Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH:13]([C:36]([O:38][CH3:39])=[O:37])[CH2:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.[ClH:40]>ClCCl>[ClH:40].[NH2:8][CH2:9][C:10]([NH:12][CH:13]([C:36]([O:38][CH3:39])=[O:37])[CH2:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)=[O:11]
Reactant: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)CN
Yield: 78.8 %

Procedure:
A solution of 5-[4-(4-(2-(2-t-butoxycarbonylaminoacetamido)-2-methoxycarbonylethyl) phenoxy)benzyl]thiazolidin-2,4-dione (0.73 g, 1.31 mmol) in dichloromethane (30 ml) was bubbled with HCl gas at −10° C. for 1.25 h. The excess HCl gas was removed by N2 bubbling and the solvent was removed by distillation to provide the title compound (0.51 g, yield 78.8%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3([CH3:15])[C:11](=[CH:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[H-].[Na+].[CH3:20]I.O>C(COC)OC>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3([CH3:15])[C:11](=[CH:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH3:20])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CI
Reactant: CC12CCC(=O)NC1=CCc1cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1C(=O)CCC2(C)C1=CCc1cc(F)ccc12
Temperature: 25 °C
Yield: 56 %

Procedure:
8-fluoro 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (1.38 g; 6mmol) was added to a suspension of NaH (475 mg; 20 mmol) in glyme (15 ml). The mixture was refluxed for 1.5 hours and cooled quickly to room temperature. Methyl iodide (15 ml) was added and the mixture refluxed for 4 hours, then allowed to cool to room temperature. After addition of water, the mixture was concentrated to near dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed three times with water, dried over MgSO4 and concentrated under vacuum. Recrystallization from hexane afforded 737 mg (56% yield) of the subtitle compound. Melting point 110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:26])(=[O:25])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:4].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:22][CH2:23]2)=[CH:16][CH:17]=1)(=[O:25])=[O:26])=[O:4]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from 3-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-thiophene-2-carboxylic acid methyl ester (which was obtained in Example 234) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.70-1.90 (m, 2H), 2.50-2.75 (m, 5H), 3.40-3.55 (m, 2H), 3.89 (s, 2H), 4.46 (dd, J=8.0, 4.2 Hz, 1H), 6.75-6.85 (m, 3H), 6.90 (d, J=9.0 Hz, 2H), 7.00 (dd, J=8.3, 2.0 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.32 (d, J=3.3 Hz, 1H), 7.89 (d, J=3.3 Hz, 1H); MS (ES) m/z: 624.9 (MH+); HRMS Calcd. for C26H34N4O8S3 (MH+): 625.1455. Found: 625.1441.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1.[Cl:15]C1C=CC(N)=C(C)C=1>>[Cl:15][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: Cc1cc(F)ccc1N1CCNCC1
Product: Cc1cc(Cl)ccc1N1CCNCC1
Yield: 73 %

Procedure:
The title compound was prepared following the method described for the Compound 31A of Example 31 but starting from 4-chloro-2-methylaniline instead of 4-fluoro-2-methylaniline. Purification by flash chromatography (chloroform-2N ammonia in methanol 100:3 to 100:5) afforded the title compound (73%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C.BrBr>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Br)cc2)=NN1
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(Br)cc2)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 86.3 g of 6-(p-bromophenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Example 5 of U.S. Pat. No. 3,689,652) in 500 ml. of glacial acetic acid is heated to 80° C. with continuous stirring. A solution of 60 g. (19.2 ml) of bromine in 80 ml. of acetic acid is added dropwise at 75°-80° C. over a period of 1 hour. The mixture is heated with stirring on a steam bath for 1/2 hour more and then poured into 3 liters of cracked ice and water. The white solid is collected by filtration and air dried, yielding 6-(p-bromophenyl)-3(2H)-pyridazinone.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][C:13](OCC)=[O:14])[CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CCOCC>[OH:14][CH2:13][CH2:12][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CCOC(=O)CCc1cnc2ccccc2c1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCCCc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a cooled (0° C.) solution of ethyl 3-(3-quinolyl)propionate (1.01 g, 4.4 mmol) in 20 ml of ether was added 2.6 ml (2.6 mmol) of 1M LAH solution at 0° C. After stirring at 0° C. for 15 min, the mixture was allowed to warm and stirred at 20° C. for 3 h, and Rochelle salt (equiv) was added. The mixture was extracted with methylene chloride, and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica (10 cm column, ethyl acetete/hexane, 1/2-5/1; methylene chloride/acetone, 2/1-1/4) to afford 700 mg (85%) of 3-(3-hydroxypropyl)quinoline, as a thick oil. 3-[3-[4-(5-Trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-quinoline (I, Q=3-quinolyl Y=1,3-propylene, R1, R2 =3,5-dimethyl, R3 =5-trifluoromethyl-1,2,4-oxadiazol-3-yl)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:25]([O:27][CH3:28])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl.C(=O)=O>CO>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:25]([O:27][CH3:28])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C=O
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1

Procedure:
1.6 g of Z-His-Lys(Boc)-OMe [S. Guttman et al., Helv. Chim. Acta 52, 1789 (1969)] are dissolved in 33 ml of MeOH, 3 ml of 1N HCl and 160 mg of Pd-on-carbon (10% pd) are added thereto, and hydrogenation is carried out with CO2 -absorption until saturation. After filtering off the catalyst, the whole is concentrated, the oily residue is dissolved in 20 ml of DMF and again concentrated to approximately 10 ml, yielding H-His-Lys(Boc)-OMe in the form of a solution which is immediately further processed in stage 2.2.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[NH:87]1[C:91]([CH2:92][C:93]([OH:95])=O)=[N:90][N:89]=[N:88]1>>[NH:87]1[C:91]([CH2:92][C:93]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:95])=[N:90][N:89]=[N:88]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)Cc1nnn[nH]1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3nnn[nH]3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (1H-tetrazol-5-yl)-acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 640.5 (M+H)+, 1.58 min (method 6). 1H NMR (500 MHz, METHANOL-d4) δ=7.95 (d, J=8.2 Hz, 2H), 7.48 (s, 1H), 7.25 (d, J=8.2 Hz, 2H), 5.33 (dd, J=1.5, 6.1 Hz, 1H), 4.82 (d, J=1.8 Hz, 1H), 4.68 (s, 1H), 4.12-4.00 (m, 2H), 2.79 (dt, J=5.0, 11.2 Hz, 1H), 2.72-2.62 (m, 1H), 2.45-2.35 (m, 1H), 2.19 (dd, J=6.4, 17.1 Hz, 1H), 2.07-1.92 (m, 2H), 1.84 (d, J=11.6 Hz, 1H), 1.77 (br. s., 1H), 1.76 (s, 3H), 1.73 (d, J=7.3 Hz, 1H), 1.66-1.56 (m, 3H), 1.56-1.49 (m, 4H), 1.48-1.27 (m, 6H), 1.23-1.15 (m, 1H), 1.12 (s, 3H), 1.08 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:32][C:31](=[O:34])[NH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:7]2[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH2:29][CH2:28]1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)NC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)NC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C
Yield: 41.5 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.17 mmol, from Example 47, Step 2), methyl piperidin-4-ylcarbamate hydrochloride (0.028 g, 0.14 mmol), palladium acetate (0.64 mg, 0.0029 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.7 mg, 0.0043 mmol), and cesium carbonate (0.18 g, 0.55 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4, evaporated and then purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (21 mg, 40%). LCMS calculated for C18H21ClN3O3 (M+H)+: m/z=362.1; Found: 362.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28]CC3C=CC=CC=3)=[CH:24][CH:23]=2)=[O:20])=[CH:13][N:12]=1)=[O:10].C(OCC)(=O)C>[Pd].CO>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:20])=[CH:13][N:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1ccc(CN(CCCCCN2CCOCC2)C(=O)Nc2ccc(OCc3ccccc3)cc2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1NC(=O)c1ccc(CN(CCCCCN2CCOCC2)C(=O)Nc2ccc(O)cc2)cn1
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, 10% palladium on carbon (30 mg) was added to a solution of N-(2-aminophenyl)-5-[3-(4-benzyloxyphenyl)-1-[5-(morpholin-4-yl)pentyl]ureidomethyl]pyridine-2-carboxylic acid amide (Compound No. 1-182, 45 mg, 0.072 mmol) in a mixed solvent (ethyl acetate (2.0 mL) and methanol (3.0 mL)), and then the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the insoluble was filtered off with celite, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 32 mg of the title compound as a yellow oil. (Yield 84%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([OH:17])=[C:11]2[CH:10]=[N:9]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:60][N:61](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:60]#[N:61])[N:9]=[CH:10][C:11]=12
Reactant: Oc1ncnc2c1cnn2-c1ccccc1Br
Reactant: CN(C)C=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccccc1-n1ncc2c(O)ncnc21
Temperature: 160 °C

Procedure:
1-(2-bromophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol B17b (1.456 g, 5 mmol) and zinc cyanide (0.528 g, 4.50 mmol) were dissolved in DMF (15 mL) and sealed into a microwave tube. The tube was evacuated and back flushed with nitrogen several times. 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.289 g, 0.50 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.229 g, 0.25 mmol) were added. The reaction was heated to 160° C. for 10 minutes in the microwave reactor and cooled to RT. This was repeated on exactly the same scale. The two reaction mixtures were combined and diluted with EtOAc (200 mL) and water (30 mL). The biphasic mixture was filtered, and the organic phase separated and washed with brine (20 mL) then dried over MgSO4, filtered and evaporated. The residue was purified by hot filtration, then crystallization from MeOH, providing 2-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (1.225 g). 1H NMR (400 MHz, DMSO-d6) δ 7.70-7.75 (1H, m), 7.86-7.88 (1H, m), 7.91-7.95 (1H, m), 8.08-8.10 (1H, m), 8.17 (1H, s), 8.43 (1H, s), 12.49 (1H, s), m/z (ESI+) (M+H)+=238; HPLC tR=1.15 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18]>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
1,4-dioxa-8-azaspiro(4,5)decane (20.0 g, 0.14 mol), DCM (300 ml) and 1N aqueous sodium carbonate solution (200 ml) were charged to a flask and cooled to <10° C. A solution of 4-cyanobenzenesulfonyl chloride (26.8 g, 0.133 mol) in DCM (100 ml) was added dropwise, maintaining the temperature below 10° C. (typically addition takes 40-50 min). Cooling was removed and stirring at room temp continued for 2 h. The layers were separated, the organic layer was washed with water (2×100 ml) and concentrated in vacuo to approximately 100 ml. Hexane (about 300 ml) was added to initialise crystallisation. The precipitate was aged at 0-5° C. for 10-30 min, filtered and washed with hexane (2×100 ml) to yield 38.2 g (88%) of 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)benzonitrile 7a as white solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.O[NH:9][C:10](=[NH:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1>CN(C=O)C>[CH3:20][S:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[N:9]=[C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[O:7][N:21]=2)=[CH:16][CH:15]=1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)c1ccc(C(=N)NO)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2noc(CCC(=O)O)n2)cc1
Temperature: 120 °C

Procedure:
Succinic anhydride (85 mg, 0.85 mmol) and N-hydroxy-4-methanesulfonyl-benzamidine (180 mg, 0.85 mmol) were dissolved in 2.0 mL of DMF and heated at 120° C. overnight. The cooled solution was evaporated and dried to yield 3-[3-(4-methanesulfonyl-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[C:15](=[O:32])[CH2:14]3)(=[O:12])=[O:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH-].[Na+].Cl.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]=[C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([N:19]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[C:38](=[O:40])[CH3:39])[C:15](=[O:32])[CH2:14]3)(=[O:11])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1NC1CCN(c2ccncc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)N(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CC1=O

Procedure:
A solution of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-piperazinone (95 mg) in acetic anhydride (4 ml) was stirred at 80° C. for 10 hours. The reaction mixture was concentrated and the residue obtained was combined with a 1N aqueous solution of sodium hydroxide and extracted with dichloromethane. The organic phase was washed with aqueous sodium bicarbonate and brine, dried and concentrated to obtain N-[(7-chloro-2H-benzopyran-3-sulfonyl)-2-oxo-1-piperazinyl]-N-[1-(4-pyridyl)-4-piperidinyllacetamide. The resultant free form was dissolved in ethyl acetate, and combined with a solution of hydrochloric acid in ethyl acetate to form a precipitate, which was collected by filtration, washed with ethyl acetate, dried under reduced pressure to obtain the title compound (90 mg) as a colorless solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[O:14]1[CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15]1>>[ClH:1].[OH:14][CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: CCCCC1CO1
Agent: Cl
Product: CCCCC(O)CNCc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 1, the title compound was synthesized from 4-aminomethylbenzenesulfonamide hydrochloride and 1,2-epoxyhexane.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:12][CH2:13][C:14]([OH:16])=[S:15])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.O>O1CCCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[OH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:12][CH2:13][C:14]([OH:16])=[S:15]
Reactant: COc1ccc(CCC(O)=S)cc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1ccc(CCC(O)=S)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a cooled solution of 3-[(tert-Butyldimethylsilyl)oxy]-4-methoxybenzylthio acetic acid 16 (8.75 g, 25.5 mmol) in tetrahydrofuran (40 mL) was added 1.0 M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (6.68 g or 25.54 mL, 25.5 mmol) slowly and stirred under nitrogen for 2 h at room temperature. The progress of the reaction was monitored by TLC (9:1—chloroform:methanol on silica gel plate). Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and dried. Removal of the solvent in vacuo yielded a semi solid that was subjected to column chromatography (initial with chloroform and finally with ethyl acetate) afforded the pure product 17. Yield: 50%; white solid mp 128-130° C. 1H NMR: δ 3.34 (s, 2H, CH2), 3.84 (s, 3H, OCH3), 4.04 (s, 2H, CH2), 6.80-7.01 (m, 3H, Ar—H). Anal. Calcd for C10H12O4S: C, 52.62, H, 5.30. Found: C, 52.58, H, 5.35.
Reaction SMILES: C(O[C@@:5]1([OH:33])[C@:9](OC(=O)C)([OH:10])[C@@H:8]([CH:15](OC(=O)C)[OH:16])[O:7][C@H:6]1[N:21]1[C:30]2[C:24]([C:25](Cl)([N:27]=[C:28]([Cl:31])[N:29]=2)[NH2:26])=[N:23][CH2:22]1)(=O)C.[CH:34]1(N)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)C>C(OCC)(=O)C.O>[Cl:31][C:28]1[N:27]=[C:25]([NH:26][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:24]2[N:23]=[CH:22][N:21]([C:30]=2[N:29]=1)[C@@H:6]1[O:7][C@H:8]([CH2:15][OH:16])[C@@H:9]([OH:10])[C@H:5]1[OH:33]
Reactant: CC(=O)OC(O)[C@H]1O[C@@H](N2CN=C3C2=NC(Cl)=NC3(N)Cl)[C@@](O)(OC(C)=O)[C@@]1(O)OC(C)=O
Reactant: NC1CCCC1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
2′,3′,5′-triacetoxy-2,6-dichloroadenosine (1.5 g) and cyclopentylamine (8 eq.) were diluted with ethanol (50 eq.) and the resulting solution was heated at reflux for about 15 hours, then cooled to room temperature and concentrated in vacuo to provide a crude residue which was diluted with a mixture of ethyl acetate and water and transferred to a separatory funnel. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to provide a crude residue which was purified using flash column chromatography on silica gel (8% MeOH-dichloromethane as eluent) to provide 2-chloro-N6-cyclopentyladenosine (0.948 g). MS m/z 370.32 [M+H]+.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[N:23](C=C=O)[N:22](OC)[NH:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:11][C@@H:12]([CH2:17][CH2:18][C:19]1[N:20]=[N:21][N:22]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:23]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CCC1=NNN(OC)N1C=C=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nnc(CC[C@H](N)C(=O)OC)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 151.8 %

Procedure:
To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-4-(2-methoxy-carbonylmethyltetrazol-5-yl)butyrate (0.820 g, 2.10 mmol) in ethyl acetate (100 ml) was added 10% Pd/C (0.220 g). The black reaction mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated to give methyl (2S)-2-amino-4-(2-methoxycarbonylmethyl-tetrazol-5-yl)butyrate (0.410 g, 76%) as a colourless oil. This was immediately used in section (5) below without further purification.