Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25]N=[C:23](OC)[CH:22]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:30]1SN=C(C2C=CN=C(Cl)C=2)N=1.BrCCC1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:30]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(CCN2CCN(c3nc(-c4ccnc(Cl)c4)ns3)CC2)ccn1
Reactant: Clc1cc(-c2nsc(Cl)n2)ccn1
Agent: BrCCc1ccccc1
Product: Clc1cc(-c2nsc(N3CCN(CCc4ccccc4)CC3)n2)ccn1

Procedure:
In analogy to the procedure described for the synthesis of 3-(2-chloropyridin-4-yl)-5-(4-(2-(2-methoxypyridin-4-yl)ethyl)piperazin-1-yl)-1,2,4-thiadiazole (Example 168), the tile compound was prepared from 5-chloro-3-(2-chloropyridin-4-yl)-1,2,4-thiadiazole and (2-bromoethyl)benzene.
Reaction SMILES: NC1C=C(C)C2C(=CC3C(C=2)=CC=CC=3)C=1C#N.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[NH:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])#[N:20].C[O:40]C1C(C(Cl)=O)=CC=CC=1>N1C=CC=CC=1>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[NH:20][C:19](=[O:40])[C:21]2[C:22](=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:28]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccccc1C(=O)Nc1cc(C)ccc1C#N
Agent: Cc1cc(N)c(C#N)c2cc3ccccc3cc12
Solvent: c1ccncc1
Product: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
N-(2-Cyano-5-methyl-phenyl)-2-methoxy-benzamide 2-Amino-4-methyl anthronitrile (50.0 g, 378.3 mmol) was dissolved in 1 L dry pyridine and cooled to 0° C. O-Anisoyl chloride (63.0 ml, 453.96 mmol) was added dropwise over a 40 minute period and the reaction was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 16 hours. The reaction was poured over 2 L of ice and the product formed a precipitate. The product was collected by vacuum filtration and dried for 3 days to produce the desired product a fluffy tan solid. Recovered 92.0 g 91% yield. LC/MS (10-99%) M/Z 267.2, retention time 3.34 minutes.
Reaction SMILES: C(C1C=CC2OC(C)(C)C=C([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][N+:15]=3[O-])C=2C=1)#N.ClC1C=CC(C2C=CC=CC=2)=CN=1.[IH:41]>>[I:41][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][N:15]=1
Reactant: I
Reactant: CC1(C)C=C(c2ccc(-c3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1
Agent: Clc1ccc(-c2ccccc2)cn1
Product: Ic1ccc(-c2ccccc2)cn1

Procedure:
The 2,2-dimethyl-4(5-phenyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows: (A) 15.98 g of 2-chloro-5-phenylpyridine were dissolved in 150 ml of 55% aqueous hydroiodic acid and the solution was heated at reflux for 2 hours. Upon cooling a solid precipitated and this was filtered off and washed with water. The solid was partitioned between diethyl ether and 2M sodium hydroxide solution, and the organic phase was dried over sodium sulphate and evaporated to give 15.87 g of 2-iodo-5-phenylpyridine which was used without further purification. (B) In an analogous manner to that described in Example 6 (A) and (B), from 2-iodo-5-phenylpyridine and 4-(1,1-dimethyl-2-propynyloxy)benzonitrile there was obtained 2,2-dimethyl-4-(5-phenyl-2-pyridyl)-2H-1-benzopyran -6-carbonitrile.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)=[O:25])[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH:18](OC)[O:19]C)=[O:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].P(=O)(O)(O)O>O>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[C:11]([NH:23][C:24]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:30][CH:31]=2)=[O:25])[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH:18]=[O:19])=[O:13])=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: COC(CCCNC(=O)C(=Cc1ccc(N=[N+]=[N-])cc1)NC(=O)c1ccc(CN2CCOCC2)cc1)OC
Agent: O=P(O)(O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C=C(NC(=O)c2ccc(CN3CCOCC3)cc2)C(=O)NCCCC=O)cc1

Procedure:
The compound produced in Example 2 [photosensitive material C] (2 g) was added to a mixture of water (40 g) and phosphoric acid (0.5 g), and the resultant mixture was stirred at 20° C. for 5 hours, to thereby remove the acetal protective group. Thereafter, the temperature of the deprotected mixture was adjusted to 10° C. and neutralized with 1 weight % aqueous sodium hydroxide to a pH of 8. The precipitates formed through neutralization were immediately separated through filtration and dried, to thereby yield 1 g of photosensitive material F as a target compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16]C)(=[O:4])[CH2:2][CH3:3].B(Br)(Br)Br>ClCCl>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][CH:11]=[CH:10][C:9]=2[OH:16])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(OC)cccc2c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(=O)c1cnc2c(O)cccc2c1Cl
Temperature: 25 °C

Procedure:
3-Propanoyl-4-chloro-8-methoxyquinoline (32 g) was dissolved in dichloromethane (250 ml), cooled to -78°, and boron tribromide (37 ml) added slowly. The solution was allowed to warm slowly to room temperature overnight, then recooled in ice and quenched cautiously with water. The resulting solid was filtered off and washed with water to give crude 3-propanoyl-4-chloro-8-hydroxyquinoline (115 g crude weight), which was used without further purification.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[OH:27][CH:28]([CH3:37])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/B(O)O.OO>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](/[CH:33]=[CH:32]/[CH2:31][CH2:30][CH2:29][CH:28]([OH:27])[CH3:37])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: CC(O)CCC/C=C/B(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.6 g (17 mmol) of 5-decyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-hydroxy-1-heptenyldihydroxyborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 5.9 g (yield 82%) of (-)-5-decyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.2 (c=1.0, CHCl3).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21]C4C=CC(C(O)=O)=CC=4OC)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CC2N(C)C(=O)C(F)(F)CN(C3CCCC3)C=2N=1.N[C:55]1[CH:65]=[CH:64][C:58]2[O:59][CH2:60][C:61](=[O:63])[NH:62][C:57]=2[CH:56]=1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:55]4[CH:65]=[CH:64][C:58]5[O:59][CH2:60][C:61](=[O:63])[NH:62][C:57]=5[CH:56]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Agent: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4c(c3)NC(=O)CO4)ncc21

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.80 (m, 6 H) 1.95 (br. s, 2 H) 3.40 (s, 3 H) 4.01 (t, J=14.15 Hz, 2 H) 4.52 (s, 2 H) 4.72 (t, J=8.08 Hz, 1 H) 6.77 (d, J=8.34 Hz, 1 H) 7.20 (dd, J=8.59, 2.02 Hz, 1 H) 7.46 (d, J=2.27 Hz, 1 H) 8.20 (s, 1 H) 9.35 (s, 1 H) 10.54 (br. s., 1 H) [M+H] calc'd for C21H22F2N6O3, 445; found 445.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:32])[C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH2:25]([O:24][C:23]1[C:16]([CH3:15])=[CH:17][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:21][C:22]=1[CH3:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCc4ccccc4)c(C)c3)nc2c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.71 g, 3.71 mmol), 3,5-dimethyl-4-benzyloxy benzaldehyde (0.94 g, 3.90 mmol), sodium hydrogensulfite (0.68 g, 3.90 mmol) and p-toluenesulfonic acid (70 mg, 0.37 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 150° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The resulting solid was collected by filtration and washed with hexanes to afford 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one as a white solid (1.2 g, 79%).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][C:16](F)=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[N:11]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:8][CH:5]3[CH2:6][CH2:7][O:3][CH2:4]3)=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[N:11]=1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1F
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC1CCOC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
NaH (70 mg) was carefully added to a solution of tetrahydro-furan-3-ol (0.2 ml) in DMF (3 ml) and the mixture was stirred for 1 hour. [1-Chloro-6-fluoro-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added under N2, and the mixture was heated at 90° C. overnight. The mixture was poured to 50 ml of water. The mixture was extracted by ethyl acetate (50 ml×3). The organic layer was evaporated to give [1-Chloro-7-(2-methoxy-ethoxy)-6-(tetrahydro-furan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine as oil (100 mg). LC-MS: m/e 419(MH+).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[C:25]([O:34][C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:40]=[C:39]([C:38]2[CH:37]=[CH:36][C:35]([O:34][C:25]3[C:24]([Cl:23])=[CH:29][C:28]([C:30]([F:33])([F:31])[F:32])=[CH:27][N:26]=3)=[CH:42][CH:41]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A mixture of 1.30 g of N-methyl-N-phenylsulfonyl-2-chloro-6-fluorobenzohydrazonoyl chloride, 1.00 g of 4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)benzonitrile, 0.50 g of anhydrous aluminum chloride and 3 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 100 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 0.70 g of the given compound (measurement of nD20 was impossible). NMR data (60 MHz, CDCl3 solvent, δ value)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]5)=[N:17]4)[CH:14]=3)[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]5)=[N:17]4)[CH:14]=3)[NH:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccn(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(c2ccn(-c3ccc4[nH]nc(-c5ccncc5)c4c3)n2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 135 %

Procedure:
To tert-butyl 3-(1-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (140 mg, 0.2 mmol) in DCM (5 mL) were added triethylsilane (40 mg, 0.34 mmol) and trifluoroacetic acid (1 mL), the reaction mixture was stirred at room temperature for 3 h. After concentration, crude mixture was column purified with mixture of methanol, dichloromethane and ammonia to give tert-butyl 3-(1-(3-(pyridin-4-yl)-1H-indazol-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (120 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.C1(C)C=CC(S[C:24]#[N:25])=CC=1>C1COCC1.[Cl-].[NH4+]>[Cl:11][C:9]1[C:10]2[C:2]([C:24]#[N:25])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Cc1ccc(SC#N)cc1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ncnc(Cl)c12
Reaction time: 1 h
Yield: 22.4 %

Procedure:
To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.31 g, 1.3 mmol) in dry THF (4 ml), cooled in a dry ice-acetone bath, was added dropwise n-butyllithium (1.3 ml, 3.3 mmol, 2.5 M In hexanes). The reaction mixture was stirred for 1 hour, then p-toluenesulphenyl cyanide (0.44 g, 2.4 mmol) suspended in dry THF (7 ml) was added. The solution was stirred for 18 hours at ambient temperature then diluted with aqueous ammonium chloride. The phases were separated and the organic phase washed with water and aqueous NaCl. The organic phase was dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (15 g, 40 mm mesh) using 3% methanol/methylene chloride to afford 4-chloro5-cyano-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (52 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]2[O:30][C:28](=[O:29])[CH2:27][CH2:26]2)[CH:12]=[C:13]([S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[OH:29][CH:28]1[CH2:27][CH2:26][CH:25]([C:11]2[CH:12]=[C:13]([S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[O:30]1
Reactant: CCCOc1c(OCc2ccccc2)cc(C2CCC(=O)O2)cc1S(=O)(=O)CCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCCOc1c(OCc2ccccc2)cc(C2CCC(O)O2)cc1S(=O)(=O)CCC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-benzyloxy-4-propoxy-5-propylsulfonylphenyl) butyrolactone (6.90 g, 0.015 mol) in dry toluene (65 ml) at −78° C. was added 0.9 M toluene solution of DIBAL-H (3.40 g, 26.61 ml) dropwise at −78° C. and stirred for 1 h. Upon completion, the reaction was quenched by adding methanol (7 ml) at −78° C. The mixture was warmed to −20° C. followed by the addition of saturated sodium potassium tartarate solution while maintaining the temperature between −10° C. and 0° C. The mixture was stirred at 0° C. for 1 h. Then the two phases were separated, the aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water followed by brine, dried (Na2SO4), filtered and concentrated. The crude 2-hydroxy-5-(3-benzyloxy-4-propoxy-5-propylsulfonylphenyl) tetrahydrofuran (6.86 g) was used for the next step without further purification (99%). TLC: Acetone:benzene (1:9), Rf=0.33; 1H NMR(CDCl3, 200 MHz): δ 1.03 (m, 6H), 1.65-2.15 (m, 7H), 2.3-2.6 (m, 1H), 3.35 (m, 2H ), 4.15 (t, J=6.45 Hz, 2H), 4.98 (apparent t, J=6.97 Hz, 0.5H), 5.18 (t, J=6.51 Hz, 0.5H), 5.15 (2s, 2H), 5.6, 5.75 (brs, 1H), 7.1-7.22 (m, 1H), 7.3-7.48 (m, 6H). FAB Mass: 434 (M+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.Cl>CO>[CH3:1][C:2]1[S:3][C:4]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: COc1ncc(-c2sc(C)nc2C)c(OC)n1
Agent: Cl
Solvent: CO
Product: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)s1
Yield: 109.5 %

Procedure:
5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4-bis(methyloxy)pyrimidine (521 mg, 2.073 mmol) was dissolved in Methanol (30 ml), then 1N Hydrochloric acid aqueous solution (16.59 ml, 16.59 mmol) was added and the mixture was refluxed for 3 hours. Solvents were then evaporated under reduced pressure, the residue was triturated with acetone and filtered providing the title compound (507 mg, 2.27 mmol) as a white solid.
Reaction SMILES: C(O[CH2:5]/[CH:6]=[C:7](/[CH3:21])\[CH2:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[C:12]([CH3:19])[C:11]=1[OH:20])(=O)C>CS(C)=O.O>[CH3:21][C@@:7]1([CH:6]=[CH2:5])[CH2:8][CH2:9][C:10]2[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[C:12]([CH3:19])[C:11]=2[O:20]1
Reactant: CC(=O)OC/C=C(/C)CCc1c(C)c(O)c(C)c(C)c1O
Solvent: CS(C)=O
Solvent: O
Product: C=C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Yield: 86.1 %

Procedure:
A solution of 125 mg (0.43 mmol) of (Z)-5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate, 8 mg (3%) of (S)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene and 2.3 mg (1.5%) of π-allylpalladium chloride dimer in DMSO (3 ml) was left at 60° C. for 17 hours. After cooling the mixture was diluted with water and extracted with ether. The extracts were washed with water, dried, concentrated and the residue was purified as in Experiment 1, yielding 86 mg of (S)-3,4-dihydro-2,5,7,8-tetramethyl-2-vinyl-2H-[1]-benzopyran-6-ol. O.P. 36%.
Reaction SMILES: [C@@H:1]1([N:10]2[C:14]([NH:15][C:16](=S)[NH2:17])=[C:13]([C:19]([NH2:21])=[O:20])[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]>[OH-].[Na+].S([O-])([O-])(=O)=O.[Cu+2]>[C@@H:1]1([N:10]2[CH:11]=[N:12][C:13]3[C:19](=[O:20])[NH:21][C:16]([NH2:17])=[N:15][C:14]2=3)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1NC(N)=S
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
The crude product of 1-(β-D-ribofuranosyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (5.0 g) was added to a suspension of copper sulphate (2.9 g, 18 mM) in 3N sodium hydroxide (60 ml) and refluxed for 1 hour. After filtration 33% aqueous acetic acid (30 ml) was added to the filtrate and it was refluxed again while being treated with activated coal. The coal was filtered off, and the solution was cooled to room temperature overnight. Filtration, washing with water and drying gave 2.0 g (65%) of 9-β-D-ribofuranosyl guanine, H2O (guanosine, H2O) as a white powder, mp. 250° C. (dec.). The product had the same physical data as an authentic sample of guanosine, H2O.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[CH:43]1([N:49]([CH:60]([CH3:62])[CH3:61])[CH2:50][CH2:51][NH:52][C:53](N2C=CN=C2)=[O:54])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:43]1([N:49]([CH:60]([CH3:62])[CH3:61])[CH2:50][CH2:51][NH:52][C:53]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]3)=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)=[O:6])=[O:54])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C1CCCCC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN(C(C)C)C4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-{2-[cyclohexyl(isopropyl)amino]ethyl}1H-imidazole-1-carboxamide (Preparation 29) by a similar method to Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]>>[CH2:33]([N:37]1[CH2:42][CH2:41][N:40]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)Nc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 16.5 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide following procedure C and using 1.2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: N[C@H](C(O)=O)CS.N[C@H](C(O)=O)C.C([S:22][CH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:31]([OH:33])=[O:32])[CH2:29][SH:30])=[O:26])(=O)C1C=CC=CC=1>>[SH:22][CH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:31]([OH:33])=[O:32])[CH2:29][SH:30])=[O:26]
Reactant: O=C(CCSC(=O)c1ccccc1)N[C@@H](CS)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: N[C@@H](CS)C(=O)O
Product: O=C(CCS)N[C@@H](CS)C(=O)O

Procedure:
By susbtituting L-cysteine for the L-alanine in the procedure of Example 1, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-L-cysteine and N-(3-mercaptoproanoyl)-L-cysteine are obtained.