Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.CO.C([O:13][C@@H:14]1[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@:17]([CH2:46][O:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)(=[O:50])=[O:49])([CH2:27][O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C@H:15]1[N:58]1[CH:65]=[C:64]([CH3:66])[C:62](=[O:63])[NH:61][C:59]1=[O:60])(=O)C>C(O)(=O)C>[CH2:20]([O:19][C@@H:18]1[C@@:17]([CH2:46][O:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)(=[O:49])=[O:50])([CH2:27][O:28][Si:29]([C:42]([CH3:44])([CH3:43])[CH3:45])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C@@H:15]([N:58]2[CH:65]=[C:64]([CH3:66])[C:62](=[O:63])[NH:61][C:59]2=[O:60])[C@@H:14]1[OH:13])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)O[C@H]1[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(COS(=O)(=O)c2ccc(C)cc2)[C@H]1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OC[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.9 %

Procedure:
Potassium carbonate (12.75 mg, 0.0923 mmol) and water (0.5 ml) were added, under cooling with ice, to a methyl alcohol solution (4 ml) of Compound 35 (250 mg, 0.308 mmol), and the mixture was stirred for 22 hours at room temperature. Under cooling with ice, acetic acid was added to the reaction mixture to neutralize it, whereafter the solvent was distilled off under reduced pressure. After water was added to the residue, the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and then the resulting crude product was purified by silica gel column chromatography (AcOEt-hexane, 3:2) to obtain a white powder, Compound 36 (216.7 mg, 0.283 mmol, 92%). mp. 74-77° C. [α]D23 +5.15° (c=1.23, CHCl3). IR ν max (KBr): 3048, 2934, 1695, 1363, 1181, 1108, 977, 819, 704 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCOc1ccc(F)cc1
Temperature: 50 °C
Yield: 95.4 %

Procedure:
To a solution of 4-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) is added potassium carbonate (828 mg, 6.0 mmol) followed by chloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture is stirred and heated at 50° C. for 14 h. The reaction mixture is cooled to RT, diluted with EtOAc, and washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane gives 721 mg of the product 388.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH3:3].COC(C1C=NC(Cl)=C(Br)N=1)=O.[F:31][C:32]1[CH:37]=CC(CO)=[CH:34][CH:33]=1.N1CCCC1.[OH-].[K+]>>[F:31][C:32]1[CH:33]=[CH:34][C:2]([CH2:1][O:4][C:5]2[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=2[N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:37]=1
Reactant: OCc1ccc(F)cc1
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Agent: COC(=O)c1cnc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNC1
Product: O=C(O)c1cnc(N2CCCC2)c(OCc2ccc(F)cc2)n1
Yield: 13 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, (4-fluoro-phenyl)-methanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 13% yield. m/z (ES+): 318.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C.C(Cl)[Cl:27]>C(O)(C)C>[ClH:27].[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH3:2]
Reactant: ClCCl
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1OC
Solvent: CC(C)O
Product: CCOC(=O)Cn1c(-c2ccccc2OC)nc2cccnc21
Product: Cl
Reaction time: 0.03 h
Yield: 11 %

Procedure:
Solid N-[3-[(2-methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester, 13.75 g (0.042 mole) was heated in glass in a Wood's metal bath at 210°-20° C. for 2 minutes, then at 215°-20° C. for 2 minutes. The residue was dissolved in methylene chloride, treated with activated charcoal, and filtered through a Celite pad. The filtrate (dark orange) was treated with Florisil® to give a dark filtrate, which was evaporated to give an oil. The oil was dissolved in isopropyl alcohol, filtered and the filtrate acidified with methanolic hydrogen chloride and diluted with isopropyl ether. The crystalline crop was collected, washed with isopropyl etherisopropyl alcohol (minimum), and dried under high vacuum at room temperature overnight to give 1.6 g (11%) of title compound, mp 177°-80° C.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][C:28]#[N:29])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(O)(C(F)(F)F)=O.C(Cl)Cl.CO.[OH-].[NH4+]>>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]3[CH2:22][CH2:23][C@H:24]([CH2:27][C:28]#[N:29])[CH2:25][CH2:26]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CC#N)CC4)c3)ncnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#CC[C@H]1CC[C@@H](n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile (0.080 g, 0.00018 mol) and TFA (0.50 mL, 0.0065 mol) were added to DCM (3.00 mL, 0.0468 mol) and the mixture was stirred at 25° C. for 16 hours. The reaction was concentrated by roto-evaporation and the concentrate was dissolved in methanol (3.0 mL, 0.074 mol) and ammonium hydroxide (0.5 mL, 0.01 mol) was added. This reaction was stirred at 25° C. for 6 hours at which time LCMS analysis showed no starting material present. The reaction was chromatographed on silica gel using 5% MeOH/EtOAc to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C@H:50]([NH2:52])[CH3:51]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:52][C@@H:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[O:43][CH3:42])[CH3:51])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1ccccc1[C@@H](C)N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccccc4OC)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 121.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1R)-1-(2-methoxyphenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (64 mg, yield 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[Cl-].[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:39]COC)=[C:17]([CH:38]=1)[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:18][C:17]2[CH:38]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=2[OH:39])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: COCOc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Oc1ccc(F)cc1CCc1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
610 mg of 3,4-difluorobenzaldehyde, 2000 mg of 5-fluoro-2-methoxymethoxybenzyltriphenylphosphonium chloride and 0.64 ml of DBU were allowed to react together in 20 ml of acetonitrile, subsequently treated, and purified by silica gel column chromatography, using a 15:1 by volume mixture of hexane and ethyl acetate as the eluent, in the same manner as described in Preparation 2, to give 1230 mg of an oily substance. This oily substance was dissolved in 10 ml of ethanol, and 300 mg of tris-(triphenylphosphine)rhodium(I) chloride were added to the resulting solution. The resulting mixture was then stirred under a hydrogen atmosphere at atmospheric pressure and at 60° C. for 14 hours. At the end of this time, the reaction solution was filtered with a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and allowed to adsorb on a silica gel column for some time. The filtrate was then allowed to elute slowly, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give an eluate containing the title compound. This eluate was concentrated by evaporation under reduced pressure, and dried in vacuo, to give 1010 mg (yield 93%) of the title compound as a solid substance.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[CH2:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.Cl>C(COC)OC>[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[C:10](=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: CC1=CC(C(C)(C)C)=CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(C)cc1)c1ccc(C)cc1

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.56 g of powdery potassium hydroxide (27.8 mmol) and 100 ml of dehydrated dimethoxy ethane were added in a nitrogen atmosphere. To the suspension, 2.46 g of 3-tert-butyl-1-methyl-cyclopentadiene (18.0 mmol) was gradually added dropwise at room temperature and stirred under reflux for 2 hr. To the reaction solution, a solution prepared by dissolving 3.99 g of 4,4′-dimethylbenzophenone (19.0 mmol) in 40 ml of dehydrated dimethoxy ethane was gradually added and stirred under reflux for 3 days. To the reaction mixture, 50 ml of a hydrochloric acid aqueous solution (1N) was gradually added dropwise in an ice bath, and stirred at room temperature for some time. The organic phase was separated by adding diethyl ether and washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, and thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a dark red liquid. The liquid was purified by a column chromatography using 170 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 2.55 g (7.76 mmol) as a red solid (yield: 43%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1.O>CN(C)C=O>[CH3:37][O:36][C:33]1[N:34]=[CH:35][C:30]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:31][N:32]=1
Reactant: COc1ncc(CCl)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a stirred solution of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.28 g, 1.0 mmol) in dry N,N-dimethylformamide (6 mL) was added cesium carbonate (2.30 g, 7.1 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 30 min, and 5-(chloromethyl)-2-methoxypyrimidine (0.34 g, 2.1 mmol) in dry N,N-dimethylformamide (3 mL) was added dropwise. The mixture was stirred at ambient temperature for 16 h, and additional cesium carbonate (0.68 g, 2.1 mmol) and 5-(chloromethyl)-2-methoxypyrimidine (0.20 g, 1.3 mmol) were added. The mixture was stirred at ambient temperature for 64 h. Water (60 mL) was added and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 1:1) to afford 1′-[(2-methoxypyrimidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.29 g, 73%) as a colorless solid: mp 203-204° C.; 1H NMR (300 MHz, CDCl3) δ8.57 (s, 2H), 7.30-7.23 (m, 1H), 7.22-7.17 (m, 1H), 7.11-7.04 (m, 1H), 6.86-6.81 (m, 1H), 6.44-6.41 (m, 2H), 4.89 (ABq, 2H), 4.81 (ABq, 2H), 4.59-4.50 (m, 2H), 4.01 (s, 3H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 165.4, 161.9, 161.3, 158.8, 141.1, 132.7, 128.8, 124.3, 123.9, 122.8, 120.1, 119.7, 118.7, 108.5, 93.3, 80.5, 72.4, 57.6, 55.1, 38.8, 29.0; MS (ES+) m/z 402.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:22]([Cl:23])=[C:21]([Cl:24])[C:20]([Cl:25])=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:27])[CH3:2].[CH2:28]([N:30]([CH2:42][CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH3:29]>C(OC(=O)C)(=O)C>[CH2:38]([N:37]([CH2:40][CH3:41])[C:33]1[CH:32]=[C:31]([N:30]([CH2:28][CH3:29])[CH2:42][CH3:43])[CH:36]=[CH:35][C:34]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:18])[O:17]1)[CH3:39]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1

Procedure:
Following a procedure similar to that described in part B of Example 2 above, 4.45 g (0.01 mole) of 2-(1-ethyl-2-methyl-3-indolyl)carbonyl-3,4,5,6-tetrachlorobenzoic acid and 2.20 g (0.01 mole) of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted in the presence of ten ml of acetic anhydride to obtain 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)4,5,6,7-tetrachlorophthalide (Formula III: R0 =R1 =R2 =R3 =Cl; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; Y1 =H) melting at 100°-103° C. and showing a significant infrared absorption maxima at 1770 cm-1 (C=O; s). A toluene solution of this compound developed an intense blue color when spotted on silica gel.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][CH:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[S:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH3:11].[OH2:29]>>[CH3:11][CH:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[S:21]([CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)(=[O:2])=[O:29])[CH3:9]
Reactant: CC(C)c1ccc2[nH]cc(SC3CCN(C)CC3)c2c1
Reactant: O
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Product: CC(C)c1ccc2[nH]cc(S(=O)(=O)C3CCN(C)CC3)c2c1
Reaction time: 4 h

Procedure:
A solution of potassium peroxymonosulfate (49.5% KHSO5, 21.2 g) in water (95 ml) is added drop-wise at 0° C. to a methanolic solution (95 ml) of 5-(1-methylethyl)-3-[(1-methylpiperidin-4-yl)thio]-1H-indole (7.5 g, prepared in Example 43). After 4 hours at room temperature, the white precipitate is filtered off and the filtrate is concentrated, rendered basic with sodium carbonate and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. 5-(1-Methylethyl)-3-[(1-methylpiperidin-4-yl)sulfonyl]-1H-indole (2.4 g) is obtained after purification on silica gel (eluent: CH2Cl2 /iPrNH2 95/5).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26].CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([NH:8][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: CCC(=O)Cl
Reactant: N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate (0.304 g, 1.0 mmol) in THF (10 mL) is treated with DIPEA (0.387 g, 3.0 mmol) followed by propionyl chloride (0.093 g, 1.0 mmol). After stirring at room temperature for 2 hours, the solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA). MS (ES+) m/e 360 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH:30]1([CH:33]=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClCCCl>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][CH2:33][CH:30]2[CH2:32][CH2:31]2)[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CC1CC1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(Cn2cc(-c3ccc4[nH]nc(NCC5CC5)c4c3)nn2)cc1
Reaction time: 16 h

Procedure:
A mixture of Example 64A (100 mg, 0.256 mmol), cyclopropanecarbaldehyde (0.057 mL, 0.76 mmol), sodium triacetoxyborohydride (163 mg, 0.76 mmol) and acetic acid (0.044 mL, 0.76 mmol) in 1,2-dichloroethane (5 mL) was stirred at ambient temperature for about 2.5 hours. Hydrochloric acid (4 N in dioxane, 4 mL) was added and the reaction mixture was stirred for about 16 hours. The precipitate was collected by filtration, rinsing with ether (10 mL). The solid was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (0.1 mL) and the reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was neutralized by the addition of 15% aqueous sodium hydroxide solution (about 15 mL) and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.32-7.45 (m, 5H), 7.26 (d, J=8.6 Hz, 1H), 6.08 (t, J=5.7 Hz, 1H), 5.64 (s, 2H), 3.12 (t, J=6.2 Hz, 2H), 1.04-1.22 (m, 1H), 0.35-0.53 (m, 2H), 0.17-0.32 (m, 2H). MS (ESI+) m/z 345 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([C:17]#[C:18]/[CH:19]=[CH:20]/[C:21]([OH:23])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>O>[OH:29][NH:28][C:21](=[O:23])/[CH:20]=[CH:19]/[C:18]#[C:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:8](=[O:10])(=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: O=C(O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1)NO
Reaction time: 0.17 h

Procedure:
To a solution of (E)-5-(3-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid (56a) (0.25 g 0.77 mmol) in methylene chloride (5 ml) oxalyl chloride (0.42 g 3.1 mmol) was added. The resultant mixture was stirred for 1 hour at ambient temperature and the solvents were removed under reduced pressure. The crude product (57a) was dissolved in acetonitrile (5 ml) and the obtained solution to a mixture of hydroxylamine hydrochloride (0.3 g, 4.3 mmol) and NaHCO3 (0.3 g, 3.6 mmol) in water (8 ml) was added. The reaction mixture was stirred for 10 min. and the product was extracted with ethyl acetate (30 ml). The extract was washed with 10% Na2CO3, and the aqueous phase was acidified with 3% HCl. The precipitate was filtered and dried to give the title compound (0.12 g, (46%). M.p 88-90° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.41 (1H, d, J=15.8 Hz, CH); 6.82 (1H, d, J=15.8 Hz, CH); 6.92-7.41 (5H, m, C6H5); 7.47-8.01 (4H, m, C6H4); 8.94-11.21 (3H, br s, NH, NH, OH). Anal. Calcd for C17H14N2O4S* 0.4H2O: C, 58.58; H, 4.27; N, 8.01. Found: C, 58.12; H, 4.03; N, 7.80.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=2[O:10]1>>[O:17]1[C:16]2[CH:15]=[CH:14][C:13]([C:2]3[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=3)=[CH:12][C:11]=2[O:10][CH2:9]1
Reactant: O=C1C=C(Br)CCC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=C1C=C(c2ccc3c(c2)OCO3)CCC1
Yield: 85 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 3,4-methylenedioxyphenylboronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 80% ethyl acetate/hexanes) yielded the product (164 mg, 85%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.07-7.00 (m, 2H), 6.81 (d, J=8.0 Hz, 2H), 6.31 (s, 1H), 5.99 (s, 2H), 2.70 (t, J=5.5 Hz, 2H), 2.45 (t, J=6.3 Hz, 2H), 2.12 (quintet, J=6.3 Hz, 2H). 13C (75 MHz, CDCl3): 199.7, 159.0, 149.2, 148.2, 132.8, 124.2, 120.7, 108.4, 106.3, 101.6, 37.4, 28.3, 23.0. LCMS (ESI): mass calcd for (C13H12O3) m/z 216.08; measured [M+H]+: m/z 216.95.
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[CH3:20][O:19][C:12]1[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: COc1cc2c(cc1S(C)(=O)=O)CCN(C(C)=O)CC2
Agent: Cl
Product: COc1cc2c(cc1S(C)(=O)=O)CCNCC2

Procedure:
Alternatively, 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine was treated with 3N hydrochloric acid to give 8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 228.5°-229.5°. Refluxing this compound with 48% hydrobromic acid gave 8-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.