Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:27][CH2:18][C:13]1[C:12]([Cl:19])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:16]([F:17])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(Oc2cc(Cl)cc(C#N)c2)c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2Cl)c1
Yield: 61.2 %

Procedure:
The title compound was prepared as described herein using 3-chloro-5-[(2-chloro-6-fluoro-3-methylphenyl)oxy]benzonitrile (940 mg, 3.17 mmol), NBS (593 mg, 3.33 mmol) and AIBN (26.1 mg, 0.159 mmol) in CCl4 (30.0 ml) to give the title compound as a white solid (728 mg, 61%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41 (1H, dd, J=8.7, 5.3 Hz) 7.36 (1H, s) 7.18 (1H, s) 7.12-7.16 (1H, m) 6.99 (1H, s) 4.58 (2H, s). LCMS: m/z 375 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:6][C:5]=1[CH2:18][OH:19].O[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:30]=2)=[CH:25][CH:24]=1>>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=[CH:6][C:5]=1[CH2:18][O:19][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:30]=2)=[CH:27][CH:28]=1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Reactant: COC(=O)Cc1cccc(-c2ccc(O)cc2)c1
Product: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3cccc(CC(=O)OC)c3)cc2)c1C(OC)OC
Yield: 549 %

Procedure:
According to a method similar to Example (6-7), from [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (1.96 g, 6.32 mmol) obtained in Example (6-6) and methyl (4′-hydroxy-1,1′-biphenyl-3-yl)acetate (1.68 g, 6.95 mmol) obtained in Example (8-1), methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-3-yl)acetate was obtained (1.83 g, yield: 549%).
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[K+].[K+].CC#N>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:6]=[C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH3:8])[S:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1nsc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1-c1nc(Cl)ns1
Temperature: 100 °C

Procedure:
A mixture of 3,5-dichloro-1,2,4-thiadiazole (0.14 g, 0.93 mmol), 2-methoxyphenylboronic acid (0.16 g, 1.0 mmol), Pd(PPh3)4 (11 mg, 9.3 μmol), K2CO3 (0.26 g, 1.9 mmol), and CH3CN (3 mL containing 10% H2O) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for three minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole. LC/MS: m/z 227 (M+H)+ at 3.45 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34]([NH:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCCN1CCCC1
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCCN1CCCC1
Yield: 17 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 1-(2-aminoethyl)pyrrolidine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 17% yield: mp 183-184° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 2H), 7.04-6.97 (m, 2H), 6.33 (br s, 1H), 4.43 (s, 2H), 4.07-4.01 (m, 2H), 3.47-3.32 (m, 4H), 2.64-2.50 (m, 9H), 1.85-1.70 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 162.6, 162.5 (d, JC-F=245.2 Hz), 157.3, 155.4, 152.0, 131.4 (d, JC-F=3.0 Hz), 130.0 (d, JC-F=8.2 Hz), 118.3, 115.8 (d, JC-F=21.0 Hz), 54.3, 53.8, 47.2, 42.0, 41.6, 38.4, 23.5, 17.1; MS (ES+) m/z 432.4 (M+1).
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].O>[OH:8][CH2:9][C:10]1([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOCCC1(CO)CCC(=O)O1

Procedure:
A mixture containing 10.2 g (21.83 mmol) of the compound prepared in (e) above, 300 ml of a mixture of ethyl alcohol and water in a ratio of 9:1 and 1.5 g of 5% palladium on carbon (50% water content) was placed in a pressure bottle and hydrogenated at 40° C. under a pressure of 50 lbs. of hydrogen until uptake was complete. The catalyst was then filtered off and the filtrate concentrated in vacuo. The residue was crystallized from methanol to yield a solid.
Reaction SMILES: C(C1C=CC=CC=1)C.N([O:11][C:12](C)(C)[CH3:13])=O.ON1C(=O)C2=CC=CC=C2C1=O.C(=NO)(C1C=CC=CC=1)C.[N+](C(C1C=CC=CC=1)C)([O-])=O.[C:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:51])[CH3:50]>C(O)(=O)C>[C:12]([O:51][CH:49]([CH3:50])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:11])[CH3:13]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)c1ccccc1
Agent: CC(=NO)c1ccccc1
Agent: CC(c1ccccc1)[N+](=O)[O-]
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Solvent: CCc1ccccc1
Product: CC(=O)OC(C)c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
Ethylbenzene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 100° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that acetophenone oxime, (1-nitroethyl)benzene, acetophenone, and α-methylbenzyl acetate were formed in yields of 32%, 5%, 23%, and 15%, respectively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](Br)[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33].O>O1CCOCC1.[Cu]I>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[CH:13]=1
Reactant: O=C1CCCN1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1
Yield: 77.4 %

Procedure:
870 mg (2.78 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester, 53 mg (0.28 mmol) of copper (I) iodide, 1.126 g (5.5 mmol) of potassium phosphate and 0.26 ml (3.6 mmol) of pyrrolidin-2-one are refluxed in 15 ml of dioxane for 8 hours. After water is added, the dioxane is distilled off in a vacuum, made alkaline with about 12% ammonia solution and shaken out several times with ethyl acetate. The collected ethyl acetate phase is washed, dried, filtered and concentrated by evaporation. As a residue, 700 mg (77% of theory) of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid methyl ester is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:4])=[O:3].CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(N(C)S(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of methyl 3-[(methylsulfonyl)amino]-5-nitrobenzoate obtained in Reference Example 88.22 g (30 mmol), methyl iodide 2.0 mL (32 mmol), potassium carbonate 10.4 g (75 mmol) and acetone (250 mL) was stirred at room temperature for 16 hours. The mixture was filtered to remove the precipitates and the solvent was evaporated. To the residue was added water (150 mL) and the mixture was extracted twice with ethyl acetate (100 mL). After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 8.55 g (29.7 mmol) of the title compound (yield: 99%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]=[O:29])=[CH:20][C:19]=1[CH3:44]>O1CCCC1.CCCCCC>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:20][C:19]=1[CH3:44]
Reactant: Cc1cc(C(=C(C=CC=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)c(C)c1)c1ccc(F)c(C)c1)c1nnnn1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A solution of the dianion of ethyl acetoacetate (1.42 mL, 11.1 mmoles) in dry tetrahydrofuran (15 mL) was generated as described in Example 10 using 450 mg (11.3 mmoles) of NaH (60% in mineral oil) and 4.5 mL (11.1 mmoles) of 2.5M n-BuLi in hexane at 0° C. under argon. The orange dianion solution, after being chilled to -78° C., was transferred via a cannula into a tetrahydrofuran (15 mL) solution containing 5,5-bis(4-fluoro-3-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (2.12 g, 5.6 mmoles) at -78° C. The reaction mixture was stirred at -78° C. for 15 minutes. Analytical TLC eluted once with 50% (v/v) ethyl acetate in hexanes showed a major product at Rf =0.16. The reaction mixture was diluted with 20 mL of 1N HCl and the organic residues were extracted with ethyl acetate (30 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give a pale syrup. The crude product was chromatographed on a silica gel column eluted with 35% (v/v) ethyl acetate in hexanes to give 1.39 g (48.7%) of the title compound. MS (CI): m/e=511 for (M+H)+ ;
Reaction SMILES: [OH-].[K+].C(OC(C)C)(C)C.[CH:10]#[C:11][CH:12]([OH:14])[CH3:13].[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1=[O:25])[CH3:16]>O>[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1=[O:25])[CH3:16].[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1([OH:25])[C:10]#[C:11][CH:12]([OH:14])[CH3:13])[CH3:16]
Reactant: C#CC(C)O
Agent: CCC1CCCC(C)(C)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCC1CCCC(C)(C)C1(O)C#CC(C)O
Yield: 78 %

Procedure:
448 g (8 mole) of KOH and 1100 ml of di-isopropyl-ether were first introduced into a reaction vessel fitted with cooling and stirring devices. 154 g (2.2 mole) of but-1-yn-3-ol were then added to the above mixture (temperature 25°-30°; addition period:30 min), followed by 308 g (2.0 mole) of 2-ethyl-6,6-dimethyl-cyclohexanone (addition period:30 min; dropwise). The reaction mixture was then stirred at 35° for 17 hours and, after cooling, 500 ml of water were progressively added thereto. After separation of the organic phase, washing with 5% aqueous H2SO4 (200 ml), drying over Na2SO4, concentration and final distillation, there were isolated a first portion of unreacted 2-ethyl-6,6-dimethyl-cyclohexanone (46 g) and 313 g (78% yield) of 2-ethyl-6,6-dimethyl-1-hydroxyl-1-(3-hydroxy-but-1-yn-1-yl)-cyclohexane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10].C(N(CC)CC)C.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[CH3:20][Si:19]([CH3:22])([CH3:21])[O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1C=CC(=O)N1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-hydroxyethyl)maleimide (0.2 g, 1.41 mmol) in dry dichloromethane (10 ml) and triethylamine (0.22 ml, 1.57 mmol) at 0° C. was added chlorotrimethylsilane (TMS-Cl, 0.2 ml, 1.57 mmol). After stirring for 1 hour at room temperature, TLC analysis (ethyl acetate/petroleum ether 1:1) indicated one spot (Rf=0.67). Solvent was removed in vacuo and the residue was dissolved in dichloromethane and filtered through a small silica gel column eluting with dichloromethane. The fractions containing product were pooled and evaporated in vacuo to afford N-(2-trimethylsiloxyethyl)-maleimide (formula II) as colorless flakes (0.3 g; 100% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:14]=3[N:15]=2)=[C:5]([O:29]COC)[CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:14]=3[N:15]=2)=[C:5]([OH:29])[CH:4]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of 7 (100 mg, 0.23 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1 mmol) in methanol (20 mL) was stirred overnight at room temperature. After the solvent was evaporated, ethyl acetate (20 mL) was added to the resulting residue which was neutralized by Na2CO3, washed with brine and water, dried over MgSO4, and concentrated in vacuo to give a pale yellow solid that was purified by silica gel column chromatography (ethyl acetate) and crystallized from ethanol to afford a white solid of Zinbo-5 (80 mg, 89%): 1H-NMR (500 MHz, CDCl3) δ3.95 (s, 3H), 3.96 (s, 3H), 4.01 (s, 2H), 4.21 (s, 2H), 6.66 (s, 1H), 7.17 (dd, 1H, J=7.5, 5.0 Hz), 7.31 (t, 1H, J=8.0 Hz), 7.37–7.40 (m, 2H), 7.41 (s, 1H), 7.48 (d, 1H, J=8.0 Hz),7.67 (t, 1H, J=7.5 Hz), 8.66 (d, 2H, J=5.0 Hz), 11.27 (s, 1H); Anal. Calcd for C22H21N3O4: C, 67.51; H, 5.41; N, 10.74. Found: C, 67.12; H, 5.25; N, 10.57.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[Cl:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCC[C@H](Oc1cccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxybutyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol) was dissolved in DMF (1.0 mL, 13 mmol). NaH (5.9 mg, 246 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (67.8 mg, 411 μmol) was added. The mixture was stirred at 70° C. for 3 hours, then concentrated. 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19 mg, 100% purity). MS in/z: [M+H]+ calcd for C14H19Cl2NO, 288.08. found 288.0.
Reaction SMILES: C([S:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)[N:13]=1)C1C=CC=CC=1>[Hg].CN(C=O)C>[NH:16]1[C:15]([CH2:14][N:12]2[N:11]=[N:10][C:9]([SH:8])=[N:13]2)=[N:19][N:18]=[N:17]1
Reactant: c1ccc(CSc2nnn(Cc3nnn[nH]3)n2)cc1
Agent: [Hg]
Solvent: CN(C)C=O
Product: Sc1nnn(Cc2nnn[nH]2)n1
Reaction time: 0.14 h

Procedure:
5-Benzylthio-2-(1H-tetrazole-5-ylmethyl)-2H-tetrazole, 175 mg., prepared as described above under part C, was dissolved in 40 ml. of distilled DMF and reduced at the mercury pool cathode (14 cm2Hg pool) with a platinium wire anode. The electrodes were separated by a glass frit. The electrolyte was tetraethylammonium perchlorate, 0.1 M in the DMF solution of the substrate. The electrolysis was carried out at -2.7 to -2.85 volts for 500 seconds and at -2.80 v. for about 630 seconds.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:26])C=1.C(OC(C)C)(C)C>C(Cl)Cl>[Cl:17][C:2]([Cl:1])([Cl:16])[C:3]([NH:5][C:6]1[CH:7]=[N+:8]([O-:26])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1cnc2c(c1)CCCC2)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: O=C(Nc1cc2c([n+]([O-])c1)CCCC2)C(Cl)(Cl)Cl
Yield: 98.9 %

Procedure:
To a solution of 24.03 g of Compound 2 obtained in the above step (2) in 40 ml of methylene chloride is added 21.2 g of 80% m-chloroperbenzoic acid at room temperature, and the resultant mixture is stirred for 45 minutes. The reaction mixture is mixed with isopropyl ether and the crystals are filtered to give 25.06 g of the titled compound 3 as crystals. Yield: 99% mp.: 244° to 246° C. (dec.)
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:7]=1.[CH3:20]O>>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:20])=[O:11])=[C:8]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(Cl)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
Thionyl chloride (21 ml) was added to methanol at 10° C. and the solution stirred for 0.5 hours before being added to 4-chloro-2-(methylsulphonylamino)benzoic acid (11.1 g). The mixture was heated under reflux conditions for 2 days after which time a further addition of thionyl chloride (6 ml) was made and reflux resumed for a further 2 days. The solvent was evaporated to dryness, water added and the mixture extracted with ethyl acetate. The extract was washed with sodium hydroxide solution (2N) then with water, dried (magnesium sulphate) and evaporated to dryness to give methyl 4-chloro-2-(methylsulphonylamino)benzoate (3.85 g) as a cream solid, NMR (CDCl3) 3.25(s,3H), 3.9(s,3H), 7.3(dd,1H), 7.6(m,1H), 7.95(d,1H), 10.2(brs,1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH2:6]2)=[CH2:2].B1C2CCCC1CCC2.C1C[O:25]CC1>>[OH:25][CH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH2:6]2
Reactant: C=Cc1ccc2c(c1)CCCO2
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc2c(c1)CCCO2
Reaction time: 8 h
Yield: 24 %

Procedure:
A solution of the 6-vinylchroman intermediate (0.12 g, 0.27 mmol) in anhydrous THF (1 mL) was cooled to 0° C. and treated with 9-BBN (0.60 mL, 0.5 M in THF, 0.3 mmol). The reaction mixture was heated to reflux for 8 h. The reaction was quenched with water (1.5 mL) and treated with NaBO3·4H2O and the resulting slurry was stirred overnight. Diethyl ether (4 mL) and the reaction mixture were extracted with CH2Cl2 (2×20 mL). The organic layers were concentrated to a clear oil that was purified by silica gel chromatography eluting with ethyl acetate (50%, v/v) in hexane. This yielded the desired 6-(2-hydroxyethyl)chroman intermediate as a colorless oil (30 mg, 24%). 1H-NMR (CDCl3/TMS, ppm): 0.87 (m, 12H, 4a′-, 8a′-, 12a′-, 13′-CH3), 1.0-1.6 (m, 24H, 4′-, 8′-, 12′-CH, 1′-, 2′-, 3′-, 5′-, 6′-, 7′-, 9′-, 10′-, 11′-CH2, 2a-CH3), 1.81 (m, 2H, 3-CH2), 2.17, 2.24, 2.28 (3×s, 9H, 5a-, 7a-, 8a-CH3), 2.68 (t, J=6.8 Hz, 2H, 4-CH2), 3.01 (t, J=7.5 Hz, 2H, Ar-CH2), 3.74 (t, J=7.5 Hz, 2H, OCH2); 13C-NMR (CDCl3, ppm): 12.0, 15.1, 16.0 (5a-, 7a-, 8a-CH3), 19.6, 19.7 (CH3), 20.6, 21.0 (CH2), 22.6, 22.7 (CH3), 23.8 (2a-CH3), 24.4, 24.8 (CH2), 28.0 (CH), 31.2 (3-CH2), 32.7, 32.8 (CH), 37.3, 37.4, 37.5, 39.4, 40.0 (CH2), 62.2 (OCH2), 72.6 (2-C), 116.8, 122.3, 124.9, 132.4, 133.9 (aryl C), 150.1 (aryl C—O); HRMS (CI, m/z): 458.412154 (M+H+, Calc. for C31H54O2 458.412384).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:31]=[C:30]([CH:32]=[CH2:33])[N:29]=[CH:28][N:27]=2)=[CH:21][CH:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2](/[CH:33]=[CH:32]/[C:30]3[N:29]=[CH:28][N:27]=[C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:34])([F:17])[F:35])=[CH:24][CH:23]=4)[N:31]=3)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: C=Cc1ncnc(Nc2ccc(C(F)(F)F)cc2)n1
Reactant: Ic1ccc2c(cnn2C2CCCCO2)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)c1ccc(Nc2ncnc(/C=C/c3ccc4c(cnn4C4CCCCO4)c3)n2)cc1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
To a stirred solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.05 g, 0.152 mmol) in ACN (5 mL) were added N-(4-(trifluoromethyl)phenyl)-4-vinyl-1,3,5-triazin-2-amine (0.041 g, 0.152 mmol), tri-o-tolylphosphine (0.019 g, 0.061 mmol) and triethylamine (0.064 mL, 0.457 mmol). Nitrogen was purged for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.014 g, 0.015 mmol) was added and the reaction mixture was heated at 90° C. overnight. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate, and the organic layer was concentrated. The crude product was purified by flash chromatography on silica gel using 25% ethyl acetate in hexane to give (E)-4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine as a pale yellow solid (0.04 g, 42% yield). LCMS: R.T.=1.21 min; [M+H]+=467.33.