Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1[O:15][C:4]([CH3:14])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=2)OC1.[C:16]([C:21](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:22])([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[C:16]([C:21]([CH3:22])=[CH:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:15])[CH3:14])=[CH:11][CH:10]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC1(Cc2ccc(C=O)cc2)OCCO1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(CC(C)=O)cc1

Procedure:
A mixture of 4-formylphenylpropan-2-one-2-ethylene acetal (3.11 g) and 1-carboethoxyethylidenetriphenylphosphorane (5.47 g) was refluxed in tetrahydrofuran under nitrogen for 1 h. The solvent was evaporated and the residue chromatographed on alumina (200 g). Elution with dichloromethane gave the title compound as the ethylene acetal (1.7 g). This was dissolved in ethanol-2 N hydrochloric acid and stirred at ambient temperature until tlc showed no acetal present. The aqueous was extracted with ether (3×50 ml) and the combined ether layers washed with water (×2), sodium bicarbonate solution, and dried (MgSO4). Removal of the solvent gave the title compound (1.05 g). τ(CDCl3) 8.7 (3H, t, 3=7 Hz), 7.92 (3H, s), 7.9 (3H, s), 6.35 (2H, s), 5.8 (2H, q, J=7 Hz), 2.8 (2H, d, J=8 Hz), 2.6 (2H, d, J=8 Hz), 2.35 (1H, broad s).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[NH2:1][C:2]1[N:11]=[C:10]([Cl:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1nc2ccccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2ccccc2n1
Yield: 18.9 %

Procedure:
2-Amino-4-(3H)-quinazolone (2.0 g, 0.0124 mol) was heated under reflux in phosphoryl chloride (19.02 g, 0.0124 mol) for 2.5 hours. The reaction mixture was partitioned between chloroform, ice and NaOH solution (pH 9) and the organic phase dried, filtered, excess solvent removed and the residue triturated with chloroform to give 2-amino-4-chloroquinazoline (0.42 g, 19%) m.p. 275°-278°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].C(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccc(Br)cc2)cc1
Temperature: 80 °C

Procedure:
In a 500 mL three-necked flask were placed 30 g (82 mmol) of 4,4′-dibromobenzil, 9.3 g (86 mmol) of 1,2-phenylenediamine, and 300 mL of chloroform. This solution was refluxed at 80° C. for 5 hours under a stream of nitrogen. After a predetermined time, the solution was cooled to room temperature, and water was added thereto. This aqueous layer was extracted with chloroform, and the extracted solution was combined with the organic layer and then dried with magnesium sulfate. After drying, the mixture was subjected to suction filtration and the filtrate was concentrated. The obtained solid was dissolved in toluene, and this solution was subjected to suction filtration through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855) and alumina. The filtrate was concentrated, and 30 g of a white powder of 2,3-bis(4-bromophenyl)quinoxaline, which was a target substance, was obtained at a yield of 99%.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:31]=[CH:30][C:12]([O:13][CH2:14][C:15]([N:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[N+:27]([O-])=O)[CH3:18])=O)=[CH:11][CH:10]=2)[S:3]1.CO.[ClH:34].[H][H]>[C].[Pd].CC(N(C)C)=O>[ClH:34].[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:20]2[N:27]=[C:15]([CH2:14][O:13][C:12]3[CH:30]=[CH:31][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[N:17]([CH3:18])[C:19]=2[CH:24]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(N(C)C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 48 %

Procedure:
To a solution of 2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}-N-(5-methoxy-2-nitrophenyl)-N-methylacetamide (444.7 mg) in a mixed solvent of methanol (20 ml) and dimethylacetamide (5 ml) were added successively concentrated hydrochloric acid (0.344 ml) and a 10% wet palladium-carbon catalyst (244 mg). The atmosphere in the reaction flask was replaced with hydrogen gas (5 kg/cm2), and the resulting mixture was shaken at 50° C. for 3.5 hours. After shaking, the reaction mixture was cooled to room temperature and filtered to obtain a pale yellow filtrate. When the filtrate obtained was concentrated to about 5 g, the product crystallized out of solution. The crystals precipitated were collected by filtration and washed with methanol to afford the title compound (210 mg, yield: 48%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10](F)=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[CH:14]=2)[CH:3]=1.[Br:29][Si](C)(C)C>O1CCOCC1>[Br:29][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:10]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: Nc1cnc(Cl)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Reactant: C[Si](C)(C)Br
Solvent: C1COCCO1
Product: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 100 °C
Yield: 65.3 %

Procedure:
To a solution of 6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine (1.6 g, 0.004 mol) in 1,4-dioxane (30 mL) was added bromotrimethylsilane (27 mL, 0.2 mol) which immediately produced a white precipitate. The reaction was heated at 100° C. for 48 h. The solid from the cooled reaction mixture was collected by filtration and washed with ethyl acetate (2×20 mL). The resultant solid was then purified by flash chromotagraphy (silica, 25 g column, Biotage, 040% methanol in (DCM containing 1% 2M ammonia in methanol)) to afford the title compound as an off-white solid (1.1 g, 45%). 1H NMR (DMSO-D6, 500 MHz,): 8.62 (s, 1H), 8.25 (d, J=7.3 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=6.5 Hz, 2H), 7.42 (d, J=6.5 Hz), 7.35 (s, 1H), 5.57 (s, 2H), 3.47 (s, 2H), 2.34 (s, 4H), 1.51 (s, 4H), 1.40 (s, 2H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:30])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25][C:26]([F:29])([F:27])[F:28])[CH:23]=4)[N:18]([CH3:30])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(OC(F)(F)F)cc34)nc12
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a slightly yellow clear solution of N-isopropyl-2-(1-methyl-5-(trifluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (113 mg, 206 μmol) in dichloromethane (5 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol), the reaction mixture was stirred overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide (60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (40 g column, 50 μm from Analogix, 0 to 5% MeOH containing 10% ammonium hydroxide)/dichloromethane). The pure product was suspended in dichloromethane and cyclohexane added to promote solid formation, then the solid was separated by filtration and dried to give N-isopropyl-2-(1-methyl-5-(trifluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 186 μmol, 91%) as a white solid. MS (M+H)+=419; 1H NMR (DMSO-d6) δ: 12.86 (br. s., 1H), 9.12 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.88-7.97 (m, 2H), 7.56 (d, J=9.1 Hz, 1H), 4.14-4.36 (m, 4H), 1.30 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([OH:17])[CH2:15][OH:16])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>>[CH:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C@H:14]([OH:17])[CH2:15][OH:16])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: OCC(O)CN1CCN(c2ccccc2)CC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: OC[C@@H](O)CN1CCN(c2ccccc2)CC1

Procedure:
According to the invention, resolution of dropropizine is carried out by treating it with L(+)tartaric acid in aqueous medium: the precipitated salt is then crystallized, alkalinized and recrystallized to give levodropropizine.
Reaction SMILES: COC1C=C2C(OC(=O)C2=C(C)C=1)=O.[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=O)[NH:22][C:23]2=O)=[C:19]([CH3:28])[CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH3:28])[C:20]2[C:24]([CH:25]=1)=[CH:23][NH:22][CH:21]=2
Reactant: COc1cc(C)c2c(c1)C(=O)NC2=O
Agent: COc1cc(C)c2c(c1)C(=O)OC2=O
Product: COc1cc(C)c2c[nH]cc2c1

Procedure:
5-Methoxy-3-methyl-phthalic anhydride was used to prepare 6-methoxy-4-methyl-isoindole-1,3-dione. 1H NMR (DMSO-d6) 11.05 (1H, br.s), 7.13 (1H, d), 7.10 (1H, d), 3.88 (3H, s), 2.55 (3H, s). Reduction of 6-methoxy-4-methyl-isoindole-1,3-dione according to the method of preparation C2 afforded 6-methoxy-4-methyl-isoindole. 1H NMR (DMSO-d6) 6.64 (1H, s), 6.57 (1H, s), 4.05 (2H, s), 3.96 (2H, s), 3.70 (3H, s), 2.16 (3H, s). MS: [M+H]+ 164.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.[N+:30]([C:33]1[NH:34][CH:35]=[CH:36][N:37]=1)([O-:32])=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:12]([CH2:11][C:3]1([CH2:2][N:34]2[CH:35]=[CH:36][N:37]=[C:33]2[N+:30]([O-:32])=[O:31])[CH2:4][O:5][C:6]([CH3:10])([CH3:9])[O:7][CH2:8]1)[Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC1(C)OCC(CBr)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2ccnc2[N+](=O)[O-])CO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
1.70 g (3.56 mmol equivalents) of 5-bromomethyl-5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-1,3-dioxane was dissolved in 36 mL of dimethylformamide, 402 mg (3.56 mmol equivalents) of 2-nitroimidazole and 1.48 g (10.7 mmol equivalents) of potassium carbonate were added thereto, and the mixture was heated in an oil bath to 80° C. and then stirred for 18 hours. After completion of the reaction, water was added dropwise, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=3/1) to give 362 mg (0.71 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][C:18]#[N:19])[N:8]=1.[NH3:23].O.CCOC(C)=O>CN(C=O)C.CCO>[F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:23])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][C:18]#[N:19])[N:8]=1
Reactant: N#CCCC/C=C/c1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCCC/C=C/c1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.67 h

Procedure:
The above thiourea (350 mg.) was dissolved in DMF (8 ml.) and 8M ammonia in EtOH (4 ml.). Mercuric oxide (1 g.) was added and the mixture stirred for 40 minutes, then poured into water/EtOAc 1:1 (100 ml.) and the resulting mixture filtered through diatomaceous earth. The EtOAc extract was dried (MgSO4) and evaporated in vacuo to give trans-6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hex-5-enenitrile as a gum which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([NH:42][C:43]1[NH:44][CH2:45][CH2:46][CH2:47][N:48]=1)[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:41]=[CH:40][C:17]([CH2:18][C@@H:19]([C:33]([O:35]C(C)(C)C)=[O:34])[NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[N:23][N:22]=2)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>ClCCl>[O:8]=[C:9]([NH:42][C:43]1[NH:44][CH2:45][CH2:46][CH2:47][N:48]=1)[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:41]=[CH:40][C:17]([CH2:18][C@@H:19]([C:33]([OH:35])=[O:34])[NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[N:23][N:22]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nnnn1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCOc1ccc(C[C@H](Nc2nnnn2Cc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
2 ml of trifluoroacetic acid is added to 135 mg of ester 5-2 in 5 ml of dichloromethane, followed by agitating for 3 hours at ambient temperature, adding 10 ml of toluene, evaporating under reduced pressure, taking up in dichloromethane and crystallizing by adding an Et2O/pentane mixture. 92 mg of 5-3 is obtained.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)CCC>[ClH:2].[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[N:12]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Nc1ccccc1F
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Fc1ccccc1N1CCNCC1
Yield: 20.5 %

Procedure:
This compound was prepared according to the procedure used in Preparation 1. A mixture of 15.1 g (0.09 mol) of bis(2-chloroethyl)amine hydrochloride, 10.0 g (0.09 mol) of 2-fluoroaniline and 25.0 g of solid potassium carbonate in a total volume of 100 mL of 1-butanol gave an oil as residue. The oil was converted to the hydrochloric acid salt (ethereal HCl) and recrystallized from methanol-ether to give 4.0 g (20%) of white solid, mp 185°-187° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:13]=[C:12]([NH:14][C:15]([C:17]2[N:18]=[CH:19][N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:21]=2[CH2:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:16])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.C1COCC1.CO.O.[OH-].[Li+]>O>[CH2:30]([N:20]1[C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:17]([C:15]([NH:14][C:12]2[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[C:4]([CH:13]=2)[C:3]([OH:37])=[O:2])=[O:16])[N:18]=[CH:19]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)c1cc(NC(=O)c2ncn(Cc3ccccc3)c2CC2CCCCCC2)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(NC(=O)c2ncn(Cc3ccccc3)c2CC2CCCCCC2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of the product of step c above (110 mg, 0.22 mmol) in 1:1 THF/methanol (2 ml) was added the solution of lithium hydroxide monohydrate (30 mg, 0.66 mmol) in water (1 ml). The solution was stirred at room temperature for 16 h, concentrated under reduced pressure, diluted with water (1 ml) and acidified (pH=2.0, 1M HCl). The precipitate was collected by filtration, washed with water and dried to afford the title compound as a white solid (92 mg, 89%). 1H NMR (300 MHz, d6-DMSO) 13.00 (2H, br s), 10.23 (1H, s), 8.64 (2H, s), 8.15 (1H, s), 7.92 (1H, s), 7.32 (3H, m), 7.14 (2H, m), 5.28 (2H, s), 2.83 (2H, d), 1.51 (5H, m), 1.37 (4H, m), 1.14 (4H, m). The acid was converted to the di(N-methyl-D-glucamine) salt and lyophilised from water/dioxan. Found: C, 54.47; H, 7.63; N, 7.59%; C41H63N5O15.2.2 H2O requires: C, 54.35; H, 7.50; N, 7.73%.
Reaction SMILES: N[C@H](C(O)=O)CC1C=CC=CC=1.[NH:13]([N:25]=[N+:26]=[N-:27])[C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[NH:13]([N:25]=[N+:26]=[N-:27])[C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N:13]([C@@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]([NH:60][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:24])=[N+:25]=[N-:26]
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1

Procedure:
N3(L)PheOH (1 SL) was synthesized from L-phenylalanine essentially by the procedure of Lundquist and Pelletier.17 N3(L)PheOH (1.08 g, 5.7 mmol) was dissolved in anhydrous DMF (40 mL). HOBt (0.87 g, 5.7 mmol) was then added, followed by DCC (1.17 g, 5.7 mmol). Once precipitate was observed in the reaction, benzyl amine (0.62 mL, 5.7 mmol) was added. The reaction was allowed to stir under Ar(g) for 3 h. The resulting precipitate (DCU) was removed by filtration, and the filtrate was concentrated under reduced pressure to give a yellow oil. This oil was purified by flash chromatography (silica gel, 35% v/v/ethyl acetate in hexanes). N3(L)Penh (48-L) was isolated as an off-white solid in 90% yield. The procedure was repeated with D-phenylalanine to give N3(D)Penh products (D and L enantiomers) are identical. N3(L)Penh (48-L) 1H NMR (500 MHz, CDCl3δ 7.31-7.12 (m, 8 H), 7.11 (m, 2 H), 6.55 (bus, 1 H), 4.38 (m, 2 H), 4.22 (did, J=7.8, 4.6 Hz, 1 H), 3.34 (did, J=14.0, 4.5 Hz, 1 H), 3.07 (did, J=14.1, 7.5 Hz, 1 H) ppm; 13C NMR (125 MHz, CDCl3) δ 168.30, 137.35, 135.96, 129.51, 128.61, 128.66, 128.61, 128.55, 127.70, 127.68, 127.66, 127.57, 127.16, 65.40, 43.41, 38.41 ppm; MS (ESI) m/z 303.1235 (MNa+[C16H16N4ONa]=303.1222).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)=[C:32]([Cl:52])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.FC(F)(F)C(O)=O.CO>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:49])[F:50])[CH:43]=3)=[C:32]([Cl:52])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(Cl)c(-c3cccc(C(F)(F)F)c3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
5-Chloro-4-(2-chloro-5-(pyridazin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 53, 231 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) added. The resulting solution was stirred at room temperature for 18 hours. Methanol (2 mL) was added and the reaction was stirred for 10 minutes. The resulting mixture was evaporated and azeotroped with methanol (2×10 mL). The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The ethyl acetate was separated and dried over MgSO4 and evaporated. The residue was chromatographed on silica eluting with dichloromethane:methanol:acetic acid 100:0:0 to 95:5:0.5 in 1% stages of methanol. The column product was stirred in dichloromethane (10 mL) for 20 minutes, the solid filtered off, and stirred in dichloromethane (5 mL) at reflux for 10 minutes. The solid was filtered to give the title compound (45 mg, 25%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[C:12]([CH3:36])=[C:13]2[C:18]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[C:17]([C:33]#[N:34])[CH:16]=[N:15][N:14]2[CH:35]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:9][C:11]1[C:12]([CH3:36])=[C:13]2[C:18]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][CH:25]=3)=[C:17]([C:33]#[N:34])[CH:16]=[N:15][N:14]2[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1c(CNCc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 70 %

Procedure:
Benzylamine (10 μl, 0.09 mmol) was added to a solution of 6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 8) (32 mg, 0.087 mmol) in CH2Cl2/DMF (10/1) (2.2 ml). The mixture was stirred overnight, then treated with NaBH(OAc)3 (55 mg, 0.26 mmol) and stirred overnight again. Diluted with CHCl3, washed with saturated NaHCO3 and H2O, dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (28 mg, 70%) as yellow-green oil (10% MeOH—CHCl3). It has a retention time of 6.46 min (standard LCl method, 8 min run). LCMS Found: (M+H)+=460.20
Reaction SMILES: [N+]([O-])(OCCC(C)C)=O.N[C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]#[N:30])[CH:22]=2)=[N:13][S:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[C:29]([C:23]1[CH:22]=[C:21]([C:12]2[CH:11]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28])#[N:30]
Reactant: CCOC(=O)c1snc(-c2ccc(OC)c(C#N)c2)c1N
Agent: CC(C)CCO[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(OC)c(C#N)c2)ns1

Procedure:
3-Methylbutyl nitrate was dissolved in a tetrahydrofuran solution of ethyl 4-amino-3-(3-cyano-4-methoxyphenyl)isothiazole-5-carboxylate, followed by heating under reflux for 5 hours to obtain ethyl 3-(3-cyano-4-methoxyphenyl)isothiazole-5-carboxylate. AP: 311.