Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[N:14]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:13]=2[N:12]=[CH:11][CH:10]=1.[CH:32](=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:32]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[N:14]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:13]=2[N:12]=[CH:11][CH:10]=1)[CH3:33]
Reactant: CC=O
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(OC[C@H]3CCCCN3)ccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCCC[C@@H]1COc1ccnc2c1c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (R)-4-(piperidin-2-ylmethoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (96 mg, 0.22 mmol) in methylene chloride (1.4 mL) was added acetaldehyde (19 uL, 0.33 mmol) followed by sodium triacetoxyborohydride (70 mg, 0.33 mmol), and the reaction mixture was stirred at ambient temperature for 5 minutes. The mixture diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 1-15% methanol in methylene chloride) to afford the title compound as a yellow solid, which was used in the next step without any further purification (64 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:11]1[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]1>O1CCOCC1.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:11]1[C:15]([CH:16]=[O:17])=[CH:14][N:13]=[CH:12]1
Reactant: CC1(C)Cc2ccccc2C1n1cncc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC1(C)Cc2ccccc2C1n1cncc1C=O
Temperature: 90 °C

Procedure:
To a solution of [3-(2,2-dimethyl-indan-1-yl)-3H-imidazol-4-yl]-methanol (120 mg, 0.5 mmol), which can be prepared as described in Example 23, in 1,4-dioxane (5 mL) is added manganese (IV) oxide (434 mg, 5 mmol). The reaction is then heated at 90° C. for 1 hour, at which time the reaction is cooled to room temperature and filtered to furnish 3-(2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carbaldehyde without the need for further purification; MS: (ESI) m/z 241.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=[N:20][C:14]=3[CH:15]=[N+:16]([O-])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:36]=C=O)=O.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:21]=[N:20][C:14]=3[C:15]([NH2:36])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: [O-][n+]1cc2ncn(CCOc3ccccc3)c2c2ccc(OCc3ccccc3)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1ncn2CCOc1ccccc1
Reaction time: 4.5 h
Yield: 59.3 %

Procedure:
A modification of the general method described in Part C of Example 3 was used to treat 7-benzyloxy-5-oxido-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline (1.59 g, 3.86 mmol). Chloroform (10 mL) was added to help keep the starting material in solution. The reaction with trichloroacetyl isocyanate (0.6 mL, 5 mmol) was stirred for 4.5 hours. Following the reaction with sodium methoxide, a tan precipitate formed, which was isolated by filtration, washed with hexanes, and dried overnight in a vacuum oven. The solid was then stirred with water overnight, isolated by filtration, and dried in a vacuum oven to provide 0.94 g of 7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder, mp 200.3-200.9° C.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]=[S:36]>>[F:38][C:24]([F:37])([F:23])[C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]=[C:35]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:36]1
Reactant: O=[N+]([O-])c1ccc(N=C=S)c(C(F)(F)F)c1
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: CC(C)C[C@H]1CSC(=Nc2ccc([N+](=O)[O-])cc2C(F)(F)F)N1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-(Trifluoromethyl)4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1c to give (4S)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(2-(trifluoromethyl)-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=2)=[N:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 79.7 %

Procedure:
Potassium carbonate (1.4 g) and 2-bromo-5-trifluoromethylpyridine (450 mg) were added to an acetonitrile solution (10 mL) of ethyl 4-hydroxybenzenecarboxylate (221 mg), and heated overnight under reflux. The reaction solution was concentrated under reduced pressure, water was added to the residue and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 4/1) to obtain the entitled compound (330 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[NH:13][C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23].N1C2C(=CC=CC=2)[C:26]2([C:36]3=CC4OCOC=4[CH:43]=[C:35]3[O:34][CH2:33]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:43][C@H:35]5[CH2:36][CH2:26][CH2:33][O:34]5)[C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methyl benzenesulfonate, 3-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-2H-spiro[benzofuro[6,5-d]oxazole-7,3′-indoline]-2,2′(3H,6H)-dione was obtained (69%) as a colorless solid: mp 186-187° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.36-7.29 (m, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.06-7.02 (m, 2H), 6.63 (d, J=6.9 Hz, 1H), 4.85-4.73 (m, 2H), 4.24-4.16 (m, 1H), 3.81-3.59 (m, 4H), 3.31 (s, 3H), 2.00-1.75 (m, 3H), 1.69-1.55 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 157.3, 154.9, 143.4, 136.6, 133.3, 131.9, 129.3, 123.9, 123.3, 122.3, 110.2, 105.0, 92.9, 80.0, 76.1, 67.7, 57.7, 44.3, 29.1, 28.6, 25.5; MS (ES+) m/z 392.7 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:24]=[CH:23][CH:22]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(-c2ccccc2)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(-c4ccccc4)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-biphenyl-3-yl-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.04 min; [M+H]+=453.15.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.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>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C@H:8]([O:10][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH3:9])[N:7]=1
Reactant: Oc1ccccc1Cl
Reactant: C[C@H](O)c1cccc(Br)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccccc1Cl)c1cccc(Br)n1
Temperature: 0 °C
Yield: 93.7 %

Procedure:
A solution of (S)-1-(6-bromopyridin-2-yl)ethanol (1 g) (prepared by the method of S. Ishikawa, T. Hamada, K. Manabe, and S. Kobayashi, Synthesis 2005, 13, 2176-2182), 2-chlorophenol (0.615 mL, 0.764 g) and triphenylphosphine (1.558 g) in tetrahydrofuran (20 mL) under N2 and cooled to 0° C. A solution of diisopropyl azodicarboxylate (1.17 mL, 1.2 g) in tetrahydrofuran (10 mL) was then added dropwise and reaction warmed to room temperature overnight. The solvent was removed under reduced pressure, then heptane added to precipitate the triphenylphosphine oxide side product. Filtration and evaporation of the filtrate followed by purification by flash chromatography on silica eluting with heptane/ethyl acetate 8:2 gave the title compound (1.45 g) as a clear liquid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[C:9]([NH2:24])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:13]=1.[NH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>O1CCOCC1.CN(C=O)C>[NH2:24][C:9]1[C:8]([C:31]2[CH:32]=[CH:33][C:28]([C:26]([NH2:25])=[O:27])=[CH:29][CH:30]=2)=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][N:10]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc(C(N)=O)cc3)c2)cc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 56 %

Procedure:
Aqueous K2CO3 solution (1 M, 0.4 mL) was added to a suspension of 3-bromo-5-[4-(methylsulfonyl)phenyl]pyridin-2-amine obtained as described above (0.15 g, 0.46 mmol), 4-aminocarbonylphenylboronic acid (0.120 g, 0.51 mmol) and Pd[(PPh)3]4 (0.016 g, 0.02 mmol) in dioxane (5 mL) and DMF (2 mL) under N2. The reaction mixture was stirred at 120 ° C. for 14 h, poured onto H2O (10 mL) and extracted with MeOH/CHCl3 (1:4) (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (5% MeOH/EtOAc) to yield the desired product (0.26 g, 56%). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, 1H, J=2.4 Hz), 8.07 (s, 1H), 8.02-7.92 (m, 6H), 7.78 (d, 1H, J=2.4 Hz), 7.64 (d, 2H, J=8.4 Hz), 7.44 (bs, 1H), 6.11 (bs, 2H) and 3.24 (s, 3H). LC-MS APCI: Calculated for C19H17N3O3S, 367; Observed m/z 368 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([NH2:33])=[C:29]([CH3:34])[CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:33][C:30]3[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][C:29]=3[CH3:34])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: COc1cc(C)c(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2cnc(OC)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 10 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 1.50 g, 4.04 mmol), 6-methoxy-4-methylpyridin-3-amine (1.10 g, 8.09 mmol) and p-toluenesulfonic acid monohydrate (487 mg, 2.83 mmol) in 1-methyl-2-pyrrolidinone (8 mL) was irradiated by microwave at 180° C. for 10 min. After cooling, the mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give an amorphous which was recrystallized from ethyl acetate/n-hexane to give the title compound (190 mg, 0.402 mmol, 10%) as a colorless solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(=O)=O.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>CN(C)P(N(C)C)(N(C)C)=O.O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCOc1ccc2ccccc2c1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1
Yield: 63.4 %

Procedure:
A solution of 10.0 g of 6-(2-naphthyloxy)-1-hexanol O-methanesulfonate and 9.7 g of ethyl 4-aminobenzoate in 50 ml of hexamethylphosphoramide is heated at 110° C. for 16 hours. The solution is cooled, diluted with water, filtered and the solid washed with ethanol and water to give 7.7 g of product. Recrystallization from ethanol and once from acetone-hexane gives crystals, mp 109°-110° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:13]4[CH:14]=[CH:15][C:16]5[N:17]([C:18]([CH3:21])=[N:19][N:20]=5)[C:12]=4[CH:11]=3)=[N:6]2)[CH2:2]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:22]1[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:18]([CH3:21])=[N:19][N:20]=3)[C:12]=2[CH:11]=[C:10]1[C:7]1[CH:8]=[CH:9][N:5]([CH:3]2[CH2:2][N:1]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:4]2)[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5CN(S(C)(=O)=O)C5)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.03 h
Yield: 67.7 %

Procedure:
To 7-(1-azetidin-3-yl-1H-pyrazol-3-yl)-6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6.0 mg, 0.014 mmol, from Example 108, Step 1) was added methanesulfonyl chloride (1.3 μL, 0.017 mmol, Aldrich) in DCM (0.50 mL). This was followed by triethylamine (4.0 μL, 0.029 mmol) and the reaction was stirred for 2 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded clean product (4.7 mg, 66%).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][C:28]6[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=6)[CH:26]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C(OO)(=[O:37])C>C(Cl)Cl>[CH3:1][C:2]1([CH3:34])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][C:28]6[CH:29]=[N+:30]([O-:37])[CH:31]=[CH:32][CH:33]=6)[CH:26]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(-c5cnn(Cc6cccnc6)c5)cc43)sc2C(=O)N1
Reactant: CC(=O)OO
Solvent: ClCCl
Product: CC1(C)Cc2nc(N3CCOc4ccc(-c5cnn(Cc6ccc[n+]([O-])c6)c5)cc43)sc2C(=O)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
To a stirred solution of Example 323 (0.013 g, 0.028 mmol) in DCM (1.0 mL) was added peracetic acid (0.010 mL, 36-40 wt % in acetic acid, 0.055-0.061 mmol). The reaction mixture was stirred at r.t. for 150 minutes and then additional peracetic acid (0.040 mL, 36-40 wt % in acetic acid, 0.214-0.238 mmol) was added. After 46 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.003 g, 20%) as a white solid. δH (CDCl3) 8.19-8.13 (2H, m), 7.98 (1H, d, J 1.9 Hz), 7.78 (1H, s), 7.66 (1H, s), 7.32-7.27 (1H, m), 7.20-7.14 (2H, m), 6.97 (1H, d, J 8.5 Hz), 5.42 (1H, s), 5.33 (2H, s), 4.37-4.31 (2H, m), 4.23-4.17 (2H, m), 2.89 (2H, s), 1.41 (6H, s). LCMS (ES+) 489 (M+H)+, RT 2.48 minutes (Method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH2:15]2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(CC2CNCCN2)ccn1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CC2CN(S(=O)(=O)c3cccs3)CCN2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a 100-mL round-bottomed flask was added 2-((2-methoxy-4-pyridinyl)methyl)piperazine (350 mg, 1.69 mmol), triethylamine (0.353 mL, 2.54 mmol), and 2-thiophenesulfonyl chloride (0.34 mL, 1.86 mmol, Aldrich, St. Louis, Mo.) in DCM (5 mL). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (10 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc to give 3-((2-methoxy-4-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (198 mg) as colorless glass.
Reaction SMILES: NC1C=C(/C=C/[N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])C=C(C(F)(F)F)C=1.[H][H]>[Pd].C1COCC1>[C:15]1(=[O:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[NH:14]1
Reactant: Nc1cc(/C=C/N2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccccc21
Yield: 41.4 %

Procedure:
A slurry of 2-{(E)-2-[3-amino-5-(trifluoromethyl)phenyl]vinyl}-1H-isoindole-1,3(2H)-dione (1.99 g, 5.98 nunol) and Pd/C (0.20 g, 10% by weight) in ETOH (123 mL) and THF (88 mL) was allowed to stir under 50 psi of hydrogen at rt until reaction was judged to be complete. The mixture was filtered through Celite and concentrated. The residue was purified by column chromatography to give 2-12-[3-amino-5-(trifluoromethyl)phenyl]ethyl)-1H-isoindole-1,3(2H)-dione (365 mg, 16% yield). LCMS: (FA) ES+ 335.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc4ccccc34)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-napthalene-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)napthalene-ylmethyl-piperidine-4- carboxylic acid ethyl ester (6.3 g, 13 mmol) dissolved in methanol (30 mL), 10N sodium hydroxide (30 mL) and tetrahydrofuiran (30 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.3 g (36%). yellow solid mp 226-228° C., MS: 440.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1.[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:15][O:14][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cnc(Cl)nc1N1CCOCC1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cnc(-c2cccc([N+](=O)[O-])c2)nc1N1CCOCC1
Temperature: 80 °C
Yield: 39.9 %

Procedure:
A mixture of 4-(2-chloro-5-methoxy-pyrimidin-4-yl)-morpholine (0.2 g, 1.0 eq), 3-nitrophenyl boronic acid (0.17 g, 1.2 eq), (PPh3)4Pd (0.10 g, 0.1 eq) and 2 M Na2CO3 (1.3 ml, 3.0 eq) was heated at 80° C. and refluxed overnight. The solvent was removed in vacuo, and the residue was extracted with EA and water. The combined organic layers were washed with brine, dried and evaporated in vacuo. The crude was purified by chromatography to give a yellow solid (0.11 g, 39.97%).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[C:11]([N:15]=[N:16][C:17]([C:24]#[N:25])([CH3:23])[CH2:18][CH2:19][C:20](Cl)=[O:21])([CH3:14])([CH3:13])[CH3:12].O>CCOCC>[C:11]([N:15]=[N:16][C:17]([C:24]#[N:25])([CH3:23])[CH2:18][CH2:19][C:20]([O:4][CH2:1][CH:2]=[CH2:3])=[O:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CCO
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: C=CCOC(=O)CCC(C)(C#N)N=NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.32 g (0.040 m) of allyl alcohol and 10 ml of pyridine in 50 ml of ether cooled to 10° C. in a 250 ml 4 neck round bottom flask was added a solution of 10 g (0.0435 m) of 4-t-butylazo-4-cyanovaleryl chloride* in 10 ml ether. The acid chloride solution was added dropwise holding the reaction temperature below 20° C. After the addition was complete, the reaction was stirred an additional 2 hours at room temperature and poured into 100 ml water. The ether layer was separated, washed with 20 ml portions of 10% HCl, 10%, NaHCO3 and water. The ether solution was dried over anhydrous sodium sulfate, filtered and the ether evaporated off. The crude produce weighed 8.95 g (89%). The infrared spectra indicated there was a small amount of unreacted acid chloride present in the product. The crude product was purified by column chromatography over alumina using pentane as the eluent. The acid chloride did not come off the column. The pentane was evaporated off to leave the pure product.