Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]2[CH2:32][NH2:33])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:33][CH2:32][C@H:27]2[CH2:28][CH2:29][CH2:30][CH2:31][N:26]2[CH2:25][CH:22]2[CH2:24][CH2:23]2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: NC[C@H]1CCCCN1CC1CC1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Product: Cc1c(Cl)nc(NC[C@H]2CCCCN2CC2CC2)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preperation 17) and [(2R)-1-(cyclopropylmethyl)piperidinyl]methylamine [see preparation 70]. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (95:5), to afford the product as a yellow oil, (87%).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17]C)[C:10]=3[CH:9]=2)=[N:5][CH:4]=1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[O:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(-c2cc3c(OC)cccc3o2)o1
Agent: BrB(Br)Br
Product: CCc1cnc(-c2cc3c(O)cccc3o2)o1
Yield: 65.8 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(5-ethyloxazol-2-yl)-4-methoxybenzo(b)furan (2.00 g) and boron tribromide (2.0 ml), the title compound (1.24 g) was obtained as colorless crystals.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[H-].[Na+].[C:31](OC)(=O)[CH3:32]>C1COCC1>[CH:25]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]4[N:28]=[C:31]([CH3:32])[O:1][N:2]=4)=[CH:5][CH:6]=3)[CH2:12][CH2:13]2)=[O:18])[CH2:24][CH2:23]1)([CH3:26])[CH3:27]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=N)NO)cc3)CC2)CC1
Reactant: COC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(O[C@H]3CC[C@H](C(=O)N4CCN(C(C)C)CC4)CC3)cc2)no1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 0.1 g (0.26 mmol) of trans-N-Hydroxy-4-[4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzamidine and 0.24 g of molecular sieves 4A in 3 ml THF, 17 mg (0.39 mmol, 55% purity) of sodium hydride was added and the mixture was stirred at 60° C. for 45 min. After cooling down, 0.1 ml (1.45 mmol) of methyl acetate was dropwised to the mixture and the mixture was refluxed for 5 hr. After that, 56 mg (1.28 mmol, 55% purity) of sodium hydride and 1 ml (14.5 mmol) of methyl acetate were added to the mixture. The mixture was refluxed for 16 hr. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel eluting with dichloromethane and methanol=from 98:2 to 19:1, after that, purified with cyclohexane and ethyl acetate=from 3:1 to 2:1. The combined product fractions were evaporated to dryness to yield 0.022 g (20% yields) of the titled compound. MS (m/e): 413.4 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[Na+].I[CH3:22]>CN(C=O)C>[CH3:22][O:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: Cc1ccc(C(=O)N[C@@H](CO)CC(C)C)cc1C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC[C@@H](CC(C)C)NC(=O)c1ccc(C)c(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of (R)—N-(1-hydroxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (1.59 g, 6.39 mmol) (example 71a) in dry DMF (20 mL) was added powdered NaOH (281 mg, 7 mmol) an the solution was stirred at 0° C. for 2 hrs. Iodomethane (1 eq, 6.39 mmol) was added in DMF (10 ml) drop-wise over period of 1 hr. The temperature was kept at 0° C. and the mixture was stirred for 1 hr. The reaction was quenched by adding 300 ml of water. The aqueous layer was extracted with dichloromethane, dried over MgSO4 and evaporated. The residue was purified by flash chromatography on silica-gel (toluene-ethyl acetate; 5-20% gradient) to give 1.23 g (R)—N-(1-methoxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (73%). 1H NMR (500 MHz, CDCl3): δ 0.94-0.97 (t, 6H), 1.41-1.47 (M, 1H), 1.54-1.60 (m, 1H), 1.64-1.68 (m, 1H), 2.29 (d, 6H), 3.36 (s, 3H), 3.45-3.50 (m, 2H), 4.34-4.39 (m, 1H), 6.23-6.25 (d, 1H), 7.16-7.17 (d, 1H), 7.47-7.49 (dd, 1H), 7.56 (s, 1H). MS (M+H, 264.3)
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([SH:25])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26](I)[CH2:27][CH3:28]>N>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([S:25][CH2:26][CH2:27][CH3:28])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCI
Reactant: Cc1cnc(S)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Agent: N
Product: CCCSc1ncc(C)c(-c2c[nH]c(C(=O)N[C@H](CO)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-mercapto-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueous ammonia (15%) was added at room temperature n-propyliodide (11.6 mmol, 1.1 mL). The solution was stirred overnight at room temperature. The resulting solid was collected by filtration and used directly for the next step. 1H NMR consistent with the structure.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:26])(=[O:25])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:4]([C:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21](=[O:26])(=[O:25])[N:22]([CH3:23])[CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2S(=O)(=O)N(C)C)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1
Product: CN(C)S(=O)(=O)c1ccccc1-c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2mmol), and 4-fluorobenzylamine (0.11 mL, 1.0 mmol). The title product was obtained as white needles (0.0549 g, 60% yield). 1HNMR (500 MHz, CDCl3) δ: 12.08 (1H, s), 7.91 (1H, d, J=7.33 Hz), 7.71–7.66 (3H, m), 7.37 (1H, dd, J=7.32, 1.83 Hz), 7.22 (2H, q, J=5.50 Hz), 7.00 (2H, t, J=8.55 Hz), 4.62 (1H, dd, J=15.26, 7.02 Hz), 4.40 (1H, dd, J=14.64, 5.49 Hz), 3.23 (3H, s), 2.64 (6H, s). HRMS (ESI) calcd for C21H22FSN4O5 (M+H): 461.1295; found: 461.1300.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16](SC)=[NH:17])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[N:20]#[C:21][NH2:22]>CO>[C:21]([N:22]=[C:16]([NH2:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1)#[N:20]
Reactant: CSC(=N)Cc1ccc2c(c1)Nc1nccnc1S2
Reactant: N#CN
Solvent: CO
Product: N#CN=C(N)Cc1ccc2c(c1)Nc1nccnc1S2
Yield: 73.5 %

Procedure:
To 15 ml of a solution of 410 mg of methyl (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate in methanol was added 250 mg of cyanamide and the resulting mixture was heated to 60° C. or below for 1 hour. Then the reaction mixture was brought back to room temperature and the solvent was distilled off under reduced pressure to reduce its amount. The crystals thus precipitated were taken up by filtration and washed successively with methanol and ethyl acetate. Thus, 295 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.O>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]2[O:5][CH:4]=[CH:3][C:11]=2[CH:10]=1)[CH2:14][CH3:15]
Reactant: CCCOc1ccc(OCC(OC)OC)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1ccc2occc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a suspension of polyphosphoric acid (5.2 g) in toluene (120 ml) was added 4-(2,2-dimethoxy)ethoxy-propoxybenzene (5.0 g), and the mixture was stirred at 100° C. overnight and cooled. To the mixture was added water, and the mixture was separated. The organic layer was washed with 1N sodium hydroxide solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give brown oil of 5-propoxybenzofuran (1.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2SC(NCCF)=N[C:6]=2[CH:14]=1.[CH3:15][N:16](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)[C:17](=[O:23])[O:18]C(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=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>[C:6]1([O:23][C:17](=[O:18])[NH:16][CH3:15])[CH:5]=[CH:4][CH:3]=[CH:2][CH:14]=1
Reactant: FCCNc1nc2cc(Br)ccc2s1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1ccccc1
Temperature: 95 °C
Yield: 198.5 %

Procedure:
A mixture of 5-Bromo-N-(2-fluoroethyl)benzo[d]thiazol-2-amine (60 mg, 0.2 mmol), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (68 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) in 2 mL dioxane and 0.5 mL of a 1 M Na2CO3 aqueous solution was heated at 95° C. in a microwave reactor for 10 min. After cooling to rt, it was diluted with EtOAc (30 mL) and washed with brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (5% to 50% EtOAc in hexane) to afford tert-butyl 44242-fluoroethylamino)benzo[d]thiazol-5-yl)phenyl(methyl)carbamate as a white solid (60 mg, 75%). MS (ESI) m/z 402 (M+H+).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>ClCCl.CN(C)C1C=CN=CC=1>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:35](=[O:36])[C:34]5[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (40 mg, 0.123 mmol, 1.0 equivalent, prepared as described in Example 46, Part H) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial, and triethylamine (0.051 mL, 0.37 mmol, 3.0 equivalents) was added. 3-(Trifluoromethyl)benzoyl chloride (33.4 mg, 0.160 mmol, 1.3 equivalents) was added as a solution in 0.1 mL of dichloromethane followed by 4-(dimethylamino)pyridine (1.50 mg, 0.012 mmol, 0.1 equivalent). The reaction was stirred for 30 minutes. The reaction solution was loaded directly onto a 4 g silica column and eluted with 50:50 to 100:0 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (31 mg, 54%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 8.07 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.3 Hz, 1H), 7.91 (s, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 5.47 (t, J=4.4 Hz, 1H), 4.51 (s, 1H), 4.34 (dd, J=17.0, 9.1 Hz, 1H), 4.22 (d, J=13.6 Hz, 2H), 3.84-3.75 (m, 1H), 3.26 (dd, J=12.7, 11.1 Hz, 1H), 3.04 (dd, J=14.2, 9.5 Hz, 1H), 2.94-2.77 (m, 1H), 2.71 (dd, J=15.4, 4.9 Hz, 1H), 2.41 (dd, J=14.0, 6.7 Hz, 1H), 2.05-1.82 (m, 2H), 1.00 (dt, J=4.9, 2.9 Hz, 2H), 0.93-0.80 (m, 2H); MS (ESI+) m/z 461.1 (M+H)+; [α]D23.6=−0.09 (c=0.13, CH3OH).
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:4][CH:3]([N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11])[C:2]#[CH:1]
Reactant: C#CC(C)O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)N1C(=O)c2ccccc2C1=O
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a solution of but-3-yn-2-ol (13.3 g, 0.19 mol), phthalimide (28.5 g, 0.19 mol) and triphenylphosphine (76.0 g, 0.28 mol) in tetrahydrofuran was added diethyl azodicarboxylate (123.8 g, 0.28 mol, 310 mL of 40% toluene solution) drop wise at room temperature. The reaction mixture was stirred for 16 h. Solvent was removed and the residue was treated with 600 mL mixture of ether and hexane (1:1). The precipitate was filtered off and the filtrate was concentrated to give 90 g of the crude. The crude was then purified on silica gel eluting with 15% ethyl acetate in hexane to give 24 g of the title compound as a white solid (63% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.72 (d, J=6.99 Hz, 3H) 2.35 (d, J=2.21 Hz, 1H) 5.22 (dt, J=14.34, 7.35, 2.57 Hz, 1H) 7.68-7.78 (m, 2H) 7.82-7.90 (m, 2H), MS (ESI), M/Z: 200.0 (M+H)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:16][OH:17].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[OH:17][CH2:16][CH2:15][CH:14]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH2:12][N:11]([CH3:10])[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CNCCC(CCO)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCC(CCO)c1ccccc1)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
N,N-Diisopropylethylamine (0.352 mL, 261 mg, 2.02 mmol) and 5-(methylamino)-3-phenylpentan-1-ol (300 mg, 1.68 mmol) from Example 180, Step B, were dissolved in 4.0 mL of dichloromethane. The solution was cooled to 0° C., benzoyl chloride (0.205 mL, 248 mg, 1.77 mmol) was added dropwise, and the mixture was stirred for an additional 30 min. The mixture was then partitioned between 15 mL of dichloromethane and 15 mL of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with 2×15 mL of dichloromethane. The combined organic extracts were washed with 20 mL of brine, dried over sodium sulfate, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 10% ethyl acetate in dichloromethane, to give 467 mg of the title compound. 1NMR (400 MHz, CD3OD) was complicated by the presence of a mixture of rotamers: δ 7.45-7.06 (m, 9H), 6.97 (d, 1H, J=8 Hz), 3.53-3.23 (m, 2H), 3.17-3.00 (m, 2H), 3.02 and 2.85 (two singlets, 3H), 2.88-2.78 and 2.57-2.49 (two multiplets, 1H), 2.07-1.64 (m, 4H). Mass spectrum (ESI): m/z=298 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:22](Br)[CH:23]=[CH2:24]>O>[CH2:24]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH:23]=[CH2:22]
Reactant: O=Cc1cc(F)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(F)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a round bottom flask were added 5-fluorosalicylaldehyde (47c, 4.0 g, 28.5 mmol, 1.0 equiv.), potassium carbonate (4.92 g, 35.6 mmol, 1.25 equiv.), and DMF (20 mL). Allyl bromide (3.7 mL, 42.8 mmol, 1.5 equiv.) was added slowly to the mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×25 mL), 0.1M KOH (2×25 mL), water (2×25 mL), and brine (2×25 mL), dried over MgSO4, filtered, and concentrated to yield 53b (4.64 g, 90.2%) as a pale yellow liquid. 1H-NMR (500 MHz, CDCl3) δ 10.47 (d, 1H, J=3.0 Hz), 7.50 (dd, 1H, J=3.0, 8.0 Hz), 7.23 (ddd, 1H, J=3.0, 7.5, 11.0 Hz), 6.95 (dd, 1H, J=4.0, 9.0 Hz), 6.06 (tdd, 1H, J=5.0, 10.5, 17.5 Hz), 5.44 (qd, 1H, J=1.5, 17.0 Hz), 5.34 (ddd, 1H, J=1.5, 2.5, 10.5 Hz), 4.64 (td, 2H, J=1.5, 5.0 Hz). 13C-NMR (125 MHz, CDCl3) δ 188.8, 157.4 (d, JC-F=1.9 Hz), 157.2 (d, JC-F=240.5 Hz), 132.4, 126.1 (d, JC-F=5.9 Hz), 122.6 (d, JC-F=23.8 Hz), 118.5, 114.8 (d, JC-F=7.1 Hz), 114.2 (d, JC-F=23.1 Hz), 70.1. 19F-NMR (470 MHz, CDCl3) δ −125.5. HRMS (EI): 180.05789 (M+); calcd. for C10H9FO2: 180.05866.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:6].[CH3:20]I>O1CCCC1>[F:3][C:4]([F:18])([F:19])[C:5]([N:7]([CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:6]
Reactant: CI
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a suspension of a 60% dispersion of sodium hydride in mineral oil (96 mg, 2.4 mmol) in dry tetrahydrofuran (5 mL), cooled to 0° C., was added a solution of 2,2,2-trifluoro-N-[(3-nitrophenyl)methyl]acetamide (500 mg, 2.0 mmol) in 5 mL dry teterahydrofuran. After stirring for 1 hour at 0° C., methyl iodide (132 μL, 2.2 mmol) was added in one portion. The reaction was stirred for 1 hour at 0° C., and warmed to rt overnight. After 16 h, the reaction mixture was concentrated, and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was dried over Na2SO4, filtered, adsorbed onto silica, and purified by column chromatography to yield the desired compound (0.36 g, 1.4 mmol, 69% yield). 1H NMR (400 MHz, CDCl3): δ 8.13-8.22 (m, 2H), 7.56-7.64 (m, 2H), 4.74 (s, 2H), 3.14 (s, 3H). MS (ESI) m/z=263 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([S:17]([CH3:16])(=[O:19])=[O:18])[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(Br)cc1)S(C)(=O)=O
Temperature: 0 °C

Procedure:
4-bromoaniline (500 mg, 2.91 mmol) and triethylamine (1215 μl, 8.72 mmol) were placed in a dry flask and dichloromethane (1.45 ml) was then added. The solution was cooled to 0° C. for 20 minutes. Methanesulfonyl chloride (226 μl, 2.91 mmol) was then added dropwise and the solution was allowed to warm to room temperature overnight. It was quenched with water and aqueous sodium bicarbonate, and extracted using ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was conducted via silica gel chromatography (0-100% ethyl acetate in hexanes) to yield the title compound. 1H NMR (600 MHz, d6-DMSO): δ 7.63 (d, 2H), 7.38 (d, 2H), 3.42 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([NH:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])(=[O:13])=[O:12])=[C:7]([CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CO.[C:27](N1C=CN=C1)(N1C=CN=C1)=O>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([NH:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([O:20][CH3:27])=[O:19])(=[O:12])=[O:13])=[C:7]([CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2c(Cl)cccc12
Solvent: CO
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3c(Cl)cccc3c2C)c1
Yield: 74 %

Procedure:
The product was prepared from 3-{[(7-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (9.2 mg, 0.024 mmol) (Example 44) and MeOH (50 μL, 1.23 mmol) according to the General Procedure 8, described in Example 119, using a different amount of 1,1′-carbonyldiimidazole (10.0 mg, 0.0621 mmol). The title compound was obtained in 74% yield (7.0 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.46 (s, 3 H) 3.87 (s, 3 H) 6.79 (s, 1 H) 7.37 (dd, J=8.06, 7.70 Hz, 1 H) 7.41 (dd, J=8.06, 7.69 Hz, 1 H) 7.43 (ddd, J=8.06, 2.32, 1.21 Hz, 1 H) 7.48 (dd, J=7.69, 0.98 Hz, 1 H) 7.65 (dd, J=8.06, 0.98 Hz, 1 H) 7.74 (dd, J=2.32, 1.51 Hz, 1 H) 7.84 (ddd, J=7.70, 1.51, 1.21 Hz, 1 H). MS (ESI+) m/z 396 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1I)[CH2:15][N:16]([CH3:20])[CH2:17][CH:18]=[CH2:19])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C([Li])CCC.CCCCCC.[CH2:38]([Sn:42](Cl)([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH3:41].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]([F:26])([F:25])[C:3]([C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[Sn:42]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:15][N:16]([CH3:20])[CH2:17][CH:18]=[CH2:19])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: C=CCN(C)Cc1ccc(I)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCN(C)Cc1ccc([Sn](CCCC)(CCCC)CCCC)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Compound 12 (470 mg, 945 μmol) was dissolved in freshly distilled THF (5 mL) under nitrogen atmosphere and cooled to −78° C. n-butyllithium 1.6M in hexane solution (886 μL, 1.42 mmol) was then added and the mixture stirred 30 min at −78° C. Tributyltin chloride (462 mg, 1.42 mmol) in solution in THF (2 mL) was added and the mixture let to warm to room temperature overnight. A 0.1M ammonium chloride solution (5 mL) was added to the reactionnal mixture. The organic layer was isolated and the aqueous layer was extracted with dichloromethane (2×5 mL). The organic layers were combined and dried over sodium sulfate. After solvent evaporation under reduced pressure, the residue was purified over silica gel with heptane/acetone (98/2) as eluant to give 524 mg (794 μmol, 84% yield) of a yellowish oil.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:24]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)=[CH:12][CH:11]=1>C(O)C.CN(C)C=O>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:24]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)=[CH:12][CH:11]=1)=[O:2]
Reactant: BrCc1ccc(-c2nc3ccccn3n2)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=Cc1ccc(-c2nc3ccccn3n2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
11.6 g of 2-nitropropane are introduced at about 30° C. into a solution of 2.3 g of sodium in 450 ml of absolute ethanol. The mixture is stirred for a further 1 hour and a solution of 28.8 g of 2-(p-bromomethyl-phenyl)-s-triazolo[1,5-a]pyridine (I) in 290 ml of dimethylformamide is now added. Subsequently, the reaction mixture is warmed to 50° C., then stirred for 20 hours without external warming and finally cooled to -10° C. The product which has precipitated is filtered off, washed with cold methanol and dried. This gives 19.3 g (86.5% of theory) of compound (II) in the form of a pale yellow powder with a melting point of 243° to 244° C. After recrystallising twice from dimethylformamide, 14.67 g (65.7% of theory) of small, virtually colourless, glossy needles with a melting point of 246° to 247° C. are obtained.