Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:20])=[C:4]2[CH2:8][CH2:9][C@@H:10]([CH3:11])[C:3]=12
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.0 g, 30 mmol) in CHCl3 (80 mL) at 0° C. was treated with m-CPBA (12 g, 53 mmol) in portions. The reaction was stirred at about room temperature overnight. The reaction was cooled to 0° C. and to this was added Na2SO3 (25 g, 200 mmol) in water (100 mL) (slurry), followed by dropwise addition of Na2CO3 (14 g, 130 mmol) in water (100 mL). The mixture was stirred for about 30 minutes. The aqueous phase was extracted with CHCl3. The organic phase was dried with MgSO4 and concentrated under reduced pressure at low temperature (<25° C.) to afford the crude (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (5.5 g, 100%) which was not purified further. 1H NMR (CDCl3, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H), 3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][CH2:37][OH:38]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:36][CH2:37][OH:38])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCCBr
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCO
Temperature: 60 °C
Reaction time: 120 h
Yield: 45.4 %

Procedure:
To a solution of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (1.26 g, 3.32 mmol) in DMF (20 mL), Cs2CO3 (6.49 g, 19.9 mmol) is added. The mixture is stirred at rt for 10 min before 2-bromoethanol (2.07 g, 16.6 mmol) is added. The mixture is stirred at 60° C. for 5 days. The mixture is cooled to rt, diluted with sat. aq. NaHCO3 solution (50 mL) and extracted twice with EA (2×200 mL). The org. extracts are combined and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)ethanol (639 mg) as a pale yellow oil; 1H NMR (CDCl3): δ: 7.90 (s, 1H), 7.88 (s, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 4.02 (s, 3H), 3.97-4.01 (m, 4H), 3.21-3.29 (m, 1H), 2.79 (q, J=7.6 Hz, 2H), 2.42 (s, 3H), 2.15 (t, J=5.5 Hz, 1H), 2.06-2.14 (m, 2H), 1.83-1.95 (m, 4H), 1.68-1.80 (m, 2H), 1.33 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C>C(O)CCC>[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: NCCCCN
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NCCCCNc1nc(Cl)nc2[nH]ccc12
Yield: 49.6 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol), 1,4-diaminobutane (0.125 mL, 1.25 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (4 mL) was stirred at 70° C. for 4 h. It was then purified by HPLC to give N-(4-aminobutyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (63 mg).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[C@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[NH:8][C:9](=[O:25])[CH2:10][C:11]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])([CH3:13])[CH3:12]>O.O1CCOCC1>[CH2:18]([O:17][C:15]([NH:14][C:11]([CH3:13])([CH3:12])[CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:35])=[O:5])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:25])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)CC(C)(C)NC(=O)OCc2ccccc2)C(=O)O)cc1
Reaction time: 1 h

Procedure:
0.184 g (4.39 mmol) of lithium hydroxide hydrate dissolved in 8 ml of water is added dropwise to a solution of 1.7 g (3.84 mmol) of N-[3-[1-(benzyloxy)formamido]-3-methylbutyryl]-3-(p-methoxyphenyl)-L-alanine methyl ester in 16 ml of dioxan. The solution is stirred at 0° for 1 hour, then treated with 20 ml of water and extracted twice with ether. The aqueous phase is acidified with 6N hydrochloric acid and extracted twice with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over sodium sulphate and then evaporated under reduced pressure. N-[3-[1-(Benzyloxy)formamido]-3-methylbutyryl]-3-(p-methoxyphenyl)-L-alanine is obtained as a colourless oil, MS: 429 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([C@@H:69]([NH2:72])[CH2:70][CH3:71])[CH2:65][CH:64]1[C:73](=[O:75])[NH2:74])=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C.CCOC(C)=O>[CH2:53]([O:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([C@@H:69]([NH:72][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH2:70][CH3:71])[CH2:65][CH:64]1[C:73](=[O:75])[NH2:74])=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC[C@H](N)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 0.17 h

Procedure:
To a suspension of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (360 mg, 1.4 mmol) in DMF (4 mL) was added DIPEA (487 μL, 2.8 mmol). After 10 minutes, HATU (638 mg, 1.68 mmol) was added to the brown solution. After 10 minutes, a solution of 4-((S)-1-amino-propyl)-2-carbamoyl-piperidine-1-carboxylic acid benzyl ester (0.45 g, 1.4 mmol) in DMF (4 mL) and DIPEA (244 μL, 1.4 mmol) was added resulting in a clear solution. After 18 hours, the reaction was diluted with EtOAc (200 mL), washed with NH4Cl (50 mL), water (50 mL), brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-6% MeOH in DCM to afford 2-carbamoyl-4-((S)-1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-piperidine-1-carboxylic acid benzyl ester as a light brown foam.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([C:30]([OH:37])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[N:25]=[C:24]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([C:30]([OH:37])([CH:31]([CH3:33])[CH3:32])[CH:34]([CH3:35])[CH3:36])[N:25]=[C:24]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:18][CH:17]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
10 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 500 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-[1-hydroxy-2-methyl-1-(1-methylethyl)propyl]imidazole-5-carbonitrile [prepared as described in step (a) above] in 10 ml of ethanol, and the resulting mixture was heated under reflux for 20 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to give 220 mg of the title compound as an amorphous solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:27])[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:14][CH:13]=2)=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].C=O.[BH3-][C:33]#N.[Na+].Cl>C(#N)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:27])[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:16][CH:17]=2)[CH3:33])=[C:6]([CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1ccc(N(C)Cc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
To 3-({4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-hydroxy-methyl)-benzonitrile (138 mg, 0.36 mmol) in acetonitrile (14 mL) are added 37% aqueous solution of formaldehyde (140 μL) and NaCNBH3 (69 mg, 1.1 mmol). The pH of the mixture is adjusted to approximately 2 by dropwise addition of 1 N HCl over a 15 min period. The reaction was complete after 1.5 h, during which time the pH of the reaction mixture is monitored every 15 min using pH paper and kept at around 2 by addition of 1N HCl. The reaction mixture is quenched into H2O and basified with saturated aqueous NaHCO3. The mixture is extracted with EtOAc (3×), washed with brine, dried over Na2SO4, and concentrated. Obtained is the title compound as a yellow oil (135 mg, 94%). LC-MS (m/e): 399 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OCC)(=O)C>CN(C)C=O>[O:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C1CCc2c(O)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of 2,3-dihydro-4-hydroxy-1H-inden-1-one (1.0 g) in N,N-dimethylformamide (10 mL), imidazole (1.01 g) and tert-butyldimethylsilyl chloride (1.32 g) were sequentially added and the resultant reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ethyl acetate-saturated aqueous sodium bicarbonate and the resultant reaction mixture was subjected to a phase separation. The organic phase was washed sequentially with water and a saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate: n-hexane:ethyl acetate=95:5 to 90:10) to obtain the subject compound (1.63 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[O:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:16](=[O:17])[CH2:15][CH2:14][C:13]([OH:18])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)c1ccccc1N
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccccc1NC(=O)CCC(=O)O

Procedure:
To a solution of 2-tert-butylaniline (1.0 g, 6.7 mmol) in toluene (15 mL) was added tetrahydrofuran-2,5-dione (0.81 g, 8.1 mmol) and the reaction mixture was refluxed for 1 h. The reaction mixture was cooled and filtered to obtain 4-(2-tert-butylphenylamino)-4-oxobutanoic acid, which was dissolved in acetic acid (20 mL) and sodium acetate (3.02 g, 36.86 mmol) and was stirred at 80° C. overnight. The reaction was quenched with water, the layers separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over MgSO4, filtered and concentrated. The resulting solid was recrystallized from ethanol, to obtain pure 1-(2-tert-butylphenyl)pyrrolidine-2,5-dione (930 mg, 60%). LC/MS: m/z 232.3 (M+H)+ at 1.264 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1ncc[nH]1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3ncc[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercaptoimidazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1>C1COCC1.O>[CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: O
Product: C#CCN1CCNCC1
Yield: 22.9 %

Procedure:
Propargyl bromide (1.19 g, 10 mmol) and piperazine (8.61 g, 100 mmol) were dissolved in THF (90 ml). Stir under N2 and reflux for 4 h. Remove solvent and dissolve in 40 ml of H2O. Extracted with 4×40 ml of EtOAc, washed with 2×15 ml of brine, dried over MgSO4. After solvent was removed, brownish solid 29.83 (285 mg, 23% yield) was obtained. 1H NMR (CDCl3, 200 MHz): δ=2.28 (t, 1H, J=2.4 Hz), 2.56 (m, 4H), 2.92 (m, 4H), 3.30 (d, 2H, J=2.6 Hz).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12](S(C4C=CC=CC=4)(=O)=O)[C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>CS(C)=O.O>[C:1]1([C:7]2[O:8][CH:9]=[C:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:12][C:11]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccccc2c2coc(-c3ccccc3)c21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(-c2occ3c2[nH]c2ccccc23)cc1
Temperature: 25 °C

Procedure:
45 g (123 mmol) of 3-phenyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole and 48 g (856 mmol) of potassium hydroxide in 65 ml of DMSO and 21 ml of water are heated under reflux for 1 h. The mixture is subsequently cooled to room temperature, neutralised using 1M HCl solution and extracted with dichloromethane. The solvent is evaporated in vacuo, and the residue is purified by chromatography (heptane/ethyl acetate 10:1). Yield: 22.4 g (96 mmol), 80%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]>C(#N)C>[CH3:49][C:48]1[CH:47]=[CH:46][C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])=[CH:44][C:43]=1[Cl:42]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1Cl
Yield: 47.3 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chloro-4-methylbenzenesulfonyl chloride (0.0440 g, 0.195 mmol) to obtain 4-(4-methyl-3-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0200 g, yield 47%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Mg]Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[CH:17](OC(C)=O)[O:18]C(C)=O.Cl.CCCCCCCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH2:17][OH:18])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1c([Mg]Cl)cccc1-c1ccccc1
Reactant: CC(=O)OC(C)OC(C)=O
Agent: Cl
Solvent: CCCCCCCC
Solvent: Cc1ccccc1
Product: Cc1c(CO)cccc1-c1ccccc1
Temperature: 53 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
Under a nitrogen atmosphere, the reaction mixture from above was decanted into a clean, dry flask, leaving the unreacted magnesium turnings in the first flask. This solution, which contains (2-methyl[1,1'-biphenyl]-3-yl)magnesium chloride, was heated to reflux, and 16.5 g (0.55 mole based on formaldehyde) of polyoxymethylene diacetate (avg. mol. wgt. approx. 50,000, available commercially from E.I. du Pont de Nemours & Co., Inc., Wilmington, Delaware under the trade name Delrin 500 acetal homopolymer resin), milled to about 80 mesh, was added with stirring over three hours. Refluxing was continued for four additional hours after which the reaction mixture was allowed to cool and stand overnight. The mixture was then heated to 53° C. and was poured into a mixture of 100 g of ice, 52 g of concentrated hydrochloric acid, and 200 g of a mixture containing 95% n-octane and 5% toluene (wt/wt). This mixture was filtered and the organic phase separated. The organic solvents were distilled off, boiling range 65°-93° C. During a four hour period the solution was cooled with stirring to approximately 5° C. and was then filtered. The filter cake was washed with 100 mL of cold n-octane and air-dried for 0.5 hour. The filter cake was broken up and dried under a vacuum at 55° C. for four hours, yielding 78.9 g of (2-methyl[1,1'-biphenyl]-3-yl)methanol (89.9% purity), a yield of 70.8% of theory.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH3:32])[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH2:26][O:25]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:33](O)[CH2:34][OH:35].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH3:32])[CH2:30][CH2:29][CH2:28][C:27]2([O:35][CH2:34][CH2:33][O:31]2)[CH2:26][O:25]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCO
Reactant: CC1(CCCCOCc2ccccc2)CCCC(=O)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1(CCCCOCc2ccccc2)CCCC2(CO1)OCCO2
Yield: 99 %

Procedure:
p-Toluenesulfonic acid (200 mg) is added to a solution of 2-(4'-benzyloxybutyl)-2-methyl-oxepan-6-one (5.9 g, 0.021 mol), ethylene glycol (30 ml) and dry benzene (200 ml) and the mixture is refluxed for 17 hours in a nitrogen atmosphere with a Dean-Stark apparatus. The solution is cooled and poured into a satd. NaHCO3 solution. The benzene layer is separated and the aqueous phase is extracted with ether (3×50 ml). The organic layers are combined, dried (MgSO4) and the solvents removed at reduced pressure. The crude product is chromatographed on SilicAR CC-7 (125 g) in hexane. Elution with 10% ethyl acetate/hexane gives 2-(4'-benzyloxybutyl)-6,6-ethylenedioxy-2-methyloxepane as a clear colorless oil (6.7 g, 99%): nmr (CDCl3) δ1.10 (s., 3H, CH3), 3.5 (m, 4H, O--CH2 --and O--CH2 --CH2), 3.96 (s, 4H, ketal) 4.48 (s, 2H, O--CH2 --Ph), 730 (s, 5H, aromatic).
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[N:33][NH:34]2)=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC.SC1SC2C=CC=CC=2N=1.C(N(CC)CC)C>C(#N)C>[C:1]1([S:7]([N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:27][C:28]2[CH:36]=[C:35]3[C:31]([CH:32]=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[O:16])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Sc1nc2ccccc2s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Yield: 45.7 %

Procedure:
A solution of 3-(benzenesulfonyl-benzyl-amino)-benzoic acid (25 mg, 0.068 mmol), 6-amino-1H-indazole (18 mg, 0.136 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg, 0.075 mmol), mercaptobenzothiazole (2 mg, 0.007 mmol) and triethylamine (24 μl, 0.17 mmol) in dry acetonitrile (2 ml) were stirred at room temperature for 15 hrs. The reaction mixture was quenched with water (10 ml) and extracted with dichloromethane (3×7 ml). The organics were combined, dried (PTFE frit) and concentrated in vacuo. The crude residue was purified by preparative TLC (10% diethyl ether in dichloromethane) to afford the title compound as a brown solid (15 mg, 45%). HPLC retention time 5.80 min. Mass spectrum (ES+) m/z 483 (M+H).
Reaction SMILES: [OH:1][C:2]([CH3:20])([CH3:19])[CH2:3][NH:4][C:5]([C:7]1[C:12]([NH2:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9](Br)[N:8]=1)=[O:6].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].CSC1NC(=S)NC(=S)N=1>CCOC(C)=O.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].C(Cl)Cl.CCO.C1(C)C=CC=CC=1>[OH:1][C:2]([CH3:20])([CH3:19])[CH2:3][NH:4][C:5]([C:7]1[C:12]([NH2:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[N:8]=1)=[O:6]
Reactant: CC(C)(O)CNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CSc1nc(=S)[nH]c(=S)[nH]1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(O)CNC(=O)c1nc(-c2ccc(F)cc2)c(C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
To a stirred suspension of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide (Ex. 1.10) (180 mg, 0.505 mmol) and 4-fluorophenylboronic acid (106 mg, 0.758 mmol) in a 2:1 mixture of toluene:EtOH (12 ml) under nitrogen was added 2M Na2CO3(aq) (1.011 ml, 2.022 mmol) followed by Pd(dppf)Cl2.CH2Cl2 adduct (41 mg, 0.051 mmol). The reaction mixture was heated using microwave radiation at 140° C. for 1 hour and then allowed to cool to RT. The mixture was diluted with EtOAc (100 ml) and washed with water (100 ml). The organic phase was separated, filtered through Celite® (filter material) dried (MgSO4) and concentrated in vacuo to yield a brown oil/solid. Purification by chromatography on silica eluting with MeOH/DCM yielded a yellow oil/solid. This was passed through a 500 mg Isolute® Si-TMT cartridge (2,4,6-trimercaptotriazine silica, pre-wetted with DCM) eluting with 30% MeOH/DCM (50 ml) to afford a yellow oil/solid. The crude product was dried in vacuo and slurried in ˜0.5 ml DCM. The resulting suspension was removed by filtration and the filtrate was evaporated to yield the title compound as a light yellow/brown foam-like solid; LC-MS Rt=5.30 mins [M+H]+ 372 (Method 10minLC_v002).