Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1)=[CH2:2].[CH3:11][N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:13]>>[Cl-:8].[CH3:11][N+:12]([CH3:13])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1
Reactant: CCCCCCCCCCCCN(C)C
Reactant: C=Cc1ccc(CCl)cc1
Product: C=Cc1ccc(C[N+](C)(C)CCCCCCCCCCCC)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a 200 ml flask were added 29.8 g of 4-vinylbenzyl chloride and 50 g of N,N-dimethyldodecylamine. The reaction mixture was stirred at room temperature for 24 h. The solid precipitate from the reaction was filtered, washed with diethyl ether, and dried under vacuum at room temperature.
Reaction SMILES: [C:1]([O:12][CH:13]([CH3:15])[CH3:14])(=[O:11])[C@H:2]([CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[OH:3].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1>[CH2:18]([C@H:4]([C@H:2]([OH:3])[C:1]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a cold (−78° C.) solution of diisopropyl (S)-(−)-malate (4.74 mL; 22.9 mmol; 1.0 eq.) in anhydrous THF (8.50 mL) was slowly added under argon lithium bis(trimethylsilyl)amide (48.1 mL; 1.0 M in THF; 48.11 mmol; 2.1 eq.) keeping the temperature below −66° C. After to 45 min of addition, the reaction mixture was stirred at −78° C. for 2 h, then the temperature of the reaction mixture was allowed to reach 11° C. After 1 h at that temperature, the mixture was cooled at −78° C. and allyl bromide (2.9 mL; 34.4 mmol; 1.5 eq.) was added. The solution was stirred overnight allowing the temperature to reach RT. The reaction was then quenched with ice water and an aqueous saturated solution of NH4Cl. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers were washed with a saturated solution of NaCl, dried over MgSO4 and evaporated to obtain an orange oil (5.4 g). Purification by chromatography (SiO2, 10/90 EtOAc/c-hex) gave the title product as a colorless oil (3.05 g, 51.5%). 1H NMR (CDCl3, 300 MHz) δ 5.76-5.59 (m, 1H), 5.07-4.80 (m, 4H), 4.08 (d, J=2.3 Hz, 1H), 3.03 (br s, 1H), 2.80-2.72 (m, 1H), 2.53-2.41 (m, 1H), 2.34-2.21 (m, 1H), 1.14 (d, J=6.4 Hz, 6H), 1.07 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)cc(-c3ccccn3)nc2c1
Product: COc1ccc2c(Cl)cc(-c3ccccn3)nc2c1

Procedure:
A mixture of 7-Methoxy-2-pyridin-2-yl-quinolin-4-ol (2.2 g, 8.71 mmol) in POCl3 (92 mL) was refluxed for 3 h and then removed the solvent in vacuo. Ice water was added to the residue, adjusted the pH>10 with 1.0 N NaOH, and extrated with EtOAc (2×). The combined extract was washed with water, brine, dried (MgSO4), removed solvent to supply the product as a yellow solid (89%, 2.1 g): DMSO-D6) δ ppm 3.97 (s, 3H), 7.40 (dd, J=9.16, 2.44 Hz, 1H), 7.53 (m, 1H), 8.01 (m, 1H), 8.09 (d, J=9.16 Hz, 1H), 8.46 (s, 1H), 8.56 (d, J=7.93 Hz, 1H), 8.74 (d, J=3.97 Hz, 1H). LC-MS (retention time: 1.50, Method D), MS m/z 271 (M++1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:18]([O:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: O[C@@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
A solution of 0.595 g (2.35 mmol) of (7R,8aS)-7-hydroxy-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 17), 0.430 g (3.52 mmol) of benzoic acid and 0.738 g (2.81 mmol) of triphenylphosphine in 25 mL of dry THF was treated with 0.44 mL (2.8 mmol) of diethyl azodicarboxylate, and the mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue purified by flash silica gel chromatography with 10:1 methylene chloride:acetone. A second chromatography of the major fraction with the same system gave 0.63 g (75%) of the title compound. mp (.HCl) 202°-205° C. HRMS calcd for C19H21 ClN3O2 (MH+): 358.1322, found: 358.1320.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[C:14]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[S:16])[NH2:15].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:16][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: NC(=S)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2csc(-c3cccnc3)n2)c1
Yield: 68.6 %

Procedure:
A mixture of 2-bromo-3′-nitroacetophenone (3.66 g) and 3-thiocarbamoylpyridine (2.07 g) in ethanol (40 ml) was refluxed for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 4-(3-nitrophenyl)-2-(pyridin-3-yl)thiazole (2.91 g).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[C@@H:13]([CH3:32])[CH2:12]1)=O)C1C=CC=CC=1.[F:33][C:34]1[CH:35]=[C:36]([CH2:41][CH2:42][NH2:43])[CH:37]=[C:38]([F:40])[CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([CH2:41][CH2:42][NH:43][C:27]2[N:26]=[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][NH:17][C@@H:14]4[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]4[CH3:32])[CH:20]=3)[CH:30]=[CH:29][N:28]=2)[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1NCc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CNCC[C@H]1NCc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 136 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G3. LC-MS showed the product had the expected M+H+ of 418 LC-MS showed the product had the expected M+H+ of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.70 (s, 1H) 8.39 (d, 2H) 7.97 (d, 1H)) 7.74 (d, 2H) 7.00 (d, 2H) 6.86 (d, 1H) 4.57 (s, 2H) 4.06 (m, 1H) 3.88 (m, 1H) 3.72 (m, 1H) 3.57 (m, 1H) 3.42 (d, 2H) 3.10 (t, 2H) 2.92 (m, 2H) 2.38 (m, 2H) 1.38 (d, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:20]([NH2:22])[CH3:21])[CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:20]([NH:22][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[S:9]([CH3:12])(=[O:11])=[O:10])[CH3:21])[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: COc1ccc(Cl)cc1C(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(C)Nc1cc(F)ccc1S(C)(=O)=O
Yield: 0 %

Procedure:
2,4-Difluoro-1-(methylsulfonyl)benzene (0.55 g, 2.9 mmol), 1-(5-chloro-2-methoxyphenyl)ethanamine (0.57 g, 2.9 mmol) and N,N-diisopropylethylamine (0.77 g, 5.9 mmol) were stirred at 65° C. in dry acetonitrile (20 mL) for 24 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.36 mg, 35% yield). 1H NMR (400 MHz, CDCl3): δ 7.74 (q, 1H), 7.18 (m, 2H), 6.84 (d, 1H), 6.79 (d, 1H), 6.42 (t, 1H), 6.17 (d, 1H), 4.78 (m, 1H), 3.91 (s, 3H), 3.08 (s, 3H), 1.52 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2].[OH-].[K+].[CH:19](I)([CH3:21])[CH3:20].O>CC(C)=O>[CH:19]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)n1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
6-Nitro-1,2,3,4-tetrahydrocarbazole (5.04 g) prepared by the method described in Journal of Chemical Society, p.833 (1924) was dissolved in 50 mL of acetone, and the solution was added with 2.25 g of potassium hydroxide and 8.45 g of isopropyl iodide, warmed to 50° C. and stirred for 3 hours. The reaction mixture was added with water and the deposited precipitates were collected to obtain 2.60 g of N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole. The resulting N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole (2.60 g) was dissolved in 100 mL of acetic acid, and the solution was added with 2.75 g of iron powder, warmed to 50° C., and stirred for 3 hours. The reaction mixture was filtered and the filtrate was diluted by adding water. The reaction mixture was made basic with 1 N sodium hydroxide and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane/ethyl acetate=7/3) to obtain 1.35 g of N-isopropyl-6-amino-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: CC(C)[O-].[La+3].CC(C)[O-].CC(C)[O-].CC(C)[O-].[C:18]1([As:24](=O)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C2C3C(=CC=CC=3)C=CC=2)C(O)=CC=C2C=1C=CC=C2>>[As:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[As](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Agent: [La+3]
Product: c1ccc([As](c2ccccc2)c2ccccc2)cc1

Procedure:
A complex according to the invention is synthesized as follows. At first, lanthanum isopropoxide is used as a metal isopropoxide and triphenyl arsinoxide is used as triphenyl oxide. Lanthanum isopropoxide, optically active binaphtol (BINOL derivative) and triphenyl arsinoxide are mixed at a ratio of 1:1:1 mol % in an argon atmosphere at room temperature for 30 minutes to 1 hour to obtain La-BINOL derivative-Ph3As═O complex.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2]>C1C=CC=CC=1>[CH:4]1[CH:11]=[CH:10][C:9]([CH2:6][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:8][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1CCl
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccccc1Cc1ccccc1

Procedure:
The reactions of this example use the procedures of Example 1. 2-Nitrobenzyl chloride is reacted with benzene to give 2-nitrodiphenylmethane which is reduced to 2-aminodiphenylmethane. The 2-aminodiphenylmethane is reacted with trifluoromethanesulfonic anhydride to give 2-benzyltrifluoromethanesulfonanilide, m.p. 55°-56.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=4)[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[O:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:33][C:34]4[CH:35]=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=4)[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)=[O:15])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(F)cc3)nc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccc(F)cc4)nc3)cc2)C(=O)O)cc1
Yield: 96.4 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-[2-(4-fluorophenyl)pyridine-5-carbonylamino]ethoxy]-phenyl]-2-(4-isopropylphenoxy)propionate (540 mg), which is the product of Example 100, was reacted with aqueous sodium hydroxide solution (1N, 3.00 ml) and the reaction mixture was treated to give the title compound (495 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([NH2:14])=[O:13])=[O:4].C(Cl)(=O)[C:21](Cl)=[O:22]>C(Cl)CCl>[F:19][C:2]([F:18])([F:1])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([N:14]=[C:21]=[O:22])=[O:13])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzamide (1.0 g, 3.6 mmol), oxalyl chloride (1.0 mL) and EDC (10 mL) to afford 0.750 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4](=[O:31])[CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[N:10](C(OC(C)(C)C)=O)[C:9]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4](=[O:31])[CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2F)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1F

Procedure:
Dissolve 3-[(o-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (3 mL) and stir for 5 hours. Concentrate the reaction in vacuo, dilute with ethyl acetate (100 mL), wash with saturated sodium carbonate, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound (650 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC(OC)=CC=2)=[CH:14][CH:13]=1)=[O:11].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(COc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of compound (1H-benzo[d]imidazol-2-yl)(4-(4-methoxybenzyloxy)phenyl)methanone (268 g, 0.75 mol) in dichloromethane (2.7 L) at ambient temperature was added TFA (289 mL, 3.75 mol, 5.0 eq.) slowly using an addition funnel. The reaction was stirred at ambient temp for 16 h. LCMS analysis of the reaction mixture revealed that the reaction was complete. The reaction mixture was neutralized with satd. aqueous NaHCO3 to pH=7-8, and stirred for 20 minutes. The resulting solid was filtered and washed with water and dried under vacuum oven at 45° C. to give product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-:13].[K+].[K+].C([O:25][CH2:26][CH:27]([CH2:37][CH2:38]Br)[CH2:28][O:29]CC1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[OH:25][CH2:26][CH:27]([CH2:28][OH:29])[CH2:37][CH2:38][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:13])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: O=C([O-])[O-]
Reactant: BrCCC(COCc1ccccc1)COCc1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Yield: 45.8 %

Procedure:
A mixture of 2-amino-6-chloropurine (1.275 g, 7.5 mmol) and potassium carbonate (0.69 g, 5 mmol) in dry dimethylformamide (30 ml) was sonicated for 15 min., benzyl 2-benzyloxymethyl-4-bromobutyl ether (1.82 g, 5 mmol) was added, and the mixture was sonicated for 4h and then stirred over-night. After evaporation in vacuum the residue was extracted with 3×50 ml of chloroform and the extracts were evaporated to dryness in vacuum. Chromatography (silica gel, chloroform+methanol 20+1 by volume) afforded 0.58 g (26%) of pure compound 4-(2-amino-6-chloropurin-9-yl)-2-benzyloxymethylbutyl benzyl ether. A small sample of said compound was recrystallized from toluene. M.p. 108.5°-109.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-methylsulfonylbenzoate (2.24 g, 9.2 mmol) and a 1 M aqueous potassium hydroxide solution (10 mL, 10 mmol). Heat to reflux. After 2 hours, filter while still hot, cool in an ice bath, and acidify by dropwise addition of a 1 M aqueous hydrochloric acid solution (11 mL) to give a solid. Collect the solid by filtration, rinse with water, and dry to give the title compound: mp; 189-191° C. Elemental Analysis Calculated for C9H10SO5: C, 46.95; H, 4.38. Found: C, 46.76; H, 4.40.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:9][CH:8]([CH3:10])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][N:29]=3)=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:38])=[O:5]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)cc1)C(=O)O
Reaction time: 6 h
Yield: 66 %

Procedure:
3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester (97 mg) was dissolved in CH2Cl2 (6 mL) and added with TFA (2 mL). Reaction was complete in 6 hrs as determined by TLC. After removing solvent, residue was purified by column chromatography (10% MeOH/CH2Cl2) to afford 3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid in 66% yield (54.5 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH:2]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:17][C:18]1[N:19]=[C:20]([NH:23][C:14](=[O:16])[C:10]2[CH:9]=[C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:13]=[CH:12][N:11]=2)[S:21][CH:22]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1cc(Oc2cccnc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)c2cc(Oc3cccnc3)ccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
Compound 2 (3.0 g, 14 mmol, 1.0 eq), 4-methylthiazol-2-amine (1.66 g, 14.5 mmol, 1.05 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.54 g, 14.5 mmol, 1.05 eq), and DIEA (2.6 mL, 15 mmol, 1.1 eq) were dissolved in DMF (69 mL) and stirred overnight at rt. The reaction was diluted with EtOAc and washed with H2O (2×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by preparative HPLC afforded 1.5 g (35%) of the title compound as an off-white powder: 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=5.5 Hz, 1H), 8.59-8.57 (m, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.60-7.56 (m, 2H), 7.31 (dd, J=5.5, 2.4 Hz, 1H), 6.89 (s, 1H), 2.29 (s, 3H); ES-MS [M+1]+: 313.1.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[C:16]([F:26])=[C:17]([CH:23]=[CH:24][CH:25]=3)C(OCC)=O)=[CH:12][CH:13]=2)[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28].[CH3:31][Mg]Br.[CH2:34]1[CH2:38][O:37]CC1>>[F:1][C:2]1([F:30])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[C:16]([F:26])=[C:17]([C:38]([OH:37])([CH3:34])[CH3:31])[CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28]
Reactant: CCOC(=O)c1cccc(-c2ccc3c(n2)N(C)S(=O)(=O)N3CC2CC2(F)F)c1F
Reactant: C1CCOC1
Reactant: C[Mg]Br
Product: CN1c2nc(-c3cccc(C(C)(C)O)c3F)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorobenzoate (37-1) (240 mg, 0.54 mmol, 1.0 eq) was dissolved in THF (4 mL). The reaction mixture was cooled to −78° C. and methylmagnesium bromide (0.91 mL, 2.7 mmol, 3.0 M, 5.0 eq) was added. The resulting mixture stirred at ambient temperature for 30 minutes. The reaction was quenched by the addition of NH4Cl (2 mL), extracted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (40 g SiO2, 10-70% EtOAc in hexanes) to afford 2-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-2-fluorophenyl)propan-2-ol (37-2) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.81 (td, J=1.6, 7.6 Hz, 1 H); 7.59 (td, J=1.6, 7.6 Hz, 1 H); 7.42 (dd, J=2.0, 8.0 Hz, 1 H); 7.23 (t, J=7.6 Hz, 1 H); 7.06 (d, J=8.0 Hz, 1 H); 3.81-4.03 (m, 2 H); 3.49 (s, 3 H); 2.15 (m, 1 H); 1.69 (s, 6 H); 1.66 (m, 1 H); 1.39 (m, 1 H). HRMS m/z (M+H) 428.1242 found, 428.1250 required.