Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2
Reactant: Cc1ccc2noc(-c3ccccc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2noc(-c3ccccc3)c2c1
Yield: 59 %

Procedure:
A mixture of 11.7 g (0.05 g mole) of 5-methyl-3-phenyl-2,1-benzisoxazole, 10.0 g (0.056 mole) of N-bromosuccinimide and 0.1 g of dibenzoylperoxide in 200 ml of carbon tetrachloride was heated at reflux under illumination by a flood lamp for 2.5 hr. The mixture was filtered and the filtrate was washed with 5% sodium hydroxide, dried over sodium sulfate and concentrated to give a solid as residue. This solid was recrystallized twice from 2-propanol to yield 9.5 g (59%) of crystals, m.p. 130° C. (with decomposition).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.CCN(CC)CC.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>C(Cl)Cl>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:29](=[O:32])[CH2:30][CH3:31])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: CCC(=O)Cl
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A mixture of 3-(6-(2-aminoethoxyl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one hydrochloride 103a (250 mg, 0.66 mmol) and Et3N (0.23 mL, 6.0 mmol) in DCM (15 mL) was added propionyl chloride (70 uL, 0.79 mmol). The mixture was stirred at RT for 2 h. The mixture was washed with water (20 mL*2). The organic layer was dried and concentrated to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)propionamide 119a (140 mg, 54%) as a light yellow solid. ESI-LCMS: m/z=395.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:51])=[CH:43][CH:42]=1.Cl>ClCCl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C:21]([NH:20][C:9](=[N:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][CH2:49][C:50]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:51])=[CH:45][CH:46]=2)=[O:16])=[CH:13][CH:12]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)O)cc1
Reactant: O=C(CCCc1ccc(O)cc1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CCCC(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoic acid (2.96 g) in dichloromethane (20.0 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.80 g), benzyl 4-(4-hydroxyphenyl)butanoate (2.00 g), and N,N-dimethyl-4-aminopyridine (286 mg), followed by stirring at room temperature overnight. To a reaction solution was added 1 M hydrochloric acid, followed by concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-[4-(benzyloxy)-4-oxobutyl]phenyl 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoate (3.98 g).
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:4]([Zn+])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][N:11]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1N1CCCCC1C)C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1>>[CH3:10][NH:11][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[C:4]1[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccnc1[Zn+]
Agent: [Br-]
Product: CNc1cnccc1-c1ncccc1C

Procedure:
The title compound was prepared in analogy to example 55, intermediate, from 3-methyl-2-pyridylzinc bromide (CAS RN 308795-91-7) and (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b). Light yellow sticky solid (93%). MS (ESI): m/z=200.3 [M+H]+.
Reaction SMILES: C(OC(COC1C=CC(C=C[C:16]2[N:21]3[CH:22]=[N:23][CH:24]=[C:20]3[CH:19]=[CH:18][CH:17]=2)=CC=1)=O)C.[OH-].[Na+]>C(O)C>[CH:24]1[N:23]=[CH:22][N:21]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=12
Reactant: CCOC(=O)COc1ccc(C=Cc2cccc3cncn23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccn2cncc2c1

Procedure:
5-[2-(p-[Ethoxycarbonylmethoxy]phenyl)-ethen-1-yl]imidazo[1,5-a]pyridine (3.2 g) is refluxed in 30 ml of ethanol with 20 ml of 1N sodium hydroxide for 3 hours. The ethanol is evaporated and the aqueous phase is adjusted to pH=6. Filtration yields the substituted phenoxyacetic acid 5-[2-(p-carboxymethoxy]phenyl)ethen-1-yl]imidazo[1,5-a]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([O:14][CH3:15])=[O:13].O.[CH3:22]OC(OC)N(C)C>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:22]=[C:17]([O:18][CH3:19])[C:16](=[O:20])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10]1
Reactant: COCC(=O)C(=NNc1ccc(I)cc1F)C(=O)OC
Reactant: COC(OC)N(C)C
Solvent: O
Product: COC(=O)c1nn(-c2ccc(I)cc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of methyl 2-[(2-fluoro-4-iodophenyl)hydrazono]-4-methoxy-3-oxobutanoate (6.27 g, 15.9 mmol) in N,N-dimethylformamide dimethyl acetal (60 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH to give the title compound (3.77 g, 59% yield) as off-white crystals: mp 160-162° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.90 (3H, s), 3.97 (3H, s), 7.36-7.41 (1H, m), 7.64-7.70 (2H, m), 7.73 (1H, d, J=2.6 Hz). Anal. Calcd for C13H10FIN2O4: C, 38.64; H, 2.49; N, 6.93. Found: C, 38.68; H, 2.59; N, 6.98.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:20][C:21]1[CH:22]=[C:23]([NH:31][CH2:32][CH:33]([OH:35])[CH3:34])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([N:31]2[CH2:32][CH:33]([CH3:34])[O:35][C:9]2=[O:11])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)CNc1cc(Br)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(c2cc(Br)cc(C(F)(F)F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 195.1 %

Procedure:
Add triethylamine (339 mg, 3.35 mmol) and triphosgene (250 mg, 0.838 mmol) to the solution of 1-(3-bromo-5-(trifluoromethyl)phenylamino)propan-2-ol (500 mg, 1.68 mmol) in dichloromethane (8 mL), stir the resulting mixture overnight at ambient temperature. Partition the reaction mixture between dichloromethane and water, separate the organic layer, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product. Purify with flash chromatography (silica gel, PE:EtOAc=1:1) to afford the product (530 mg, 97%). MS: (M+1): 324.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>ClCCl>[Br:19][C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Fc1ccc(-c2nc(-c3ccccn3)cs2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Fc1ccc(-c2nc(-c3ccccn3)c(Br)s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[2-(4-Fluoro-phenyl)-1,3-thiazol-4-yl]pyridine from step 1 (400 mg, 1.56 mmol) was dissolved in dichloromethane (10 mL), and N-bromosuccinimide (330 mg, 1.87 mmol) was added. The reaction was stirred at room temperature for 2 h. Then the solution was washed with water, and dried (Na2SO4). The drying agent was filtered off, and the filtrate was concentrated. The resulting residue was purified on a silica gel flash chromatography column eluted with 0-20% EtOAc-hexane to give the title compound. LC-MS m/z 337.0 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>C1COCC1.O>[CH2:3]([O:10][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) slurry of washed (hexanes) sodium hydride (14.07 g, 352 mmol) in THF (650 mL) was added dropwise a solution of benzyl alcohol (35.2 mL, 337 mmol) in THF (200 mL). After stirring for 15 minutes, a solution of 2-chloro-4-nitropyridine (50 g, 306 mmol) in THF (200 mL) was added dropwise. After heating to reflux for 16 hours, the black slurry was diluted with water (200 mL) and concentrated to remove the THF. The resulting mixture was diluted with more water and filtered. The filtrate was extracted with ether and ethyl acetate. The combine organics were dried and concentrated. The residue was chromatographed (10% ethyl acetate in hexanes) to provide the product as orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccc(Br)cc1
Product: O=[N+]([O-])c1cc(OCc2ccc(Br)cc2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromo-4-bromomethyl-benzene using the conditions described in Example 237C to provide 4-(4-Bromo-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide the title product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccc1C(F)(F)F
Product: CN(C)C=CC(=O)c1ccccc1C(F)(F)F

Procedure:
A mixture of 35 g. of o-trifluoromethylacetophenone in 35 ml. of dimethylformamide dimethylacetal is refluxed for 8 hours under anhydrous conditions and then evaporated to a yellow oil. Bulb to bulb distillation gives the desired product as a thick yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][CH:6]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1csc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
To a solution of 4-bromothiophene-2-carbaldehyde 63 (Avocado, UK) (1.20 g, 6.3 mmol) in THF (50 mL) at rt was added dropwise morpholine (0.96 g, 11 mmol). After the reaction was stirred at rt for 5 minutes, NaBH(OAc)3 (3.18 g, 15 mmol) was added in one portion. The resulting mixture was stirred at rt for 3 h. Ethyl acetate (80 mL) was added and then washed with NaHCO3 (20 mL×2) and brine (20 mL). The organic layer was dried with MgSO4. After the solvent was evaporated, the residue was purified by silica gel column chromatography to give 64 (1.31 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[C:10](F)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1>>[Cl:8][C:9]1[C:10]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:20])([F:19])[F:21])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1
Reactant: Oc1cccnc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccnc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-hydroxypyridine and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 237.8-238.8° C. 1H NMR (DMSO-d6/300 MHz) 13.3 (br s, 1H), 8.42 (m, 2H), 7.87 (s, 1H), 7.83 (s, 1H), 7.48 (m, 2H), 6.72 (s, 1H), 5.93 (q, 1H, J=7.2 Hz). 9F NMR (DMSO-d6/282 MHz) −77.8 (d, J=7.2 Hz). FABLRMS m/z 372 (M+H). ESHRMS m/z 370.0083 (M−H, Calc'd 370.0094). Anal. Calc'd for C16H9ClF3NO4: C, 51.70; H, 2.44; N, 3.77; Cl, 9.54. Found: C, 51.49; H, 2.47; N, 3.70; Cl, 9.69.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:12]1)=[O:4].[OH-].[Li+].CO.O>O1CCOCC1>[CH2:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C:14]2([N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([OH:4])=[O:2])[C:15]2=[O:16])[CH2:21][CH2:20]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of benzyl 3-(2-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.35 g, 4.7 mmol, 1 equiv.) and lithium hydroxide (394.4 mg, 9.4 mmol, 2 equiv) in a 3:1 mixture of methanol and water (20 ml t/v) was stirred at 60° C. for 16 hrs. Some dioxane was added to remove the turbidity in the reaction mixture and the stirring was continued for another 20 h. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated and dried in vacuo to afford the title compound as a cream solid (2.28 g, quant); 1H NMR (400 MHz, DMSO-d6): δ 1.88 (d, 2H, J=14 Hz); 2.38-2.45 (m, 2H); 3.52 (bs, 2H); 3.97-4.05 (m, 2H); 5.08 (s, 2H); 5.15 (d, 2H, J=16.4 Hz); 6.79-6.84 (m, 3H); 7.20-7.24 (m, 2H); 7.33-7.39 (m, 5H); 7.49-7.53 (m, 1H); 7.61 (dd, 1H, J=0.8 Hz); 7.68-7.72 (m, 1H); 791 (dd, 1H, J=1.6 Hz); 13.1 (bs, 1H); MS for C28H27N3O5 m/z 486.3 (M+H)+.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>CN(C=O)C.CCOC(C)=O>[CH2:1]([S:8][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([Br:11])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(Br)c1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cncc(SCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Benzyl mercaptan (1 g, 7.35 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.294 g, 7.35 mmol) was added, the ice bath was removed, and the reaction stirred for 15 minutes. 3,5-Dibromopyridine (1.74 g, 7.35 mmol) was added and the reaction was heated to 130° C. After heating for 1 hour the reaction was cooled then diluted with EtOAc and hexanes (1:1) and washed with 4× H2O and brine, with back-extraction. The combined organics were dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel (0-40% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:26]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)—N,N-dimethylpyrrolidin-3amine (1.2 equiv) to give 210 (M+1 410.0)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:26])([C@@H:21]([CH3:25])[C@@H:22]([OH:24])[CH3:23])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1>N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:26])([C@@H:21]([CH3:25])[C@@H:22]([O:24][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:23])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: C[C@H](OS(C)(=O)=O)[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 2.5 h
Yield: 99.9 %

Procedure:
140 mg (1.22 mmole) of methanesulfonyl chloride were added at 0° C. to a solution of 213 mg (0.72 mmole) of (2R*,3S*,4S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2,4-pentanediol [prepared as described in step (b) above] in 4 ml of pyridine, and the mixture was stirred for 2.5 hours. At the end of this time, the pyridine was removed by distillation under reduced pressure. The resulting residue was mixed with a dilute aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and freed from the solvent by evaporation under reduced pressure, to afford 270 mg of the title compound as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:20])=[O:21])=[CH:23][CH:24]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccncc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.5 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (42%); off white solid; MS: 433.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9]O)[CH:5]=[CH:6][CH:7]=1.[BrH:11]>>[Br:11][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(CCO)c1
Reactant: Br
Product: Nc1cccc(CCBr)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of 2-(3-Amino-phenyl)-ethanol (2.0 g) in 48% aq HBr (20 ml) was heated at 90° C. for 18 h. The mixture was cooled to room temperature, and the precipitate formed was collected by filtration. The solid was dried in vacuo yielding Building block M, 1.8 g (61% yield). LCMS purity 90%, m/z 200/202 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:15])=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1>[CH3:15][C:6]1[C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=[C:8]([C:11]([F:13])([F:12])[F:14])[N:7]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CN=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1CN
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3-(azidomethyl)-2-methyl-6-(trifluoromethyl)pyridine (292 mg, 1.35 mmol) in tetrahydrofuran (5 mL) was added triphenylphosphine (710 mg, 2.7 mmol), and the mixture was stirred to dissolution. After 5 min the mixture was placed in an oil bath at 50° C. and stirred overnight. The mixture was hydrolyzed with 2M HCl (3 μL) for 0.5 h, then partitioned between ethyl acetate (30 mL) and 0.5 M NaH2PO4 (30 mL). The organic phase was extracted with 0.5 M NaH2PO4 (10 mL), and the combined acidic aqueous extracts were basified with 50% KOH, and extracted with CH2Cl2 (2×30 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to a faintly yellow semi-solid (0.53 g). NMR and LC-MS showed that the material was only partially cleaved to the free amine (40%) with the remaining 60% being the phospinimine. The mixture was dissolved in MeOH (10 mL) and heated at reflux for 2 h. The mixture was concentrated in vacuo and the residue was treated with water (10 mL) and 6N HCl to pH<1, and ether (20 mL). The aqueous phase was separated and extracted with ether (20 mL). The aqueous layer was adjusted to pH>13 with 2N aq. KOH and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to yield an oil which was used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)(=[O:22])=[O:21])/[CH:9]=2)=[N:5][N:4]=[N:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(OCC)(=O)C>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:19][S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])=[CH:9][C:8]=1[S:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1
Reactant: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Yield: 99.5 %

Procedure:
13 mg (E)-N-(3-(1-methyl-1H-tetrazol-5-ylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13d) was dissolved in 50 ml ethyl acetate, to which was added 27 mg sodium hydrosulfite solid followed by 10 ml water. The mixture was shaken in a separation funnel until the yellow organic phase turned colorless. The organic phase was separated and washed with water and brine. Dried over Na2SO4, the organic phase was filtered and the filtrate was concentrated to dryness. The residue was dissolved in dichloromethylene and triturated with hexane. The precipitate was washed with dichloromethylene/hexane (1:1) affording the title compound 13 mg (99%) as a white solid, m.p.: 130° C. (dec.).