Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.C(Cl)(Cl)=O.[C:11]([O:14][CH2:15][C:16]1[CH2:17][S:18][C@@H:19]2[C@H:39]([NH:40][CH:41]=O)[C:38](=[O:43])[N:20]2[C:21]=1[C:22]([O:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:13])[CH3:12]>C(Cl)Cl>[C:11]([O:14][CH2:15][C:16]1[CH2:17][S:18][C@@H:19]2[C@H:39]([N+:40]#[C-:41])[C:38](=[O:43])[N:20]2[C:21]=1[C:22]([O:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:13])[CH3:12]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: [C-]#[N+][C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@H]12

Procedure:
Pyridine (8.1ml, 100mmole) and a solution of phosgene (2.94g, 29.7mmole) in dry methylene chloride (3.5ml) at -60° were added successively to a cold (-70°) solution of diphenylmethyl (6R,7R)-3-acetoxymethyl-7-formamidoceph-3-em-4-carboxylate (9.301g, 19.96mmole) in dry methylene chloride (150ml), under a dry nitrogen atmosphere. The reaction was allowed to warm to 0° and then partitioned between ethyl acetate (300ml) and water (100ml). The organic layer was washed with water (100ml) and combined with the ethyl acetate backwash (50ml) of the combined aqueous layers, dried, and then evaporated. The residual foam was dissolved in ethyl acetate (ca 50ml) and the solution slowly added to rapidly stirred petroleum ether (b.p. 60° to 80°). The petroleum ether was decanted from the precipitated solid which was dissolved in ethyl acetate (100ml). The solution was evaporated leaving the title compound as a pale-brown foam containing 1 /5 mole-equivalent of ethyl acetate (n.m.r., microanalysis) (7.176g, 15.4mmole, 77%), λmax 250.5nm (ε7,160); νmax 2153 (C≡N-), 1805 (azetidin-2-one), 1740 (OCOCH3) and 1730 cm-1 (CO2R); τ 2.66 (10H,s, [C6H5 ]2CH), 3.02 (1H,s, [C6H5 ]2CH), 4.81 and 5.12 (2H, 2D,J5Hz, C6 -H and C7 -H), 4.85 and 5.19 (2H, ABq, J14Hz, CH2OCOCH3), 6.49 (2H, broad s, C2 -H2), 7.98 (3H,s, C3 -CH3). (Found: C, 63.2, 62.8; H,4.5; N,5.8; S,6.8. C24H20N2O5S. 1 /5CH3CO2C2H5 (466.1) requires: C, 63.7; H, 4.65; N,6.0; S,6.9%).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH:22]([CH3:34])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:35]1[CH:40]=[C:39]([O:41]C)[C:38]([O:43]C)=[C:37]([O:45]C)[CH:36]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[OH:8][C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([CH2:20][CH2:21][CH:22]([CH3:34])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])=[CH:15][CH:16]=2)[O:11][C:10]=1[C:35]1[CH:40]=[C:39]([OH:41])[C:38]([OH:43])=[C:37]([OH:45])[CH:36]=1
Reactant: COc1cc(-c2oc3cc(CCC(C)CCCC(C)CCCC(C)C)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)CCCC(C)CCCC(C)CCc1ccc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a stirring solution of 48 (0.048 g, 0.08 mmol) in dichloromethane (2.5 ml) under argon at 0° C. was added boron tribromide (1.0M in DCM, 2.5 ml, 26 eq). The reaction was then warmed to room temperature and stirred for 19 hours. The mixture was then cooled to 0° C., methanol (2 ml) added heated to reflux for 2 hours. The reaction was then cooled and concentrated in vacuo to give a solid that was chromatographed (silica gel, chloroform:methanol, 9:1) to give 9i* (0.033g, 87%) as a waxy solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[F:25]>C(O)C>[F:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Fc1cnccc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccncc2F)n1
Temperature: 25 °C
Yield: 5.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (152 mg, 1.1 mmol) was dissolved in absolute ethanol (20 mL), then triethylamine (200 μL, 1.4 mmol) and 4-(bromomethyl)-3-fluoropyridine (260 mg, 1.4 mmol) were added. The mixture was stirred over the weekend at room temperature. The solid was removed by filtration and washed with methanol. The filtrate was evaporated, and the residue was triturated in methanol, filtered, washed with water and diethyl ether, and then dried in vacuo to afford to 2-{[(3-fluoropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (14 mg, 7% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.41 (s, 2H), 6.00 (bs, 1H), 7.58 (t, J=5.7 Hz, 1H), 8.37 (dd, J=0.8 Hz, J=4.9 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H); LRMS (ES+) m/z 252 (100%, M+1).
Reaction SMILES: C[O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH:11]([CH3:16])[CH2:12][CH2:13]2)[CH:9]=[C:8]([C:17]([OH:19])=[O:18])[C:7](=[O:20])[C:6]3=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[C:14]2=[C:15]3[N:10]([CH:11]([CH3:16])[CH2:12][CH2:13]2)[CH:9]=[C:8]([C:17]([OH:19])=[O:18])[C:7](=[O:20])[C:6]3=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Agent: Br
Product: CC1CCc2c(O)ccc3c(=O)c(C(=O)O)cn1c23

Procedure:
Using the procedure of Example 45, 6,7-dihydro-8-methoxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is reacted with hydrobromic acid to provide 6,7-dihydro-8-hydroxy-5-methyl-1-oxo-1H,5H-benzo [ij]quinolizine-2-carboxylic acid, m.p. >300° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cccnc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncccc1-c1ccc(CBr)cc1

Procedure:
A mixture of 2-cyano-3-(4tolyl)pyridine (940 mg, 4.84 mmol), N-bromosuccinimide (1.03 mg, 5.81 mmol), and dibenzoylperoxide (117 mg, 0.48 mmol) in CCl4 (70 mL) was heated to reflux to 2 h. The mixture was cooled then filtered through 50 g of silica gel eluting with CH2Cl2. The product was purified further by flash chromatography (20% EtOAc/hexanes) to give the above titled compound as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: Cc1cccnc1Br
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ncccc4C)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 2-bromo-3-methylpyridine
Reaction SMILES: [CH:1]1([C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9](=O)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:7][N:8]=1
Reactant: COc1ccc2c(C3CCCC3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(C3CCCC3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-cyclopentyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride. The product is too impure for a description by NMR. It is used as obtained in the following amination reaction.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: NC(=O)COc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: NC(=O)COc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-(4-formylphenoxy)acetamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 2-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenoxy]acetamide.
Reaction SMILES: CS[C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[ClH:24].BrC1C=C(C=CC=1)N>C(O)(C)C>[ClH:24].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12
Reactant: CSc1c2c(cc3c1=NCN=C3)=NC=N2
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2c3c(cc4c2=NCN=C4)=NC=N3)c1
Yield: 104.5 %

Procedure:
A mixture of 4-methylthio-6H-imidazo[4,5-g]quinazoline (0.5 g, 1.6 mmol) [Leonard, N. J.; Morrice, A. G.; Sprecker, M. A.; J. Org. Chem., 1975, 40, 356-363], 3-bromoaniline (0.35 g, 2.0 mmol), and 3-bromoaniline hydrochloride (0.4 g, 1.9 mmol) in isopropanol (200 mL) is heated under reflux for 1 h to give a precipitate of 4-(3-bromoanilino)-6H-imidazo[4,5-g]quinazoline hydrochloride (0.63 g, 72%). 1H NMR (DMSO) δ9.93 (1H, brs), 9.01 (1H, s), 8.66 (2H, s), 8.39 (1H, s), 8.04 (2H, m), 7.39 (1H, t, J=7.9 Hz), 7.31 (1H, brd, J=8.0 Hz). ##STR22##
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.OCC(CO)O.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [F-]
Solvent: OCC(O)CO
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 89.8 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of glycerol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 mg of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.9 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.CCN(C(C)C)C(C)C.[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH:25]2[CH2:28][NH:27][CH2:26]2)=[C:22]([F:31])[CH:21]=1>C(O)(C)C>[Cl:8][C:6]1[N:7]=[C:2]([N:27]2[CH2:28][CH:25]([O:24][C:23]3[CH:29]=[CH:30][C:20]([Cl:19])=[CH:21][C:22]=3[F:31])[CH2:26]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Reactant: Cc1nc(Cl)nc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)nc(N2CC(Oc3ccc(Cl)cc3F)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.800 g, 4.87 mmol) in isopropanol (15 mL) was added DIPEA (1.3 mL) and 3-(4-chloro-2-fluorophenoxy)azetidine (0.600 g, 2.92 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-6-methyl-1,3,5-triazine (1.0 g) as a solid. Observed mass (M+1): 329. The crude material was taken to next step without further purification.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH3:7].C(N(CC)CC)C.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.O1CCOCC1>[C:15]([N:5]1[C:6]([CH3:7])=[C:2]([I:1])[N:3]=[CH:4]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1[nH]cnc1I
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1c(I)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a cold (0° C.) solution of 4-iodo-5-methylimidazole (5.0 g, 24.0 mmol) and triethylamine (5.0 mL, 36.0 mmol) in CH2Cl2 (100 mL) and 1,4-dioxane (50 mL) was added trityl chloride (8.0 g, 29.0 mmol). The resultant mixture was stirred for 2 hours and quenched with ice and extracted with diethyl ether. The organic extracts were washed with sat. aq. NaHCO3, dried (K2CO3) and the solvent evaporated in vacuo. The product mixture was concentrated onto silica gel and chromatographed (Silica gel, 30-50% EtOAc in hexanes) to afford the title compound as a pale yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[C:18]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH3:34])[CH:28]=1)=[N:19][CH:20]=[N:21]2)=[O:11]>>[OH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[C:18]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:29]([CH3:34])[CH:28]=1)=[N:19][CH:20]=[N:21]2)=[O:11]
Reactant: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1O
Reactant: ClCc1cscn1
Product: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1OCc1cscn1
Yield: 21 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]acetamide (obtained as described in Example 79, preparation of starting materials) to give the title compound as a yellow solid in 21% yield; NMR spectrum (DMSO-d6) 2.20 (s, 3H), 3.71 (q, 2H), 3.77 (d, 2H), 4.38 (t, 2H), 5.23 (s, 2H), 5.49 (t, 1H), 7.08 (d, 1H), 7.13 (d, 1H), 7.32 (d, 1H), 7.44 (d, 1H), 7.57 (dd, 1H), 7.69 (t, 1H), 7.77 (d, 1H), 8.17 (t, 1H), 8.42 (s, 1H), 9.14 (d, 1H), 9.77 (s, 1H); Mass spectrum MH+ 466.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[C:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:24]([O:23][C:21](=[O:22])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:13]2[CH:14]=[CH:15][C:10]([C:9](=[O:20])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:33][CH:34]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of the product of Example 10A (5.132 g, 14.45 mmol) in anhydrous N,N-dimethylformamide (50 mL) was treated with N-Boc-4-hydroxyaniline (3.024 g, 14.45 mmol) and potassium carbonate (3.994 g, 28.90 mmol) at room temperature, then heated at 80° under a nitrogen atmosphere for 4.5 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with water (4×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give the product as a dark yellow solid (7.38 g, 13.97 mmol, 97%).
Reaction SMILES: CO[C:3]([C:5]#[C:6][C:7]([O:9]C)=[O:8])=[O:4].[OH:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[O:17]2.[OH-].[Na+]>O1CCOCC1.O.OS(O)(=O)=O>[CH3:23][O:22][C:20]1[C:21]2[C:3](=[O:4])[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[O:11][C:12]=2[C:13]2[CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[O:17][C:18]=2[CH:19]=1
Reactant: COc1cc(O)c2c(c1)OC(C)(C)CC2
Reactant: COC(=O)C#CC(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(c3oc(C(=O)O)cc(=O)c13)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a solution of dimethylacetylenedicarboxylate (7.5 g) in dioxan (100 ml) containing `Triton 8` (10 drops) was added 5-hydroxy-7-methoxy-2,2-dimethylchroman (10.0 g) and the resulting mixture was warmed on a steam bath for 2 hours. A solution of sodium hydroxide (4.0 g) in water (20 ml) was added and heating was continued for 2 hours more. The organic solvent was removed and water (50 ml) was added to the residue and the mixture was acidified to give an oil which was extracted into ethylacetate. This solution was dried over MgSO4, filtered and the filtrate was evaporated to dryness. The oil so obtained was dissolved in concentrated H2SO4 (50 ml) and the solution was stirred at room temperature for 30 minutes, poured into ice and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), filtered and evaporated to dryness. The oil so produced was triturated with ethyl acetate, cooled to 0°, and the solid produced was filtered and dried. The solid was crystallised from ethanol to give 8,9-dihydro-5-methoxy-8,8-dimethyl-4-oxo-4H,10H-benzo[1,2-b: 3,4-b']dipyran-2-carboxylic acid as a white solid (3.4 g, 23%) mp 225°-6°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.I[C:11]([F:16])([F:15])[CH:12]([F:14])[F:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: FC(F)C(F)(F)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Temperature: 70 °C
Yield: 22 %

Procedure:
To a solution of 3-bromo-5-fluorophenol (104 mmol crude), prepared as described in Step 1, Procedure 7, and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was cooled to rt, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated under reduced pressure to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification. LCMS: RT=1.91 min, [M+H] No Ionizable peak (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.76 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 100%); NMR: 400 MHz 1H (CDCl3) ppm 7.19 (m, 2 H), 6.92 (d, J=8.35Hz, 1 H), 5.88 (tt; J=52.95 Hz and J=2.64 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28][N:27]([C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[CH:36][C:35]=3[C:43]([F:46])([F:45])[F:44])[C:26]2=[O:47])=[CH:20][CH:19]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C1COCC1>[NH2:40][C:37]1[CH:38]=[CH:39][C:34]([N:27]2[C:26](=[O:47])[N:25]([CH2:24][C:21]3[CH:20]=[CH:19][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:9](=[O:10])(=[O:11])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[CH:23][CH:22]=3)[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28]2)=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=1
Reactant: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccc(N)cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1

Procedure:
The title compound is prepared from 4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-2-[4-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 21) by treatment with excess stannous chloride and concentrated hydrochloric acid in THF at 0° C. The reaction is worked up by treatment with excess sodium hydroxide, and the product is extracted with ethyl acetate. After drying over anhydrous sodium sulfate and removal of volatiles, the crude product is flash chromatographed over silica gel to afford the desired material.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:60])[CH3:59].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][N:68]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cccc2cnccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)CC1
Temperature: 100 °C

Procedure:
5-Bromoisoquinoline (1.37 g) from Step 1 was dissolved in 10 mL of toluene. To this solution was added palladium acetate (74 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (205 mg), 1-(tert-butoxycarbonyl)piperazine (1.29 g) and sodium tert-butoxide (885 mg). This reaction mixture was heated to 100° C. for 8 hours and then allowed to cool to room temperature. The cooled reaction mix was diluted with ethyl acetate (EtOAc) and washed with water, and the organic layer was separated, dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The resulting residue was chromatographed to yield 4-isoquinoline-5-yl-piperazine-1-carboxylic acid tert-butyl ester as 1.5 g of a white solid.