Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Cl.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]([CH:9]=1)=[N:19][N:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]=2[NH2:7]
Reactant: NNc1ccccc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1c2ccc(Br)cc2nn1-c1ccccc1
Temperature: 140 °C
Reaction time: 72 h
Yield: 25.6 %

Procedure:
To a dried flask charged with 4-bromo-2-fluorobenzonitrile (4.0 g, 18.0 mmol) in n-butanol (60 mL) was added a solution of phenylhydrazine hydrochloride (10.4 g, 72.0 mmol, 4.0 eq) and diisopropylethylamine (13.2 mL, 75.6 mmol, 4.2 eq) in n-butanol (35 mL). The reaction mixture was stirred at 140° C. under N2 for 3 days. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 10 to 65% EtOAc/hexane) and the product containing fractions were concentrated. Crystallization from DCM-hexane afforded 1.33 g (26%) of the title compound as beige solid. 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, 1H), 7.69 to 7.66 (m, 2H), 7.58 to 7.54 (m, 2H), 7.47 to 7.44 (m, 2H), 6.78 (dd, 1H), 6.50 (s, 2H); ES-MS m/z 288.1/290.1 [M+H]+, RT (min) 2.28.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]([CH3:23])[CH3:22])=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=1)=O)C.Cl.[CH:30]([NH2:32])=[NH:31].CO>CC(O)=O.CN(C=O)C>[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:32]=[CH:30][N:31]=[C:4]([OH:3])[CH:5]=2)=[CH:9][C:10]=1[C:24]([F:27])([F:26])[F:25])([CH3:23])[CH3:22]
Reactant: N=CN
Reactant: CCOC(=O)CC(=O)c1ccc(Sc2ccccc2C(C)C)c(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)c1ccccc1Sc1ccc(-c2cc(O)ncn2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 13.9 %

Procedure:
Then, 6-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyrimidin-4-ol 46 was prepared as follows. The mixture of compound 45 (10.6 g, 25.8 mmol) and formamidine hydrochloride (10.4 g, 129 mmol) in 20% HOAc in DMF (50 mL) was heated at 120° C. for 3 days. MeOH (50 mL) was added and the resulting solution was purified on a preparative HPLC column, C8 reverse-phase column, eluted with NH4OAc-H2O—CH3CN. Evaporation of solvents gave a white solid 46 (1.40 g, 14%); MS (APCI) m/z 391 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4].C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:21](=[O:22])[C:20]2[C:19]([Cl:18])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:28])=[CH:8][NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]cc1N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
A solution of 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (0.634 Kg, 4.49 mol, 1 wt) in 1,4-dioxane (8.90 L, 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6-dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25° C. Residual 2,6-dichlorobenzoyl chloride was washed in with a line rinse of 1,4-dioxane (0.990 L, 1 vol) and the reaction mixture stirred at 18 to 25° C. until complete (16 hours) by TLC analysis (eluent: ethyl acetate:heptanes 3:1; Rf amine 0.25, Rf product 0.65). The reaction mixture was filtered, the filter-cake washed with 1,4-dioxane (2×0.990 L, 2×1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation.
Reaction SMILES: [H-].[Na+].O[CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)[CH2:5][C:6]#[N:7].[H][H].C(OC(=O)C)(=O)C>O1CCCC1.O>[C:14]1([C:10]2[CH:9]=[C:8]([CH:4]=[CH:5][C:6]#[N:7])[CH:13]=[CH:12][CH:11]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#CCC(O)c1cccc(-c2ccccc2)c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: N#CC=Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
Under a nitrogen atmosphere a mixture of 1.9 grams (0.048 mole) of sodium hydride (60% in mineral oil) in 50 mL of tetrahydrofuran was stirred, and a solution of 10.7 grams (0.048 mole) of 3-hydroxy-3-(3-phenylphenyl)propanenitrile in 100 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred until the evolution of hydrogen gas ceased. After this time the reaction mixture was cooled in an ice-bath, and 4.6 mL (0.048 mole) of acetic anhydride was added dropwise. Upon completion of addition, the reaction was allowed to warm to ambient temperature where it was stirred for about 18 hours. The reaction mixture was poured into 300 mL of water, and the mixture was extracted with 200 mL of diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.0 grams of 3-(3-phenylphenyl)-2-propenenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22](O)[C:21]=2C)[OH:19])=[CH:8][CH:7]=1.I.[NH2:30][C:31]1[C:32]([C:39]([NH:41][C:42](=[NH:45])SC)=[O:40])=[N:33][C:34]([Cl:38])=[C:35]([NH2:37])[N:36]=1.C(N(C(C)C)CC)(C)C.[CH2:55]([OH:57])C>>[NH2:30][C:31]1[C:32]([C:39]([NH:41][C:42]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@H:18]([OH:19])[C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH2:55][OH:57])[CH:21]=3)=[CH:10][CH:11]=2)=[NH:45])=[O:40])=[N:33][C:34]([Cl:38])=[C:35]([NH2:37])[N:36]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: Cc1c([C@@H](O)CNCCCCc2ccc(CCCCN)cc2)ccc(O)c1O
Reactant: CCO
Agent: I
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NCCCCc1ccc(CCCCNC[C@H](O)c2ccc(O)c(CO)c2)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 65 °C
Reaction time: 5 h
Yield: 5 %

Procedure:
A solution containing 62 (0.24 g, 0.62 mmol) dissolved in ethanol (8 mL) was heated to 65° C. The reaction mixture was treated with 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.24 mg, 0.62 mmol) and diisopropylethylamine (0.47 mL). The reaction mixture was stirred at that temperature for 5 h under N2 atmosphere. The solution was concentrated vacuo. The resulting residue was first purified by column chromatography eluting with a mixture of 0-20% (10% concentrated ammonium hydroxide in methanol) and dichloromethane, and then further purified by preparative TLC using the same solvent system to afford the desired product 63 (15 mg, 5%) as a pale yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.22 (d, 1H), 7.08 (d, 4H), 6.97 (d, 1H), 6.68 (d, 4H), 6.57 (br, 1H), 4.45 (s, 2H), 3.15 (d, 2H), 2.33 (t, 1H), 1.59-1.52 (m, 6H), 1.39 (s, 2H), 1.23 (s, 1H), m/z (ESI) 600 [C29H39ClN8O4+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[NH:6][CH:7]=1.CCN(C(C)C)C(C)C.I[CH2:29][C:30]([NH2:32])=[O:31].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:6]([CH2:29][C:30]([NH2:32])=[O:31])[CH:7]=1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Br)c[nH]2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)NC2C=CC(Br)=CN2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a suspension of N-(5-bromopyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide (step 1) (11.3 g, 34.5 mmol) in DMF (70 mL) was added Huenig's base (N-ethyldiisopropyl amine) (6.62 mL, 38.0 mmol) and 2-iodoacetamide (7.03 g, 38.0 mmol). The mixture was stirred at room temperature for 15 h. The mixture was poured into 750 mL of water. The mixture was stirred for 90 min and the solid precipitate was collected by filtration. The filter-cake was washed with water and then ether, and then dried at 70° C. under vacuum for 1 h to afford 2-(5-bromo-2-(4-methylphenylsulfonamido)pyridin-1(2H)-yl)acetamide (13.0 g, 98.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.37 (d, J=2.2 Hz, 1H), 7.88 (dd, J=9.7 Hz, 2.5 Hz, 1H), 7.79 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.29 (t, J=9.3 Hz, 3H), 4.79 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Na].[H][H].CI.C(I)CC.[CH2:16](I)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:24]([N:26](CC)CC)[CH3:25]>>[N:26]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:25][CH:24]=1
Reactant: ICc1ccccc1
Reactant: [H][H]
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CI
Solvent: CCCI
Product: c1ccc2ncccc2c1

Procedure:
To the solution is added one equivalent to a small excess amount of a base, e.g. potassium carbonate, triethylamine, sodium hydrogen, one equivalent to excess amount of halogens alkyl derivative, e.g. methyl iodide, propyl iodide, benzyl iodide, and the mixture is stirred at a temperature of 0° C. to 80° C. to give a quinoline derivative (ivz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([N:13]([CH3:15])[CH3:14])=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1.[NH2:28][C:29]1[C:34]2[O:35][CH2:36][C:37](=[O:39])[NH:38][C:33]=2[CH:32]=[CH:31][CH:30]=1>C1COCC1.CN(C=O)C>[CH3:14][N:13]([CH3:15])[C:4]1[C:3]([CH2:2][NH:1][C:21]([NH:28][C:29]2[C:34]3[O:35][CH2:36][C:37](=[O:39])[NH:38][C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:22])=[CH:8][CH:7]=[C:6]([C:9]([F:10])([F:11])[F:12])[N:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: CN(C)c1nc(C(F)(F)F)ccc1CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)c1nc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2c1OCC(=O)N2
Temperature: 70 °C
Yield: 21 %

Procedure:
To a solution of 29d (0.78 g, 3.5 mmol) in THF (35 mL) was added CDI (2.1 mol eq, 1.21 g) and the mixture was heated at 70° C. overnight. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×25 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure (pale orange oil, quantitative yield). The oil obtained (0.46 g) was dissolved in DMF (25 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.2 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (7:3 EtOAc:petroleum ether) to obtain the product as a pale yellow solid (0.12 g, 21% Yield). 1HNMR (DMSO, 400 MHz) δ 2.84 (s, 6H), 4.36 (d, 2H, J=6), 4.62 (s, 2H), 6.49 (dd, 1H), 6.80 (t, 1H), 7.36 (m, 2H), 7.73 (m, 2H), 8.20 (s, 1H), 10.66 (bs, 1H). [M+1] 410.02 (C18H18F3N5O3 requires 409.36).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:14]2[CH:23]=[CH:24][C:25]([S:27]([N:30]3[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[N:31]3)(=[O:29])=[O:28])=[CH:26][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:14]2[CH:23]=[CH:24][C:25]([S:27]([N:30]3[CH:34]=[C:33]([C:35]([OH:1])=[O:36])[CH:32]=[N:31]3)(=[O:29])=[O:28])=[CH:26][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone (344 mg, 0.56 mmol) was added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carbaldehyde (201 mg, 0.47 mmol) (see example 23 for preparation) in DMF (8 mL). The resulting mixture was stirred overnight at room temperature and used directly for step A. MS (ESI) (M+H)+=447.09.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1>[OH:19][C:18]1[CH:20]=[C:21]([OH:22])[CH:23]=[CH:24][C:25]=1[C:2]1[N:4]=[C:5]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:7]=[C:8]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cccc(C)c1
Reactant: Oc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 2 °C
Reaction time: 22 h

Procedure:
A mixture of 1.84 g cyanuric chloride (10 mmol), 2.12 g of m-xylene (2 eq.), and 1.10 g of resorcinol (1 eq.) in 20 mL chlorobenzene under a nitrogen atmosphere was cooled to 2° C. Aluminum trichloride (2.12 g, 1 eq.) was added over 2 mm. The mixture was then warmed to 35° C. with stirring. After 22 hr., a sample was taken and quenched with ice and dilute aq. HCl. The resulting precipitate was filtered, washed with water, dissolved in tetrahydrofuran and analyzed by HPLC. HPLC analysis (area % at 290 nm) showed mainly tris- and bis-resorcinol containing triazine products 2,4,6-tris-(2,4-dihydroxyphenyl)-s-triazine (1) and 2-chloro-4,6-bis-(2,4-dihydroxyphenyl)-s-triazine (2) with no m-xylyl substitution. The ratio of 1 to 2 was 21:78. Unreacted m-xylene was also present. The only triazine product containing xylene observed was bisresorcinol-triazine based 2,4-bis-(2,4-dihydroxyphenyl)-6-(2,4-dimethylphenyl)-s-triazine 3. The monoresorcinol-triazine based product, 2-(2,4-dihydroxyphenyl)-4,6-bis-(2,4-dimethylphenyl)-s-triazine 4 was not formed.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.C1(C(Cl)=[O:31])CC1.[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=CC=1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:39]([CH2:33][CH:38]1[CH2:37][CH2:36]1)=[O:31]
Reactant: Cc1cccc(Oc2ccc(OCCN)c(Cl)c2)c1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Product: Cc1cccc(Oc2ccc(OCCNC(=O)CC3CC3)c(Cl)c2)c1
Reaction time: 2 h

Procedure:
To a mixture of 185 g (0.667 mol) of 2-[2-chloro-4-(3-tolyloxy)phenoxy]ethylamine, 81 g (0.80 mol) of triethylamine and 8 liter of toluene, there is added dropwise a solution of 70 g (0.67 mol) of cyclopropane carbonyl chloride in 2 liter of toluene with stirring at a temperature of from 5° C. to 10° C. After 2 hours, the reaction mixture is stirred at a room temperature for 15 hours. After the reaction is completed, the resultant mixture is washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give N-{2-[2-chloro-4-(3-tolyloxy)phenoxy]ethyl}-cyclopropane carboxyamide.
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7][CH2:8][CH3:9].NC1[CH:12]=[N:13][C:14]([Br:17])=[CH:15]C=1.N(OC(C)(C)C)=[O:19].C(Cl)Cl>C(COC)OC.CCCCC>[C:6]([O:7][C:8]1[CH:12]=[N:13][C:14]([Br:17])=[CH:15][CH:9]=1)(=[O:19])[CH3:5]
Reactant: CC(C)(C)ON=O
Reactant: CCOCC
Reactant: Nc1ccc(Br)nc1
Agent: FB(F)F
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCCCC
Product: CC(=O)Oc1ccc(Br)nc1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 60.5 %

Procedure:
To 25.6 mL of boron trifluoride etherate (208 mmol, Aldrich) cooled to −15° C. under N2 was added 18 g (104 mmol) of 3-amino-6-bromopyridine (from Step 123a above) dissolved in 35 mL of dimethoxyethane. Then t-Butyl nitrite (14.7 mL, 125 mmol, Aldrich) was added at a rate which kept the temperature below 0° C. Dimethoxyethane (65 mL) and methylene chloride (60 mL) were then added to aid stirring. After 10 minutes at −10° C. the mixture was allowed to warm to 5° C. and stirred for 30 minutes. Pentane (400 mL) was then added to the reaction mixture, the solid was collected by suction filtration, washed with cold ether, air dried, and dissolved in 125 mL of acetic anhydride. The resulting solution was heated to 100° C.±5° C. for 1 hour. The solvent was removed in vacuo, and the residue was suspended in saturated aqueous Na2CO3, and extracted with ethyl ether. The ether solution was dried over MgSO4, the solvent was removed in vacuo, and the residue was chromatographed on silica gel, eluting with 100:0 to 60:40 hexane:ethyl acetate to give 13.6 g of the title compound: 1H NMR (CDCl3 300 MHz) δ8.20 (m, 1H).7.51 (d, J=8.5 Hz 1H),7.38 (dd, J 2.9, 7.5 Hz, 1H), 2.35 (s, 3H). MS (CI/NH3) m/e: 216 (M+H)+, 233 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:11](Br)=[C:10]([N+:13]([O-])=O)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:16]([OH:18])=[O:17].[H][H]>[Pd].O>[NH2:13][C:10]1[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]([C:16]([OH:18])=[O:17])=[CH:2][CH:11]=1
Reactant: O=C(O)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: Nc1ccc(C(=O)O)c2c1OCCO2
Temperature: 50 °C
Yield: 83.7 %

Procedure:
400 ml of water, 98.5 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid, 100 ml of soda and 10 g of Pd/c were introduced into an autoclave and then hydrogen under a pressure of 40 kg/cm2 was introduced while heating to 50° C. The mixture was filtered and then treated with 95 ml of hydrochloric acid. The precipitate was dried off, washed and dried. 42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 186° C.; yield 83.7%).
Reaction SMILES: CN([CH:4]=[C:5]([C:10]1[S:14][C:13]([CH:15]([CH3:17])[CH3:16])=[N:12][C:11]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([O:8][CH3:9])=[O:7])C.Cl.[O:27]1CCCC1>>[OH:27][CH:4]=[C:5]([C:10]1[S:14][C:13]([CH:15]([CH3:17])[CH3:16])=[N:12][C:11]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=CN(C)C)c1sc(C(C)C)nc1/C=C/c1ccccc1
Reactant: C1CCOC1
Agent: Cl
Product: COC(=O)C(=CO)c1sc(C(C)C)nc1/C=C/c1ccccc1
Reaction time: 5 h

Procedure:
2 g of the enamine of Step F, 20 ml of tetrahydrofuran and 5 ml of a 2N hydrochloric acid solution were mixed together under nitrogen and left for 5 hours at 20° to 21° C. The tetrahydrofuran was evaporated off and the product was used as is for the following step.
Reaction SMILES: Cl[C:2]#[C:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13].S(=O)(=O)(O)[OH:17]>FC(F)(F)C(O)=O>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[O:5][CH2:4][CH2:3][C:2]2=[O:17]
Reactant: O=S(=O)(O)O
Reactant: FC(F)(F)c1ccccc1OCC#CCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCOc2c1cccc2C(F)(F)F
Temperature: 0 °C
Yield: 32.4 %

Procedure:
A solution of Example 18A (24.1 g, 103 mmol) and sulfuric acid (12 mL, 225 mmol) in trifluoroacetic acid (200 mL) was stirred at room temperature for 3 days. The reaction mixture was poured into ice-water and extracted with dichloromethane (2×200 mL). The organic layers were combined, washed with a saturated aqueous NaHCO3 solution (200 mL), dried (MgSO4), filtered, and concentrated. Silica gel chromatography (15% EtOAc/hexanes) gave the title compound (7.21 g, 33.4 mmol, 32%). MS (DCI/NH3) m/z 216 (M+NH4—H2O)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[N:13]1[N:14]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH2:23])[N:15]=[CH:16][CH:17]=1.N1C=CNN1S1C=CC(N)=C1>>[N:15]1[N:14]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:13]=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccsc1-n1nccn1
Agent: NC1=C[SH](N2NC=CN2)C=C1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2nccn2)cc1

Procedure:
The title compound was prepared from (2-(4-methoxyphenyl)acetic acid (1.21 g, 7.22 mmol) and a 1:1 mixture of 2-(2H-1,2,3-triazol-2-yl)thiophen-3-amine and 1-(1H-1,2,3-triazol-2-yl)thiophen-3-amine (431 mg, 2.61 mmol) according to protocol B to give N-(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide. Retention time (min)=5.712, method [7], MS(ESI) 315.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.99 (s, 1H), 8.06 (d, J=6.4 Hz, 1H), 7.67 (s, 2H), 7.28-7.31 (m, 2H), 7.02 (d, J=5.7 Hz, 1H), 6.98 (d, J=9.1 Hz, 2H), 3.88 (s, 3H), 3.76 (s, 2H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:50])([CH3:49])[CH2:15][O:16][C@H:17]1[CH2:20][C@H:19]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:49])([CH3:50])[CH2:15][O:16][C@H:17]1[CH2:18][C@H:19]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH2:20]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2C[C@H](OCC(C)(C)O)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.11 g), sodium hydrogen carbonate (0.18 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.056 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.021 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.018 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.03 g, 48%).