Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.Br[CH2:9][CH2:10][OH:11].[OH:12][C@@H:13]1[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[C@H:27]([CH3:33])[C@@H:26]([OH:34])[C@@H:25]([CH3:35])[CH2:24][CH2:23][CH2:22][C@@H:21]2[C@@H:19]([NH:20]2)[CH2:18][C@@H:17](/[C:36](/[CH3:44])=[CH:37]/[C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[O:16][C:15](=[O:45])[CH2:14]1>C(#N)C>[OH:12][C@@H:13]1[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[C@H:27]([CH3:33])[C@@H:26]([OH:34])[C@@H:25]([CH3:35])[CH2:24][CH2:23][CH2:22][C@@H:21]2[C@@H:19]([N:20]2[CH2:9][CH2:10][OH:11])[CH2:18][C@@H:17](/[C:36](/[CH3:44])=[CH:37]/[C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[O:16][C:15](=[O:45])[CH2:14]1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2N[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: OCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H]2[C@@H](CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)N2CCO
Temperature: 72.5 °C
Reaction time: 20 h
Yield: 68.2 %

Procedure:
Et3N (4.95 mL, 35.52 mmol) and 2-bromoethanol (3.02 mL, 42.62 mmol) were added to (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione (3.50 g, 7.10 mmol) in acetonitrile (35 mL) and heated to 72.5° C. After 20 hr, the reaction mixture was cooled to room temperature, concentrated to dryness through rotary vacuum distillation. The crude was dissolved in ethyl acetate (50 mL) and mixed with deionized water (35 mL). The mixture was extracted with ethyl acetate (3×35 mL), dried over Na2SO4, filtered, concentrated, crystallized in acetonitrile (35 mL), washed with acetonitrile (2×5 mL), and dried in vacuum oven at 45.5° C. overnight to isolate (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-17-(2-hydroxyethyl)-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione as a white crystalline powder (2.60 g, HPLC AP 97.1, 68.2% yield).
Reaction SMILES: Cl.[Cl-].[NH2:3][C:4]1[C:9]([CH2:10][N+:11]2[C:12]([CH3:20])=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[CH:15][CH:16]=2)=[CH:8][N:7]=[C:6](CC)[N:5]=1.[Na+].[Na+].[C:25]1([S:39]([O-:42])(=[O:41])=[O:40])[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([S:35]([O-:38])(=[O:37])=[O:36])[C:29]=2[CH:28]=[CH:27][CH:26]=1>O>[OH2:36].[C:25]1([S:39]([O-:42])(=[O:41])=[O:40])[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([S:35]([O-:38])(=[O:37])=[O:36])[C:29]=2[CH:28]=[CH:27][CH:26]=1.[NH2:3][C:4]1[N:5]([CH2:25][CH3:26])[CH2:6][N:7]=[CH:8][C:9]=1[CH2:10][N+:11]1[C:12]([CH3:20])=[C:13]2[S:19][CH:18]=[CH:17][C:14]2=[CH:15][CH:16]=1.[NH2:3][C:4]1[N:5]([CH2:25][CH3:26])[CH2:6][N:7]=[CH:8][C:9]=1[CH2:10][N+:11]1[C:12]([CH3:20])=[C:13]2[S:19][CH:18]=[CH:17][C:14]2=[CH:15][CH:16]=1
Reactant: CCc1ncc(C[n+]2ccc3ccsc3c2C)c(N)n1
Agent: Cl
Agent: O=S(=O)([O-])c1cccc2c(S(=O)(=O)[O-])cccc12
Agent: [Cl-]
Solvent: O
Product: CCN1CN=CC(C[n+]2ccc3ccsc3c2C)=C1N
Temperature: 25 °C

Procedure:
To a mixture of 6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno[2,3-c]pyridinium chloride hydrochloride (7.14 g., 0.02 mole) and 1,5-naphthalenedisulfonic acid disodium salt (7.73 g., 0.021 mole), there is added 75 ml. water. The reaction mixture is heated on a steam bath for two hours and then cooled to room temperature. The precipitate is collected by filtration, washed with some fresh water, then acetone, and finally air dried to give the product as a colorless, analytically pure solid, 11.25 g. (95%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH2:11])=[N:8][C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:2]1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([NH:11][C:21]([CH:18]3[CH2:20][CH2:19]3)=[O:22])=[N:8][C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccoc2)s1
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccoc2)s1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 μL of a 0.3M stock solution of 5-furan-3-yl-4-phenyl-thiazol-2-ylamine and 120 μL of a 0.3M stock solution of pyridine were mixed with 120 μL of a 0.3M stock solution of cyclopropanecarbonyl chloride. The reaction mixture was shaken overnight at ambient temperature. Purification was performed by preparative LC-MS.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20](OC(=S)C)[C:21]([O:23]C)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.[S:49]([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.CC(C)=O>[Si:1]([O:18][CH2:19][CH:20]([SH:49])[CH2:21][OH:23])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(C)=S
Reactant: O=S(=O)([O-])[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(S)CO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of methyl 3-t-butyldiphenylsilyloxy-2-thioacetoxypropionate (example 40) (14.3 g, 34.4 mmol) in dichloromethane (1.0 L) was added diisobutylaluminium hydride (96 mL of 1.5 M solution in toluene, 144 mmol, 4.2 eq) at -78° C. The solution was strirred at -78° C. for 1 hr and at -50° C. for another 1.5 hr. Sodium sulfate decahydrate (15 g) was added and the mixture was warmed at room temperature for 2 hr. Acetone was added and the solution was stirred overnight. Anhydrous sodium sulfate was added and the solution was strirred for 30 min and filtered over celite. The solid was washed several times with acetone and the solvents were evaporated under reduced pressure. The crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (85:15) to give the desired compound (4.25 g) in 36% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)=[O:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2[N:41]=[CH:42][CH:43]=[CH:44]C=2N=N1.C1(N)CC1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH:42]1([NH:41][C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:10][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)=[O:12])=[CH:28][CH:27]=2)[CH2:44][CH2:43]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(C(=O)CC(c2ccc(C(=O)O)cc2)c2ccc(F)cc2F)ccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)CC(c2ccc(C(=O)NC3CC3)cc2)c2ccc(F)cc2F)ccn1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-[1-(2,4-difluoro-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-benzoic acid (40 mg) in dichloromethane (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (48 mg) and triethylamine (29 μL) and the reaction mixture stirred at 40° C. After 15 min, cyclopropylamine (157 μL; CAS RN 765-30-0) was added and stirring continued for 2 h at 40° C. A saturated aq. solution of sodium hydrogencarbonate (50 mL) was added, the phases separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate and the crude reaction product purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (100:0 to 50:50) to give the title compound as a light yellow solid. MS (ESI+): m/z=421.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]>O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[O:10][S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Reactant: Cc1c(Cl)ccc(O)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Cl)ccc(OS(=O)(=O)c2nc[nH]n2)c1Cl

Procedure:
2.33 g of 2.4-dichloro-3-methylphenol was dissolved in 15 ml of tetrahydrofuran, and 1.84 ml of triethylamine was added while stirring the solution. Then, 2.0 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while cooling with ice and stirring the solution. Then, the solution was stirred at room temperature for 14 hours. Tetrahydrofuran was removed by distillation at reduced pressure, 2N hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was washed with brine, and dried with magnesium sulfate. Then, the solvent was removed by distillation, so that coarse crystals were obtained. The coarse crystals were recrystallized from n-hexane/ethyl acetate, so that 2.25 g of the titled compound was obtained.
Reaction SMILES: [CH:1]([NH:5][CH:6]1[CH:11]([N+:12]([O-])=O)[C:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])=[CH:9][CH:8]=[N:7]1)([CH2:3][CH3:4])[CH3:2].[NH4+].[OH-].[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[CH:1]([NH:5][CH:6]1[CH:11]([NH2:12])[C:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])=[CH:9][CH:8]=[N:7]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CCC(C)NC1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine (0.163, 0.44 followed by conc. NH4OH (0.4 mL) and Na2S2O4 (0.62 g, 3.55 mmol) and stirred at room temperature for 4 h. The solution was extracted with EtOAc, washed with H2O, brine, dried Na2SO4, filtered, and concentrated in vacuo to produce 0.145 g (97%) of N2-sec-butyl-4-(2-chloro-4-difluoromethoxy-phenyl)-2,3-dihydro-pyridine-2,3-diamine as a yellow oil.
Reaction SMILES: C(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9](O)=[N:10][CH:11]=1>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:3][C:9]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
75 g of phosgene are introduced at a temperature of 85°-95° C. over 1 hour into a mixture of 87.5 g of 5-chloro-2-hydroxy-3-nitropyridine in 500 ml of toluene and 3 ml of N,N-dimethylformamide. The reaction mixture is kept for 2 hours under reflux at 85°-95° C. and then allowed to cool to room temperature over a period of 18 hours. The reaction mixture is washed 3 times with water and the organic phase is dried over sodium sulfate and thereafter concentrated by evaporation. The crude product, obtained in the form of a brown oil, is crystallised from 200 ml of n-hexane, giving 67.5 g of 2,5-dichloro-3-nitropyridine (70% of theory) with a melting point of 38°-39° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1OCCOC1>[CH3:8][C:7]1[C:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[C:3]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])cc(CNC(=O)OC(C)(C)C)c1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cc(CNC(=O)OC(C)(C)C)c1N1CCN(C)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
In a oven-dried flask and under a nitrogen atmosphere, were placed tert-butyl N-[(2-bromo-3-methyl-5-nitrophenyl)methyl]carbamate (150 mg, 0.43 mmol), (+/−) BINAP (14 mg, 0.05 eq), Cs2CO3 (196 mg, 1.4 eq), Pd2dba3 (10 mg, 0.05 eq) and 3 mL of dry 1,4-dioxanne. N-Methylpiperazine (58 μL, 1.2 eq) was added and the mixture was stirred at 90° C. for 16 h. The solution was filtered through a celite pad and evaporated. The residue was purified by flash chromatography on silica gel (DCM/MeOH/NEt3//9/1/0.1) to yield expected compound as a pale brown solid (100 mg, 64% yield). m/z (ESI) 365.2 [M+H]+;
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](=[O:44])[C:41](O)=[O:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:41](=[O:42])[C:40]([C:36]2[O:35][CH:39]=[CH:38][CH:37]=2)=[O:44])[CH2:31][CH2:30]1)=[O:28]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)c1ccco1
Temperature: 25 °C
Reaction time: 45 h
Yield: 12.8 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (155 mg, 0.32 mmol), 2-(furan-2-yl)-2-oxoacetic acid (278 mg, 1.98 mmol), DIPEA (0.5 ml, 3 mmol), and HATU (251 mg, 0.66 mmol) were mixed in DMF (30 ml), the resulting reaction mixture was stirred at room temperature for 45 h until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, and the water phase was extracted with DCM (50 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford the desired product (20 mg, 20.4%) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([N:13]=[N:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[N+:22]([O-])=O)[CH:5]=1)[CH:2]=[CH2:3].[OH-].[Na+].C(S(O)=O)(N)=N.Cl>O.C(O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([N:13]2[N:22]=[C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]3=[N:14]2)[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(OC)c1
Agent: Cl
Agent: N=C(N)S(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCc1cc(OC)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Temperature: 80 °C
Yield: 19.7 %

Procedure:
In a 1 L round bottom flask equipped with a magnetic stirrer, addition funnel, powder addition funnel, and nitrogen inlet was added 4-allyl-2-((5-chloro-2-nitrophenyl)diazenyl)-6-methoxyphenol (27.9, 80.2 mmol) from Example 2 and 300 ml absolute ethanol. NaOH (19.3 g, 483 mmol) was dissolved in 140 ml deionized water and approximately one-fourth by volume was added dropwise to the reaction mixture. The reaction mixture was heated to 80° C. and formamidinesulfinic acid (Aldrich, 26.0 g, 241 mmol) was added slowly and concurrently with the remaining sodium hydroxide solution over 30 minutes. The reaction mixture was poured into 3 L deionized water and acidified to pH 4 with 1 N HCl. The yellow solid was dried for 20 hours at 42° C. and then purified by dissolving in hot toluene and then filtering out the dark impurities. The filtrate was concentrated down and purified via recrystallizions in ethanol and diethyl ether to give the pure product (5 g, 20%). 1H NMR (CDCl3) delta: 11.03 (s, 1H, phenol OH), 7.94 (s, 1H, Ar—H benzotriazole ring, 4-position), 7.89 (m, 1H, Ar—H benzotriazole ring, 7-position), 7.80 (s, 1H, Ar—H phenol, 5-position), 7.44 (m, 1H, Ar—H benzotriazole ring, 6-position), 6.81 (s, 1H, Ar—H phenol, 3-position), 6.00 (m, 1H, HC═CH2), 5.16 (m, 2H, HC═CH2), 3.97 (s, 3H, CH3O), 3.43 (d, 2H, Ar—CH2).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[N+:25]([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:25][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:16]([OH:18])=[O:17]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccc2ccccc2c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc2ccccc2c1

Procedure:
By substituting 4-(β-naphthylamino)-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 245° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(OCC)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH2:30][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=[CH:23]2
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)Cc1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of diisopropylamine (19.2 g, 0.19 mole) in diethyl ether (200 mL) was added 2.5 M n-butyllithium in hexane (74 mL, 0.185 mole) at −78° C. The clear solution was mixed for 30 min, and followed by addition of 6-bromo-2-methyl-quinoline (13.32 g, 0.060 mole) in ether (200 mL) slowly at −78° C. The brown solution was stirred for 0.5 hour, and ethyl chloroformate (7.45 g, 0.069 mole) in ether (50 mL) was syringed into the mixture slowly so that the internal temperature did not exceed −70° C. The yellow reaction mixture was quenched by addition of 50 mL water, allowed to warm up to rt, and diluted with ethyl acetate (300 mL). The solution was washed with 5% sodium bicarbonate aq. solution (700 mL×3), 25% brine (700 mL), dried over MgSO4, and filtered. The organic was concentrated to ˜50 mL volume, and the slurry diluted with heptane (50 mL). The slurry was stirred at 0° C. for 2 h, and the solid was collected by filtration, rinsed with a ice-cold heptane: ethyl acetate (10 mL, 2:1), dried at 50° C. under vacuum to give a yellow solid (12.0 g). Concentration of the mother liquid afforded a 2nd crop of the product (3.6 g). Total yield: 88%; mp: 100-101° C. (uncorrected); MS (ESI): 294, 296 (M+H)+; 1H-NMR (CDCl3) δ 8.02 (1H, d, J=8.5 Hz), 7.94 (1H, d, J=2.2 Hz), 7.91 (1H, d, J=8.9 Hz), 7.74 (1H, dd, J=8.9, 2.2 Hz), 7.44 (1H, d, J=8.5 Hz), 4.20 (2H, q, J=7.1 Hz), 4.01 (2H, s), 1.27 (3H, t, J=7.1 Hz); 13C-NMR (CDCl3) δ 169.7, 154.9, 146.0, 135.1, 132.6, 130.5, 128.9, 127.8, 122.3, 119.9, 61.2, 44.9, 14.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:3][CH:4]=1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(OCCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
A mixture of 4-hydroxybenzotrifluoride (2.08 g, 12.83 mmol), 2-(2-bromoethoxy)tetrahydropyran (3 g, 14.11 mmol), potassium carbonate (1.95 g, 14.11 mmol), and sodium iodide (2 g, 13.47 mmol) in DMF (15 ml) was stirred at 100° C. for 3 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford 2-[2-(4-trifluoromethylphenoxy)ethoxy]tetrahydropyran (2.47 g, yield 66%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[CH2:15]([N:22]1[CH2:27][C@@H:26]([CH3:28])[NH:25][CH2:24][C@@H:23]1[CH3:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([N:22]1[C@@H:23]([CH3:29])[CH2:24][N:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[C@H:26]([CH3:28])[CH2:27]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1c1ccc2nnc(C(F)(F)F)n2n1
Yield: 78.9 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.45 g, 20 mmol), (2S,5R)-1-benzyl-2,5-dimethylpiperazine (4.90 g, 24.00 mmol) and DIPEA (5.14 mL, 30.00 mmol) in DMF (40 mL) was heated at 125° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by MPLC silica chromatography, eluting with 75% EtOAc/isohexane. Pure fractions were evaporated to dryness to afford 6-[(2R,5S)-4-benzyl-2,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (6.16 g, 79%) as a tan gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][NH:36][CH3:35])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C=O)cc2)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-formylphenyl)benzamide (150 mg), methylamine (38% in methanol, 0.5 ml) and 3 Å molecular sieves (500 mg) in methanol (10 ml) was stirred at ambient temperature overnight. Sodium borohydride (39 mg) was added to the solution and the mixture was stirred at ambient temperature for 4 hours. The mixture was diluted with chloroform and the solution was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) and the product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-methylaminomethylphenyl)benzamide (160 mg) as a white powder.