)=[C:13]([O:17]C)[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([OH:19])=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)C(=O)N(c1ccc(Cl)cc1)C2
Agent: BrB(Br)Br
Product: O=C1c2cc(O)c(O)cc2CN1c1ccc(Cl)cc1

Procedure:
2-(4-Chloro-phenyl)-5,6-dimethoxy-2,3-dihydro-isoindol-1-one (0.74 g) was demethylated with 4 eq of boron tribromide as described in Example 8.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[S:13][C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1.O>CN(C=O)C>[CH2:1]([S:8][C:12]1[S:13][C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: COc1ccc(C(=O)c2ccc(Br)s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(SCc3ccccc3)s2)cc1
Temperature: 25 °C

Procedure:
Benzyl mercaptan (1.24 g, 0.01 mol) was added to a stirred mixture of sodium hydride (50% oil dispersion, 0.44 g, 0.11 mol) and degassed DMF (10 mL). The resulting mixture was warmed cautiously until gas evolution ceased. After cooling to 25° C., a solution of 2-bromo-5-(4-methoxybenzoyl)thiophene (2.97 g, 0.01 mol) in DMF (10 mL) was added dropwise. After complete addition, the mixture was heated on the steam bath for 2.5 hours and poured into waTER (200 mL). The aqueous mixture was extracted with ether (2×200 mL) and the extracts were washed with water, saturated NaCl solution and dried (Na2SO4). After evaporation of the solvent, the residue was collected with the aid of hexane and dried, 1.98 g, m.p. 103°-105° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.B1(C=C)OB([CH:48]=[CH2:49])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH:48]([C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])=[CH2:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 67 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (60.0 mg, 0.114 mmol) was dissolved in dimethoxyethane (3.0 mL), and the solution was treated with 2,4,6-trivinylcyclotriboroxane-pyridine complex (55.0 mg, 0.228 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (7.4 mg, 0.0091 mmol), potassium carbonate (79 mg, 0.57 mmol) and water (0.041 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=8/1) to obtain 4-vinyl-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.0 mg, yield 67%).