Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]CO.S(Cl)([Cl:19])=O.[CH:21]([Cl:24])(Cl)Cl>>[ClH:19].[Cl:19][CH2:2][CH2:3][N:4]([CH2:5][CH2:21][Cl:24])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCN(CCO)CCOc1ccccc1
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCCN(CCCl)CCOc1ccccc1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 2-[(2-hydroxyethyl)-(2-phenoxyethyl)-amino]ethanol (H; 43.9 g, 194 mmol) in chloroform (140 mL) was added thionyl chloride (SOCl2; 114.8 g, 965 mmol) dropwise. The reaction mixture was then reflux for 1.5 h and concentrated. The residue was then suspended in the mixture of ethyl acetate and isopropyl ether. The precipitate was filtered and dried in a vacuum oven to afford the title compound quantitatively as a light brown crystal. This product was then used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([N:11]([CH3:27])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[N:7]=1
Reactant: COc1cc(Nc2csc3cnc(Cl)nc23)cc(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N(C)c2csc3cnc(Cl)nc23)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 90 %

Procedure:
2-Chloro-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-7-amine (30 mg, 0.085 mmol) was dissolved in N,N-dimethylformamide (1 mL) and sodium hydride (5.2 mg, 0.13 mmol) was added at 0° C. After stirring for 10 minutes and adding iodomethane (15 mg, 0.10 mmol), the mixture was stirred for an hour, diluted with ethyl acetate, and washed with brine. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. The target compound (28 mg, 89% yield) was obtained without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[NH:9][C:8]2=O.Cl.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(=O)[nH]c(-c3ccccc3C(F)(F)F)nc12
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cccc2c(Cl)nc(-c3ccccc3C(F)(F)F)nc12
Yield: 89 %

Procedure:
Prepared from 8-methoxy-2-(2-trifluoromethyl-phenyl)-3H-quinazolin-4-one (1.0 g, 3.12 mmol), triethylamine hydrochloride (472 mg, 3.43 mmol), and POCl3. Purification by flash chromatography afforded a white solid (89% yield). HPLC-Method A, Rt 4.10 min, (98%), MS (m/z) 258.08 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[O:14](S(C(F)(F)F)(=O)=O)[S:15]([C:18]([F:21])([F:20])[F:19])(=O)=[O:16]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[S:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13])(=[O:16])=[O:14]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1ccc(O)c(C(F)(F)F)c1
Solvent: ClCCl
Product: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a mixture of 4-hydroxy-3-(trifluoromethyl)benzaldehyde (500 mg, 2.7 mmol), TEA (805 mg, 8.0 mmol) in anhydrous DCM (10 mL) was added Tf2O (820 mg, 2.9 mmol) drop wise at 0° C., and stirred at the same temperature for 30 mins. Followed a standard aqueous/EtOAc workup and purified by column chromatography (PE:EtOAc=10:1) to give product (560 mg, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[CH:14]1([N:11]2[CH2:12][CH2:13][CH:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][C:4]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:30])=[CH:24][CH:23]=4)=[CH:5][C:6]=3[Cl:21])[C:10]2=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Product: CN1CCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)CC1
Product: Cl
Yield: 46.7 %

Procedure:
Alternative procedure to prepare Example 46: Using the procedure to synthesize Preparation 76 and using reagents 3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (350 mg, 0.78 mmol) and N-methyl piperazine (157 mg, 1.6 mmol) affords 103 mg (23%) of the title compound: Mass spectrum (apci) m/z=528.2 (M+H−HCl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][C:3]=1[CH:11]=O.[C:13]([O:17][C:18](=[O:27])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].[CH3:28]C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC=CC=1.CCOC(C)=O>[C:18]([N:19]([CH3:28])[CH:20]1[CH2:21][CH2:22][CH:23]([NH:26][CH2:11][C:3]2[CH:4]=[C:5]([B:8]([OH:9])[OH:10])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:24][CH2:25]1)([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:27]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=Cc1cc(B(O)O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(B(O)O)ccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-fluoro-3-formyl benzene boronic acid (0.88 g, 5.99 mmol) in THF (5 mL) and toluene (5 mL) was added amine (3) (1.4 g, 7.19 mmol) followed by AcOH (0.34 mL, 7.19 mmol), and the resulting solution was stirred at RT for 18 h. After this time sodium triacetoxyborohydride (1.57 g, 8.38 mmol) was added and the resulting solution was stirred at RT for a further 6 h. EtOAc (10 mL) was added to the reaction mixture followed by dropwise addition of sat. NaHCO3 solution (10 mL). The organic layer was separated and the aqueous layer was extracted into EtOAc (2×10 mL). The combined organic layers were dried (MgSO4), filtered and reduced in vacuo to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N([CH2:34][CH3:35])CC)C.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>ClCCl.CCOCC>[CH2:40]([O:39][C:37]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:13][N:14]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][N:22]([C:37]([O:39][CH2:40][C:35]1[CH:34]=[CH:43][CH:42]=[CH:41][CH:46]=1)=[O:38])[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1ccc2c(O)c(CNC3CCCCC3)ccc2c1CNC1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)Oc1ccc2c(OC(=O)OCc3ccccc3)c(CN(C(=O)OCc3ccccc3)C3CCCCC3)ccc2c1CN(C(=O)OCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,6-dihydroxy-2,5-bis-(cyclohexylaminomethyl)-naphthalene (3.8 g, 9.9 mmol) in dichloromethane (100 ml) were added, with cooling in an ice bath, triethylamine (6.9 ml, 50 mmol) and dropwise with stirring benzyl chloroformate (5.6 ml, 40 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with ether, washed three times with water, dried (sodium sulfate) and evaporated to give the product as a thick syrup; yield 2.0 g.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].N12CCCN=C1CCCCC2>C(OCC)(=O)C>[C:12]([S:15][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])([CH3:14])([CH3:13])[CH3:11]
Reactant: OCCOCCOCCCl
Reactant: CC(C)(C)S
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)SCCOCCOCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a mixture of 2-[2-(2-chloroethoxy)ethoxy]ethanol (11.0 g, 65.24 mmol) and tert-butylthiol (7.35 mL, 65.23 mmol) cooled in an ice bath was slowly added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 9.75 mL, 65.23 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. This mixture was then diluted with ethyl acetate and filtered. The crude product in the filtrate was purified on a filter column eluted with ethyl acetate to give yellowish oil (14.4 g, 64.6 mmol, 99%): 1H NMR (300 MHz, CDCl3): d 3.73 (br s, 2H), 3.69-3.60 (m, 8H), 2.75 (t, J=7.4, 2H), 2.62 (br s, 1H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3): d 72.47, 71.08, 70.33, 70.27, 61.71, 42.09, 30.95, 27.87; MS (ESI): m/e (M+1) Calcd. for C10H23O3S: 223, obsd.: 223.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH2:15][CH:16]=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:9]1([C:15]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[NH:7][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=CCc1ccccc1
Reactant: NNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(-c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A solution of phenylhydrazine (1 mL, 10.15 mmol) and phenylacetaldehyde (1.32 mL, 10.15 mmol) in acetic acid was refluxed for 6 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of sodium carbonate (100 mL) at 0° C. After extraction with dichloromethane (2×30 mL), the organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired indole (1a) as a pale oil (940 mg, 4.86 mmol, 48%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>CN(C)C=O.C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=[C:2]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 51.9 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 93 mg (1.1 mmole) 2-methyl-3-butyn-2-ol, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 1 hour in 5 ml dimethylformamide and 5 ml diethylamine. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography (silicagel, hexane/ethyl acetate 7/3 ) and recrystallisation of the residue from ethanol yields 200 mg (52%) pure 4-[4-(4-amino-benzenesulfonyl)-6-pyrrolidine-1-yl-pyridine-2-yl]-2-methyl-but-3-yn-2-ol als a white solid mp.: 168-170° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:7]=[CH:6]2)[CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[CH:30]=O.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:8]2[N:7]=[CH:6][N:5]([CH:3]3[CH2:2][N:1]([CH2:30][C:25]4[N:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH2:4]3)[C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=2)=[CH:18][CH:19]=1
Reactant: O=Cc1ncccn1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CNC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CN(Cc3ncccn3)C2)n1
Reaction time: 0.5 h

Procedure:
A mixture of 4-[1-azetidin-3-yl-4-(4-fluorophenyl)-1H-imidazol-5-yl]pyrimidin-2-amine (C5) (11.2 mg, 0.0361 mmol), pyrimidine-2-carbaldehyde (5.9 mg, 0.055 mmol), triethylamine (0.010 mL, 0.072 mmol) and acetic acid (0.010 mL, 0.17 mmol) in 1,2-dichloroethane (1.0 mL) was stirred for 30 minutes. Sodium triacetoxyborohydride (22.9 mg, 0.11 mmol) was added and stirring was continued for an additional 18 hours, at which time the reaction was quenched with dilute aqueous sodium hydroxide solution. Extraction of the aqueous layer with 1,2-dichloroethane was followed by combination of the organic layers and concentration in vacuo. Purification of the residue was effected by reversed-phase HPLC (Gradient: 5% to 60% acetonitrile in water) to provide the product as a yellow oil. Yield: 1 mg, 0.0025 mmol, 7%. LCMS m/z 403.6 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.66-3.70 (m, 2H), 3.96-4.00 (m, 2H), 4.02 (s, 2H), 5.34 (m, 1H), 6.38 (d, J=5.2 Hz, 1H), 7.10 (dd, J=8.8, 8.8 Hz, 2H), 7.38 (t, J=4.9 Hz, 1H), 7.44 (dd, J=8.9, 5.4 Hz, 2H), 8.09 (d, J=5.2 Hz, 1H), 8.24 (br s, 1H), 8.77 (d, J=5.0 Hz, 2H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][CH:13](O)[C:14]#[CH:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl.O>[CH3:15][CH:14]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]#[CH:12]
Reactant: Oc1cccc2ccccc12
Reactant: C#CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: C#CC(C)Oc1cccc2ccccc12
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of 1-naphthol (200 mg, 1.38 mmol) and but-3-yn-2-ol (146 mg, 2.07 mmol) in anhydrous DCM (10 mL) under a N2 atmosphere and at 0° C. was added Ph3P (435 mg, 1.66 mmol) portion wise. The reaction mixture was stirred for 10 min and then DEAD (360 mg, 2.07 mmol) (70% solution in toluene) was slowly added. The resulting reaction solution was stirred at the room temperature for 24 h and then diluted with water (50 mL) and extracted with chloroform (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered concentrated in vacuo and the residue was purified by flash column chromatography using ethyl acetate/n-hexane (a gradient of 5-10%) to furnish 1-[(1-methyl-2-propyn-1-yl)oxy]naphthalene (176 mg, 65%) as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+].[OH-].[Na+].Cl>C(O)(=O)C>[CH3:1][C:2]1[N:3]([C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:7])=[O:8])[N:15]=[N:14][N:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2ccccc2c(=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nnnn1-c1ccccc1C(=O)O
Temperature: 27.5 °C

Procedure:
The crude 2-methyl-4-oxo-3,1-benzoxazine was dissolved in acetic acid (1.9 L). Sodium azide (130.0 g) was added to the solution in portions with stirring. The reaction mixture was cooled in an ice bath to maintain the reaction temperature at 25 to 30° C. during the addition. The reaction mixture was allowed to stir at ambient temperature over the weekend. The acetic acid was removed under vacuum to provide a white solid. The solid was combined with 10% sodium hydroxide (1.4 L) then heated on a steam bath for 1 hour. Additional sodium hydroxide (120 g of 50% sodium hydroxide) was added. The mixture was heated on a steam bath for an additional hour then allowed to cool to ambient temperature overnight. Additional sodium hydroxide (120 g of 50% sodium hydroxide) was added. The mixture was heated on a steam bath for 2 hours then allowed to cool. The reaction mixture was poured with rapid stirring into a mixture of concentrated hydrochloric acid (1.0 L) and ice (3 L). The resulting mixture was stirred at ambient temperature overnight. A precipitate was isolated by filtration, rinsed with water then slurried with water (4 L). The solid was isolated by filtration, rinsed with water then oven dried at 50° C. to provide 278.0 g of crude 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid as a tan solid, m.p. 157-160° C. The crude material was dissolved in 10% sodium hydroxide (2.5 L). The resulting solution was heated (95-99° C.) for 2.5 hours, cooled, then poured with vigorous stirring into a mixture of concentrated hydrochloric acid (500 mL) and ice (5 L). The resulting mixture was allowed to stir for 2 hours. The precipitate was isolated by filtration, rinsed with water, then slurried with water (3 L). The solid was isolated by filtration, rinsed with water then dried overnight at ambient temperature to provide 228 g of 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid, m.p. 164-166° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12].[CH:17]1([NH:22][C:23]2[N:31]=[C:30]([N:32]=[N+:33]=[N-:34])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[C@H:35]2[C@H:39]([OH:40])[C@H:38]([OH:41])[C@@H:37]([CH2:42][OH:43])[O:36]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1.[Cu]I>[OH:40][C@@H:39]1[C@H:38]([OH:41])[C@@H:37]([CH2:42][OH:43])[O:36][CH:35]1[N:27]1[CH:26]=[N:25][C:24]2[C:28]1=[N:29][C:30]([N:32]1[CH:12]=[C:11]([C:10]([O:14][CH2:15][CH3:16])=[O:13])[N:34]=[N:33]1)=[N:31][C:23]=2[NH:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C#CC(=O)OCC
Reactant: [N-]=[N+]=Nc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.470 g of diisopropylethylamine and ethyl prop-2-ynoate (1.9 mmol) were dissolved in 20 mL of THF. To the solution was added (4S,2R,3R,5R)-2-[6-(cyclopentylamino)-2-(azido)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol (1.3 mmol) and 350 mg of CuI. The mixture was stirred at room temperature for 24 hours. The solvent was then removed by evaporation and the residue treated with 5 mL of ethanol and ethyl ether. The yellow solid was collected by filtration, and washed with ethanol and ether to afford ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-1,2,3-triazole-4-carboxylate, a compound of Formula I.
Reaction SMILES: C1(O)CCC1.[CH3:6][C:7]1([CH3:24])[CH:9](/[CH:10]=[CH:11]\[C:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18]CC2)=[O:13])[CH:8]1[C:21]([OH:23])=[O:22].[CH3:25][C:26]1(C)[CH:28](/C=C\C(O)=O)[CH:27]1C([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:24][C:7]1([CH3:6])[C@@H:9](/[CH:10]=[CH:11]\[C:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18]2)=[O:13])[C@H:8]1[C:21]([O:23][C:26]([CH3:28])([CH3:27])[CH3:25])=[O:22]
Reactant: CC1(C)C(/C=C\C(=O)OC2CCCCC2)C1C(=O)O
Reactant: CC1(C)C(/C=C\C(=O)O)C1C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: OC1CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC2CCC2)C1(C)C

Procedure:
1.7 ml of cyclobutanol were added to a solution of 4 g of tert.-butyl (1R, cis) 2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropane-carboxylate in 20 ml of methylene chloride and 3.45 g of dicyclohexylcarbodiimide and a solution of 28 mg of 4-dimethylamino-pyridine in 20 ml of methylene chloride were added thereto at 0° to 5° C. with stirring. The mixture was stirred for 2 hours at 5° C. and 2 hours at room temperature and was then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 n-hexane-isopropyl ether mixture yielded 2.3 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[Z-2-(cyclobutoxycarbonyl)-ethenyl]-cyclopropane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12]C(O)=O)=[CH:8][C:7]=1[CH3:16])=[O:5].O>C(O)(=O)CC>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH3:12])=[CH:8][C:7]=1[CH3:16])=[O:5]
Reactant: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCC(=O)O
Product: Cc1cc(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl

Procedure:
A solution of 62.69 g (0.18 mole) 5-(2,4-dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid (4) in 550 mL of propionic acid was heated under reflux overnight then poured into water. The solution was extracted three times with diethyl ether. The ether solution was washed successively with NaHCO3, water and brine, and dried (MgSO4). Evaporation of the solvent in vacuo gave a tan solid which was recrystallized from methylcyclohexane: mp 96-98° C.; mass spectrum (Cl—CH4) m/z=282 (M+1); NMR 300 MHz (CDCl3) d 7.5 (s, 1H); 7.35-7.2 (m, 2 H); 5.8 (s, 1H ); 3.9 (s, 3 H); 2.25 (s, 3 H); 1.6 (s, 3 H). Anal Calcd for C14H13Cl2NO: C, 59.59; H, 4.64; N, 4.96. Found: C, 59.79; H, 4.39; N, 4.92.
Reaction SMILES: [OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])CO.[C:26]([O:31]CC(F)(F)F)(=O)[CH2:27][CH2:28][CH3:29].[CH2:37](C(C)=O)C>>[OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:37][C:26](=[O:31])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)OCC(F)(F)F
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CCC(C)=O
Product: CCCC(=O)CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A mixture of 1 g of 17α,21-dihydroxy-pregna-4-ene-3,20-dione and 10 ml of trifluoroethyl butanoate in 50 ml of methyl ethyl ketone was reacted at 45° C. in the presence of 5 g of Candida cylindracea lipase for 8-10 hours, adding at regular time intervals 1 g of lipase. After completion of the reaction, the lipase was filtered off, the filtrate was concentrated under vacuum, taking up the residue three times with solvent. The semi-solid residue was purified by chromatography on a silica gel column with a dichloromethane/methanol 99:1 mixture. The richer fraction was evaporated to obtain 0.89 g (2.14 mM) of 17α-hydroxy-21-butanoyl-pregna-4-ene-3,20-dione.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[F:21].[C:22](=[O:24])=[O:23]>C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: Cc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(Br)c(F)c(C(=O)O)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of diisopropylamine (1.8 mL, 12.7 mmol) in THF (20 mL) at −10° C., n-BuLi (0.68 g, 10.6 mmol) was added and the reaction was stirred for 1 hour at −10° C. and was then cooled to −78° C. A solution of 2-bromo-1-fluoro-4-methylbenzene (2.0 g, 10.6 mmol) in THF (10 mL) was added in dropwise and the reaction was stirred for 1 hour after which excess solid carbon dioxide (4.76 g, 106 mmol) was added. After 30 minutes the reaction mixture was allowed to warm to room temperature, allowing for pressure release, and was quenched with water. The resulting layers were separated and the aqueous portion was extracted with Et2O. The aqueous layer was then acidified with aqueous 6.0 M HCl solution and the resulting white precipitate was extracted into Et2O. The combined organic portions were dried (MgSO4), and concentrated in vacuo to afford 3-bromo-2-fluoro-5-methylbenzoic acid (2.1 g, 9.0 mmol, 85%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H) 7.60 (dd, J=5.9, 1.8 Hz, 1H) 7.75 (dd, J=6.2, 1.8 Hz, 1H).