Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([CH:22]=O)=[C:15]4[N:14]=3)=[CH:11][CH:12]=2)=[O:7])[CH2:3][CH2:2]1.C(O)C.[NH:27]1[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[O:29].N1CCCCC1>O>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([CH:22]=[C:33]5[C:31](=[O:32])[NH:30][C:28](=[O:29])[NH:27]5)=[C:15]4[N:14]=3)=[CH:11][CH:12]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2ccc(-c3ccc(C(=O)NCC4CC4)s3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccc(C(=O)NCC5CC5)s4)nc23)N1
Temperature: 80 °C
Yield: 29 %

Procedure:
To the reaction flask, N-(cyclopropylmethyl)-5-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxamide (10 mg, 0.030 mmol) was added to ethanol (0.5 mL) along with hydantoin (3 mg, 0.03 mmol) and piperidine (3 uL, 0.03 mmol). The reaction was heated at 80° C. for 1 hour in the microwave then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, N-(cyclopropylmethyl)-5-(3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxamide, was recovered as a solid in 29% yield. LCMS (M+1=409)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].CN(C)C=O.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1ccc(I)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C(=O)OC)cc1Br
Temperature: 50 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
A mixture of methyl 3-bromo-4-iodobenzoate (5.9 g, 17 mmol), methyl acrylate (2.01 mL, 22.3 mmol), tetra-N-butylammonium chloride (4.8 g, 17 mmol), palladium acetate (80 mg, 0.3 mmol) and finely ground potassium carbonate (5.98 g, 43.3 mmol) in N,N-dimethylformamide (21 mL) was stirred at 50° C. for 20 h. The reaction mixture was cooled to room temperature. Ethyl acetate (200 mL) and brine (50 mL) were added, and the mixture was filtered under suction. The filtrate was collected, and aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over NaSO4, filtered, and concentrated. The product was crashed out after concentration, filtered and washed with ethyl acetate to give product. The remained residue was purified with silica gel chromatography (10% ethyl acetate/hexanes) to provide white solid (3.5 g, 67%). 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J=1.7 Hz, 1H), 8.04 (d, J=16.0 Hz, 1H), 7.98 (m, 1H), 7.65 (d, J=8.2 Hz, 1H), 6.46 (d, J=15.8 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H). LCMS found for C12H12BrO4 (M+H)+: m/z=299, 301.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C-:16]#[N:17].[Na+]>O>[C:16]([CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)#[N:17]
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(CC#N)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
2-Bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (6.5 g, 18.6 mmol) was dissolved in dimethylsufoxide (30 ml). Sodium cyanide (1.43 g, 88 mmol) was added and the resulting mixture was stirred at 80° C. for 18 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexaneisopropyl ether, 2:1). The crude crystals obtained were recrystallized from methanol to obtain the desired compound (4.1 g, yield: 79.7%), m.p. 58°-59° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[CH:13]([C:16]1[C:17]([Cl:24])=[N:18][C:19](Cl)=[N:20][C:21]=1Cl)([CH3:15])[CH3:14]>CN(C=O)C>[Cl:24][C:17]1[C:16]([CH:13]([CH3:15])[CH3:14])=[C:21]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:20]=[C:19]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:18]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2nc(Cl)c(C(C)C)c(OCc3ccc(OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a stirred solution of p-methoxybenzyl alcohol (110 ml) in anhydrous DMF (50 ml) in a water bath under nitrogen atmosphere, was portionwise added 60% sodium hydride (4 g, 100 mmol). After complete reaction of sodium hydride, the mixture was cooled in an ice-water bath and 5-isopropyl-2,4,6-trichloropyrimidine (11.275 g, 50 mmol) was added. After 1 hr., the mixture was stirred for overnight at room temperature. The excess p-methoxybenzyl alcohol and DMF were distilled off in high vacuo and the residue was partitioned between ether and water. The ether layer was taken, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a colorless syrup. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 17 g (79%) of a white solid. m.p. 69-70° C.; 1H NMR (200 MHz, CDCl3) δ 1.23 (6H, d, J=7.0 Hz), 3.42 (1H, m), 3.81 (3H, s), 3.82 (3H, s), 5.31 (2H, s), 5.35 (2H, s), 6.87-6.92 (4H, m), 7.30-7.43 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CS(C)=O.O.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([S:12]([CH3:11])(=[O:14])=[O:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)o1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)o1
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-furan-2-carboxylic acid methyl ester (4.7 g, 23 mmol) in DMSO (25 mL) was added the sodium methanesulfinate (5.5 g, 46 mmol) followed by copper (I) iodide (4.4 g, 23 mmol). The mixture was then heated to 110° C. for 2 hours. The reaction was diluted with water (100 mL) and ethyl acetate (100 mL) and filtered through diatomaceous earth. The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated to afford 5-methanesulfonyl-furan-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][C@H:14]([OH:21])[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=O)=[CH:4][CH:3]=1.[B].CSC.CO.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:12][CH2:13][C@@H:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[OH:21])=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(Br)cc1)NC[C@H](O)c1cccnc1
Agent: Cl
Agent: [B]
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: O[C@@H](CNCCCc1ccc(Br)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a suspension of 3-(4-bromophenyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]propanamide (3.42 g) in tetrahydrofuran (58 ml) was added 2.0M dimethyl sulfide—borane (1:1) in tetrahydrofuran (16.1 ml) dropwise at 0-5° C. over 45 minutes. After cooling to room temperature, to the reaction mixture were added methanol (2.99 ml) and 37% hydrochloric acid (4.8 ml) at 4° C. (ice bath). The mixture was stirred at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and to the residue was added water (100 ml). The pH was adjusted to 10 with 24% aqueous sodium hydroxide solution at 4° C. and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave (1R)-2-[[3-(4-bromophenyl)propyl]-amino]-1-(3-pyridyl)ethanol (3.22 g) as a yellow oil.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH:6]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:8])[CH3:7]>CN(C=O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([NH:9][CH:6]([CH3:8])[CH3:7])(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CC(C)NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Reaction time: 18 h

Procedure:
288.8 mg (1.28 mmol) of tin(II) chloride dihydrate are added to a solution of 100 mg (0.26 mmol) of N-isopropyl-4′-nitrobiphenyl-4-sulfonamide (Example 11A) in 2.0 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 47 mg (63.2% of theory) of the title compound are obtained. HPLC (Method 1): Rt=3.57 min. MS (DCI): m/z=291 (M−H)+. Exemplary Embodiments:
Reaction SMILES: [BH4-].[Na+].C([O:6][C:7]1[C@:8]2([CH2:24][CH2:23][C@H:22]3[C@@H:13]([C@H:14]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:15][C:16]4[CH:17]=[C:18]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:19]=[CH:20][C:21]=43)[C:10]2=[CH:11][CH:12]=1)[CH3:9])(=O)C.C(O)(=O)C>C(O)C.O.O1CCCC1>[C:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C@@H:14]1[CH2:15][C:16]2[CH:17]=[C:18]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:19]=[CH:20][C:21]=2[C@@H:22]2[C@@H:13]1[C:10]1[C@@:8]([CH2:24][CH2:23]2)([CH3:9])[C@@H:7]([OH:6])[CH2:12][CH:11]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@]3(C)C(OC(C)=O)=CC=C3[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 1.25 g of sodium borohydride in 90 ml of ethanol and 18 ml of water is added in drops to a solution of 4.58 g of 17-acetoxy-7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14,16-pentaene in 26.8 ml of tetrahydrofuran and 161 ml of ethanol at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is mixed with 4 ml of glacial acetic acid, concentrated by evaporation, and the residue is taken up in ethyl acetate. The organic phase is washed with sodium bicarbonate, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate. 2.16 g of 7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10),14-tetraen-17β-ol is obtained as foam.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][N:18]=1.[Si:28]([O:35][C:36]1([CH2:40][CH:41]=[O:42])[CH2:39][CH2:38][CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1COCC1.O>[Si:28]([O:35][C:36]1([CH2:40][CH:41]([C:22]2[C:17]([F:16])=[N:18][CH:19]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=2)[OH:42])[CH2:37][CH2:38][CH2:39]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)Cc1ccc(F)nc1
Reactant: CC(C)(C)[Si](C)(C)OC1(CC=O)CCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Cc1cnc(F)c(C(O)CC2(O[Si](C)(C)C(C)(C)C)CCC2)c1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
2,2,6,6-tetramethylpiperidine (13.0 ml, 76.5 mmol) was dissolved in 500 ml THF and cooled to −78° C. Butyllithium (26.8 ml, 67.0 mmol) was added over the period of 10 min and the reaction was allowed to warm up to 0° C. and kept there for 3 min. The mixture was cooled back to −78° C. and a solution of 2-fluoro-5-neopentylpyridine (8.000 g, 47.8 mmol) in 10 ml THF was added over the period of 30 min. The mixture was stirred for 20 min at the same temperature and a solution of 2-(1-(tert-butyldimethylsilyloxy)cyclobutyl) acetaldehyde (19.7 g, 86.1 mmol) in 25 ml THF was added over the period of 20 min. The reaction was stirred for 15 min at the same temperature and hydrolyzed with 200 ml of H2O. The mixture was allowed to warm up to room temp and extracted 2 times with 1 L EtOAc (each). The combined organic extracts were dried over MgSO4 and evaporated. The crude material was used without further purification. MS found 396.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[H-].[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>CN(C=O)C.CCOC(C)=O>[Cl:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=1
Reactant: Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: COc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(CNc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5 %

Procedure:
1-(3,5-Dichloro-benzyl)-1H-imidazol-2-ylamine (see Example 12) was dissolved in anhydrous DMF and NaH was added to the solution under H2. The reaction mixture was stirred at room temperature for 10 min and 3-methoxybenzylbromide was added. The reaction mixture was stirred at 65° C. for 5 h. The reaction mixture was then diluted with EtOAc and washed with water (×5). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 95:5 to afford the title compound (7 mg, 5%); LCMS m/z 362 [C18H17Cl2N3O+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccccc1
Product: Clc1cc(-c2ccccc2)nc(Cl)n1

Procedure:
As shown in Scheme 17, reaction of 2,4,6-trichloropyrimidine (8) with phenylboronic acid occurred at position 6 of the pyrimidine ring to give 2,4-dichloro-6-phenylpyrimidine (39) as the only isolated product. This is in contrast to the amine displacement reactions of Schemes 3 and 16, which occurred largely at the 4 position. Subsequent reaction with bridged C5-C9heterobicycle compound 2 occurred as expected at position 4.
Reaction SMILES: [CH3:1][CH:2]([OH:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:18][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1
Reactant: CC(O)COc1ccc(Oc2ccccc2)cc1
Reactant: Clc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(COc1ccc(Oc2ccccc2)cc1)Oc1ccccn1
Reaction time: 6 h
Yield: 71 %

Procedure:
A mixture of 1-methyl-2-(4-phenoxyphenoxy)ethanol (2.0 g, 8.2 mmol), 2-chloropyridine (4.0 g, 35 mmol), flaked 95% sodium hydroxide (1 g, 24 mmol) and tetra-n-butylammonium bromide (0.13 g) was stirred at an inner temperature of 85° to 90° C. for 6 hours. After allowed to cool, toluene (10 g) was added thereto, and the resultant mixture was washed with water and extracted with 35% hydrochloric acid (5 g) twice. The hydrochloric acid layer was washed with toluene (10 g). A 10% aqueous sodium hydroxide solution was added thereto to make the mixture sufficiently basic. The basic mixture was further extracted with toluene (10 g) twice, and the toluene layer was washed with a 10% aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution in order and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give 2-[1 -methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine (1.87 g) as white crystals.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([OH:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([C:52]([O:54][CH3:55])=[O:53])=[CH:49][C:50]=1O)=[O:45]>C1COCC1>[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([C:52]([O:54][CH3:55])=[O:53])=[CH:49][C:50]=1[O:22][CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])[CH3:21])=[O:45]
Reactant: CC(O)c1ccccc1Cl
Reactant: COC(=O)c1cc(O)c(C(=O)OC)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(C)c2ccccc2Cl)c(C(=O)OC)s1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
Diethyl azodicarboxylate (1.29 g, 7.41 mmol, 1.3 Eq.) was added to a stirred solution of 1-(2-Chloro-phenyl)-ethanol (893 mg, 5.70 mmol, 1.0 Eq.), triphenylphosphine (1.94 g, 7.41 mmol, 1.3 Eq.) and 3-hydroxythiophene-2,5-dicarboxylic acid dimethyl ester (1.23 g, 5.70 mmol, 1.0 Eq.) in anhydrous THF (20 mL) at 0° C. under nitrogen and the reaction allowed to warm to ambient temperature overnight. The crude reaction mixture was concentrated in vacuo and purified by column chromatography (10% EtOAc/Petroleum ether) to give the sub-title compound as a white solid (1.94 g, 5.6 mmol, 93%); 1H NMR (400 MHz, CDCl3) δ 1.71 (3H, d), 3.89 (3H, s), 3.95 (3H, s), 5.80 (1H, q), 7.20-7.32 (3H, m), 7.39 (1H, d), 7.66 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[N:6]2[CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(Cl)(Cl)Cl.C(#N)C.I([O-])(=O)(=O)=[O:32].[Na+]>O.[Ru](=O)(=O)(=O)=O.CC(O)C.O>[NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([OH:32])=[O:16]
Reactant: Nc1nc(I)nc2c1nc(-c1cccc(F)c1)n2CCCCO
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)O
Product: Nc1nc(I)nc2c1nc(-c1cccc(F)c1)n2CCCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To 1.50 g of 4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanol were added 30 ml of chloroform, 30 ml of acetonitrile, 45 ml of water, 73 mg of ruthenium tetraoxide hydrate and 4.10 g of sodium periodate and the mixture was vigorously stirred in a nitrogen stream for 5 hours at room temperature. The reaction was stopped by 2-propanol and the insoluble matters were filtered off followed by washing with 1000 ml of chloroform-methanol (1:1). The filtrate was concentrated, the residue was suspended in water, and the suspension was adjusted to pH 2-3 with 1N hydrochloric acid and the crystals were collected by filtration. The crystals were washed with water and ether to give 1.41 g of the title compound. The yield was 91%.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:27][S:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:29][CH:28]=3)[CH2:14][CH2:13]2)=[O:16])=[CH:18][CH:19]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCOc3ccc(N)cc3)CC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCN2CCC(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of the amine (1.20 g, 2.88 mmol) prepared in the preceding paragraph in dichloromethane (20 mL) at 0° C. under nitrogen was added pyridine (0.47 mL, 5.76 mmol) and methanesulfonyl chloride (0.33 mL, 4.32 mmol). The mixture was stirred at 25° C. for 2 hours and was then partitioned between 5% aqueous sodium bicarbonate and 4:1 dichloromethane/isopropanol. The organic phase was dried (MgSO4), decolorized (charcoal) and concentrated to afford a residue which was triturated with ethyl acetate/diethyl ether/hexane to give the title compound as a white solid: 0.92 g (65%). mp 168°-172° C.; 1H NMR (DMSO-d6): δ 10.28 & 9.35 (2s, 2H), 7.94 (d, J=8.87 Hz, 2H), 7.27 (d, J=8.85 Hz, 2H), 7.13 (d, J=9.00 Hz, 2H), 6.92 (d, J=9.01 Hz, 2H), 4.05 (t, J=5.61 Hz, 2H), 3.32 (m, 1H), 3.09 (s, 3H), 3.00 (m, 2H), 2.86 (s, 3H), 2.75 (m, 2H), 2.30 (m, 2H), 1.75-1.50 (m, 4H). IR (KBr): 3220, 1660 cm-1 ; MS (m/z) 496 (MH+), 217,91.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9]([OH:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].CN(C)C=O>O.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9]([O:12][CH2:23][CH3:24])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc(O)c2c(C)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(OCC)c2c(C)n[nH]c12

Procedure:
2.2g. of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester (0.01 mol.), 2.8 g. of potassium carbonate (0.02 mol.), and 1.6 g. of ethyl iodide (0.01 mol.) are suspended in 50 ml. of dimethylformamide and heated for 10 hours at 70°. After this time, the mixture is acidified with acetic acid and 30 ml. of water are added. 4-Ethoxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester precipitates, is filtered and recrystallized from methanol, yield 1.9 g. (79%), m.p. 200°.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[H][H]>[Rh].CO>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Product: COc1cccc(C(O)C2CCNCC2)c1OC
Temperature: 40 °C
Yield: 89.7 %

Procedure:
A 1-L Parr reactor was charged with 12.43 g (0.051 mol) of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10), 5.74 g of a 5% Rhodium on Carbon catalyst, and 237 g of methanol. The solution was warmed to 40° C. and treated with 100 psi of hydrogen for 5.5 h. When the reaction was complete, the solution was filtered and the catalyst washed with 108 g of methanol which was added to the filtrate. The weight of the filtered solution was 310.45 g. The methanol solution was assayed for the title compound using high pressure liquid chromatography. The methanol solution was found to contain 3.7% title compound by weight. This corresponds to 11.5 g (90% yield) of title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][C@@H:29]([CH3:34])[CH2:30][C:31](O)=[O:32].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:31](=[O:32])[CH2:30][C@@H:29]([OH:28])[CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: C[C@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)C[C@H](C)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.6 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (92 mg, 0.25 mmol) in CH2Cl2 (1 mL) at 0-5° C. was treated with (S)-3-hydroxybutanoic acid (29 mg, 0.28 mmol), a catalytic amount of DMAP, and DCC (57 mg, 0.28 mmol). The reaction mixture was allowed to warm to room temperature and stir 6 h. After this time the reaction mixture was evaporated and the residue purified by silica gel flash chromatography with 50% EtOAc/hexanes as eluant to afford the title compound as an oil (64 mg, 57%). LC/MS (Method B) 3.53 min, [M+1]+ 453.