Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[OH-].[NH4+:24].[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH2:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: [NH4+]
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O
Reaction time: 0.58 h

Procedure:
58 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid [prepared as described in step (1) aboveπ were dissolved in 850 ml of dry tetrahydrofuran, and then 38.2 ml of triethylamine were added to the mixture at -15° to -20° C. A solution of 26.3 ml of ethyl chloroformate in 240 ml of dry tetrahydrofuran was then added dropwise to the mixture at -15° to -20° C., and the mixture was stirred at the same temperature for 35 minutes. At the end of this time, 258 ml of 28% w/v aqueous ammonium hydroxide were added to the mixture at -15° to -20° C., and the mixture was allowed to stand overnight at room temperature. Ammonium chloride was then added to the reaction mixture, which was then extracted with tetrahydrofuran. The extract was dried and freed from the solvent by distillation under reduced pressure. The resulting residue was triturated with diethyl ether to cause crystallization. The crystals were collected by filtration and washed with diethyl ether to afford 49.7 g of the title compound as colorless crystals, melting at 146°-148° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>>[OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(O)c1
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 2-hydroxy-4-methylbenzoic acid (20.0 g, 0.132 mol) in methanol (200 ml) was cooled in an ice bath. Concentrated, H2SO4 (20 ml) was added cautiously and the reaction heated to reflux and held at reflux for 48 hours. The reaction was allowed to cool to ambient temperature, the solvent evaporated and the residue purified by chromatography (eluant: CH2Cl2) to give methyl 2-hydroxy-4-methylbenzoate (19.76 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][CH2:6][CH2:5]2.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][N:24]=1.C(N(CC)CC)C.O>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:12])[F:13])[N:7]([C:30](=[O:31])[NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[N:24][CH:25]=1)[CH2:6][CH2:5]2
Reactant: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCC2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(OCc3ccccn3)nc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of indoline (D13, 0.30 g, 1.49 mmol), phenylcarbamate (D3, 0.48 g, 1.5 mmol) and triethylamine (0.20 ml, 1.5 mmol) in dry acetonitrile (10 mL) was warmed briefly to ensure complete solution of reactants, then stirred overnight at room temperature. The mixture was poured into water (50 ml) and the precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel (25 g) eluted with 4% methanol/dichloromethane. Eluted product was recrystallised from dichloromethane/methanol to give the title compound (0.35 g, 55%), m.p. 219-20° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH2:25])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.[OH-].[K+].[C:28](=S)=[S:29]>CCO.O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][O:5][C:4]3[CH:22]=[CH:23][C:24]4=[N:25][C:28](=[S:29])[N:1]=[C:2]4[CH:3]=3)[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: S=C=S
Reactant: Nc1ccc(OCCN2CCC(Cc3ccc(Cl)cc3)CC2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: S=C1N=c2ccc(OCCN3CCC(Cc4ccc(Cl)cc4)CC3)cc2=N1
Yield: 87.2 %

Procedure:
From a mixture of 1-[2-(3,4-diaminophenoxy)ethyl]-4-(4-chlorobenzyl)piperidine (1.30 g, 3.67 mmol), KOH (240 mg, 4.28 mmol) and CS2 (250 μL, 4.16 mmol) in EtOH (5 mL) and water (0.8 mL) was obtained 1.28 g (88%) of the title compound as a foam solid. 1H NMR (CDCl3): 1.38-1.68 (m, 5H), 2.09-2.17 (m, 2H), 2.481 (d, 2H, J=6.5), 2.851 (t, 2H, J=4.5), 3.18-3.21 (m, 2H), 4.142 (t, 2H, J=4.5), 6.561 (bs, 1H), 6.596 (d, 1H, J=8.5), 6.936 (d, 1H, J=8.5), 7.036 (d, 2H, J=8), 7.029 (d, 2H, J=8). 1H NMR (DMSO-d6): 12.360 (s, 1H), 12.402 (s, 1H). The hydrochloride, mp. 291-3° C. Analysis, Calcd. for C21H25ClN3OS: C 57.53, H 5.75, N 9.58; Found: C 57.82, H 5.65, N 9.44.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C1COCC1.CN(C=O)C>[CH:22]([NH:25][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)([CH3:24])[CH3:23]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CC(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.8 %

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Isopropylamine (511 μL, 6 mmol) was then added into the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography: SiO2, CH2Cl2/AcOEt 95:5 to give a white solid (167 mg, 58%). NMR 1H (ppm, CDCl3): 7.96 (s, 1H), 7.69 (d, J3=7.68 Hz, 2H), 7.59 (d, J3=7.14 Hz, 2H), 7.50-7.33 (m, 4H), 5.93 (br. s., 1H), 4.14 (oct., J3=6.66 Hz, 1H), 1.27 (d, J=6.43 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[NH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:13]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1cc(C)c2oc(S)nc2c1
Reactant: C1CCNCCNC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2oc(N3CCCCNCC3)nc2c1
Yield: 171.8 %

Procedure:
5,7-Dimethyl-2-mercapto-benzoxazole (109 mg) was dissolved in toluene (6 ml), and the solution was mixed with 1,4-diazacyclooctane (1.93 g) which has been obtained in accordance with the method described in Carib. J. Sci., 14, 77 (1974) and then stirred with heating for 3 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=5:1) to obtain the title compound 5,7-dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole (271 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])=[O:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:36][OH:37].C(O)C>O>[CH:20]1([N:13]([CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[C:3]([C:1](=[NH:2])[NH:36][OH:37])[CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NO
Reactant: COC(CN(C(=O)CCOCCc1cccc(C#N)c1)C1CCCCC1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(CN(C(=O)CCOCCc1cccc(C(=N)NO)c1)C1CCCCC1)OC
Temperature: 90 °C
Reaction time: 72 h

Procedure:
To 3-(3-cyanophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide [Example 10, Step i)] (1.5 g) within a 35 mL microwave vial was added potassium carbonate (0.80 g), hydroxylamine hydrochloride (0.402 g), water (2.5 mL) and ethanol (10 mL). The vial was sealed and stirred for 3 days before being heated at 90° C. for a total of 3 h. The reaction was diluted with water, extracted twice with ethyl acetate, which was pooled and washed twice with water, twice with brine, dried over sodium sulphate, filtered and the solvent removed to afford a colourless gum (1.7 g). This material was used in the next step directly.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[CH:24]=[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Nc2ccc(CNc3nc4ccccc4[nH]3)cc2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cc(Nc2ccc(CNc3nc4ccccc4[nH]3)cc2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
235 mg (1H-Benzoimidazol-2-yl)-[4-(6-chloro-pyrimidin-4-ylamino)-benzyl]-amine (prepared in Example 86) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water were added. The mixture was refluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (125 mg, 44% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](Cl)=[O:23])=[CH:14]1>>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]([O:1][CH2:2][CH:3]2[CH2:12][CH2:11][N:10]3[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:4]2)=[O:23])=[CH:14]1
Reactant: OCC1CCN2CCCCC2C1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Product: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12

Procedure:
eq-2-Hydroxymethylquinolizidine (N. J. Leonard et al., J. Org. Chem., 1957, 22, 1445) was reacted with indole-3-carboxylic acid chloride using the method described in Example 1 a to afford eq-quinolizidin-2-ylmethyl 1-H-indole-3-carboxylate mp 154-157° C.
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][N:17]([C:12]1[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:37][C:34]4[CH:35]=[CH:36][C:31]([CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:32][CH:33]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(Nc5cccnc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(3-{2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (49.0 mg, 0.258 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.029 g, 27%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.09 (dd, J=4.6, 1.4 Hz, 1H), 8.07 (d, J=6.9 Hz, 1H), 7.79 (dd, J=8.2, 1.3 Hz, 1H), 7.57 (s, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.28-7.24 (m, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.13 (d, J=7.6 Hz, 1H), 6.82 (s, 1H), 6.76 (t, J=7.0 Hz, 1H), 3.33 (s, 3H), 3.01-2.94 (m, 2H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.87-1.74 (m, 4H). MS=507 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[C:8](=[O:13])[CH:9]([CH3:12])[CH2:10][CH3:11].[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl.C(Cl)(Cl)Cl>N1C=CC=CC=1.C(Cl)Cl.C(OCC)C>[CH2:15]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([O:14][C:4]3[CH:5]=[CH:6][C:7]([C:8](=[O:13])[CH:9]([CH3:12])[CH2:10][CH3:11])=[C:2]([OH:1])[CH:3]=3)=[O:35])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCC(C)C(=O)c1ccc(O)cc1O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)C(C)CC)c(O)c3)cc2)cc1
Yield: 7.8 %

Procedure:
0.5 g of 3-hydroxy-4-(1-oxo-2-methylbutyl)phenol prepared by the process described in (1) was dissolved in 15 ml of anhydrous pyridine, to which added was a solution of 0.7 g of 4-(4'-octyloxyphenyl)benzoic acid chloride dissolved in 20 ml of anhydrous methylene chloride dropwisely over a period of about one hour under stirring. The reaction mixture was stirred at the room temperature for additional 40 hours to proceed the reaction. Then, the reaction mixture was added to 300 ml of dilute hydrochloric acid solution. After adding 50 ml of chloroform and 50 ml of ethyl ether, followed by shaking, the organic phase was separated from the aqueous phase. The organic phase was rinsed with a dilute hydrochloric acid solution for two times, rinsed with an aqueous solution of NaHCO3 for one time, and then rinsed with a 3% aqueous solution of NaCl for three times. Anhydrous Na2SO4 was added to the organic phase to dry the same. After removing the drying agent by filtration, the solvent was distilled off to obtain a crude product which was refined through silica gel column chromatography while using chlorofrom as the eluent. The thus obtained product was recrystallized from a mixed solvent composed of 10 parts by volume of chloroform and 90 parts by volume of n-hexane. As a result, 0.08 g of 3-hydroxy-4-(1-oxo-2-methylbutyl)phenyl 4-(4'-octyloxyphenyl)benzoate was obtained.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:16][CH2:2][CH2:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C1c2ccccc2CN1CCO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCl
Temperature: 20 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
To a solution of 2-(2-hydroxyethyl)isoindolinone (1.0 g, 5.64 mmol) in toluene (3.5 mL) was added thionyl chloride (1.34 g, 11.3 mmol). The reaction mixture was stirred at 20° C. for 3 h then 4 h at 60° C. The reaction mixture was concentrated in vacuo to remove excess thionyl chloride and toluene. 2-(2-Chloroethyl)isoindolinone (1.01 g, 92%) was obtained by flash chromatography on a silica gel column by elution with EtOAc/Hexanes a white solid. 1H NMR (CDCl3, 300 MHz) δ3.81 (t, 2H, J=5.5 Hz), 3.97 (t, 2H, J=5.9 Hz), 4.59 (s, 2H), 7.44-7.58 (m, 3H), 7.86 (d, 1H, J=6.9 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH:28]3[CH:26]([C:27]3([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:30]#[N:31])[CH2:25]2)=[CH:4][CH:3]=1.[OH:38]S(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:25][CH:26]3[CH:28]([C:27]3([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:30]([NH2:31])=[O:38])[CH2:29]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(N2CCOCC2)C2CN(c3ncnc4c3nc(-c3ccccc3Cl)n4-c3ccc(Cl)cc3)CC21
Product: NC(=O)C1(N2CCOCC2)C2CN(c3ncnc4c3nc(-c3ccccc3Cl)n4-c3ccc(Cl)cc3)CC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-6-morpholin-4-yl-3-azabicyclo[3.1.0]hexane-6-carbonitrile 29A-8 (28 mg, 0.052 mmol) in concentrated H2SO4 (0.6 ml) was heated at 200° C. for two hours. After the reaction mixture was allowed to cool to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with 5 M aqueous NaOH to pH 11. The mixture was extracted with ethyl acetate and then the combined organic layers were washed with brine, dried (MgSO4) and concentrated, in vacuo. The residue was purified on a Biotage™ Flash 12S column using 0–6% methanol in methylene chloride as eluant to give, after trituration from methylene chloride/hexanes, title compound 30A-1 (24 mg, 83%): +ESI MS (M+1) 550.4; 1H NMR (400 MHz, CD2Cl2) δ 8.27 (s, 1H), 7.52–7.49 (m, 1H), 7.44–7.32 (m, 5H), 7.20 (d, J=8.7 Hz, 2H), 5.54 (s, 1H), 5.47 (s, 1H), 5.03 (d, J=12.0 Hz, 1H), 4.37 (d, J=12.0 Hz, 1H), 3.97 (br d, J=9.1 Hz, 1H), 3.68–3.55 (m, 5H), 2.73–2.63 (m, 4H), 2.01 (br s, 1H), 1.96 (br s, 1H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][OH:20])[CH2:3]1.C(N(CC)CC)C.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:3]1
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of benzyl (1S,2R,4R)-4-hydroxy-2-(hydroxymethyl)cyclohexylcarbamate (8.78 g, 31.42 mMol) was dissolved in anhydrous CH2Cl2 prior to the addition of triethylamine (11 mL, 78.55 mMol) followed by DMAP (0.05 g) and then trityl chloride (10.52 g, 37.7 mMol) in one portion. The reaction mixture was stirred at rt overnight. The reaction was partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried (MgSO4), filtered, concentrated and chromatographed. Benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate was obtained as a white foamy solid (9.85 g, yield=60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:37]1C(C)=CC=C[C:38]=1C.CN.O1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](=[O:23])[NH:37][CH3:38])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, a 2.0 M solution of methylamine in tetrahydrofuran (121 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-methylcarbamoylmethyl-1H-pyrazol-3-yl)-propionamide (28 mg, 28%) as a white solid: ESI-LRMS m/e calculated for C21H27ClN4O4S [M+] 466.1, found 467.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.24 (m, 2H, CH2), 1.43-1.97 (m, 8H, 4×CH2), 2.18-2.29 (m, 1H, CH), 2.78 (d, J=4.9 Hz, 3H, NCH3), 3.27 (s, 3H, SO2CH3), 3.60 (t, J=7.5 Hz, 1H, CH), 4.67 (s, 2H, NCH2), 5.83-5.91 (m, 1H, NH), 6.77 (d, J=2.4 Hz, 1H, Ar), 7.33 (d, J=2.4 Hz, 1H, Ar), 7.49 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.06 (s, 1H, NH), 8.11 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:27][C:28]([OH:30])=[O:29])=[C:13]([CH3:26])[C:14]2=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[O:31][CH3:32].CC(C)=[O:35]>O.CO>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:27][C:28]([OH:30])=[O:29])=[C:13]([CH3:26])[C:14]2=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:25])=[O:35])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[O:31][CH3:32]
Reactant: CC(C)=O
Reactant: COc1cc2c(cc1F)C(=Cc1ccc(SC)cc1)C(C)=C2CC(=O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1F)C(=Cc1ccc(S(C)=O)cc1)C(C)=C2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium periodate, 4.28 g (20 mol) in 40 ml of water is added dropwise to 6-fluoro-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid, 3.70 g (10 mmol) in 300 ml methanol and enough acetone to cause solution. This solution is stirred overnight at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, and is cooled. Collected crystals are washed with water and methanol-water (1:1). The product is dried in vacuo over potassium hydroxide pellets and then in a vacuum oven at 70° C. The crude product is recrystallized from methylene chloride-petroleum ether to give 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinyl-benzylidene)-3-indenylacetic acid (m.p. 190°-193°). 6-fluoro-5-methoxy -2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid is prepared according to the procedure of Example 1, part G by the addition of 1.0 mol of m-chloroperbenzoic acid per mol of 6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl acetic acid in an acetone solution.