Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[C:4]([C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[CH2:15][N:16]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=1)(=[NH:6])[NH2:5].Cl.[C:37](=[NH:42])(OCC)[CH3:38].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:37]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([N:16]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:15]/[CH:14]=[CH:13]/[C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:4](=[NH:5])[NH2:6])[CH:8]=3)=[CH:18][CH:19]=2)[CH2:25][CH2:26]1)(=[NH:42])[CH3:38]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)CN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)CN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 244.1 %

Procedure:
To a solution of ethyl 2-[N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]amino]acetate trihydrochloride (400 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (270 mg) and triethylamine (0.61 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 24% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (350 mg, yield 81%) as a pale yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:36]([O:35][C:33]([N:27]1[CH2:32][CH2:31][N:30]([CH2:21][C:12]2[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:15]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[CH:11]=2)[CH2:29][CH2:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)cc1F
Yield: 94.3 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 94.3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Br:21])=[C:17]([CH3:20])[CH:18]=2)[CH:13]=[C:12]1[CH:22](C(C)(C)C(C)C)O[SiH](C)C)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[F-].[NH4+]>CO>[C:1]([O:5][C:6]([N:7]1[CH2:8][C@@H:9]([CH3:10])[N:11]2[C:19]3[CH:18]=[C:17]([CH3:20])[C:16]([Br:21])=[CH:15][C:14]=3[CH:13]=[C:12]2[CH2:22]1)=[O:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(cc1Br)cc(C(O[SiH](C)C)C(C)(C)C(C)C)n2[C@H](C)CNC(=O)OC(C)(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A mixture of 0.75 g (R)-(2-{5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-indol-1-yl}-propyl)-carbamic acid tert-butyl ester and 0.52 g ammonium fluoride in 7.5 ml methanol was stirred 18 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 10% citric acid, 10% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to dryness. The residue was taken up in 6 ml dichloromethane and 0.59 g manganese dioxide was added. The mixture was stirred 2 h at room temperature. The solids were removed by filtration over dicalite and the filtrate was evaporated to dryness. The residue was taken up in 5 ml dichloromethane and 0.072 ml acetic acid and 1.00 g molecular sieve (powder, 4 Å) were added. To the resulting suspension was added 0.536 g triacetoxyborohydride, and the mixture was stirred 1 h at room temperature. Another 0.536 g triacetoxyborohydride was added and the mixture was stirred 1 h. The solids were removed by filtration over dicalite and the filtrate was purified by chromatography on silica gel with hexane:ethyl acetate=2:1 to yield 0.295 g of the title compound as a yellow solid melting at 113-114° C. after crystallisation from hexane.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11](C(OC)=O)[NH:12][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O.NN>C(O)COCCOCCO>[CH2:1]([C:9]1[CH:10]=[CH:11][NH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)c2ccccc2)c[nH]1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: c1ccc(Cc2cc[nH]c2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
12.0 g (52.4 mmole) of methyl 4-benzoyl-2-pyrrolecarboxylate, 8.79 g (157 mmole) of potassium hydroxide and 10.5 g (210 mmole) of hydrazine hydrate are dissolved in 150 ml of triethylene glycol. Reaction is carried out by stirring the solution at 120° C. for 2 hours and then at 160° C. for 3 hours in an atmosphere of nitrogen gas. After reaction is finished, the reaction solution is allowed to cool and poured into ice water, followed by extraction with ether. The extract is washed with water saturated with sodium chloride and concentrated. The residue is distilled under reduced pressure to obtain 5.86 g of 3-benzylpyrrole as a colorless liquid. Yield 71.2%. nD29.5 1.5790. Boiling point 95°-98° C. (0.09 mmHg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([O:16][C:22]2[CH:23]=[C:18]([Cl:17])[N:19]=[CH:20][N:21]=2)[CH:3]=1
Reactant: Oc1cc(Cl)c2[nH]c(C3CCOC3)nc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOC4)nc3c2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.34 mmol) 7-chloro-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-5-ol and 51 mg (0.34 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 55 mg (0.40 mmol) potassium carbonate were added and the mixture was stirred overnight at RT. The reaction mixture was filtered and purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.N([O-])=[O:14].[Na+]>>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[O:14])[S:3][C:4]=2[CH:10]=1
Reactant: O=N[O-]
Reactant: Nc1nc2ccc(F)cc2s1
Agent: Cl
Agent: [Na+]
Product: O=c1[nH]c2ccc(F)cc2s1
Temperature: 50 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
22.4 g of 2-amino-6-fluorobenzothiazole (pure substance content: 97%) and 191.1 g of 30% hydrochloric acid are introduced into a 750 ml pressure vessel at room temperature. The mixture is subsequently heated for 30 minutes at 50° C. and then cooled to 10° C. Then, 46.7 g of aqueous, 40% sodium nitrite solution are metered in at a uniform rate in the course of 1 hour at 10° C., with vigorous stirring. After metering in has ended, stirring of the reaction mixture is continued for 12 hours at 20° C. Excess nitrite is then removed by adding approximately 12.5 g of 18% aqueous urea solution. The reaction vessel is subsequently sealed, and the reaction mixture is heated for 5 hours at 140°-150° C. (pressure approximately 4-5 bar). After the mixture has cooled to 20° C., the gray, crystalline product is filtered off with suction, washed with a small amount of water and dried at 60° C. to constant weight. 18.9 g of 6-fluorobenzothiazol-2-one with a pure substance content of 97.7% are obtained (corresponding to 85% yield). The product which is redissolved under alkaline conditions has a melting point of 188.4° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)C(=O)CC(=O)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[C-:25].[C:32]1(C)[CH:37]=CC=C[CH:33]=1>>[CH:1]1([CH2:6][CH:7]([C:25]2[NH:24][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:32]([CH3:37])[CH:33]=2)[C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cc1ccccc1
Reactant: CC(=O)CC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Product: CCOC(=O)c1[nH]c(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution (5 mL) of 6-cyclopentyl-5-[4-(methylsulfonyl)phenyl]hexane-2,4-dione (1.60 g) in toluene were added ethyl isocyanoacetate (0.29 g) and dodecacarbonyltetrarhodium(0) complex (55 mg), and the mixture was stirred under argon atmosphere at 80° C. overnight. After cooling to room temperature, the reaction mixture was concentrated, and the residue was subjected to NH silica gel column chromatography, and the title compound (0.44 g, yield 43%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 404 (MH+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[C:10]([C:6]1[CH2:7][CH2:8][CH2:9][C:5]=1[S:2]([N:1]=[C:19]=[O:20])(=[O:3])=[O:4])([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1=C(S(N)(=O)=O)CCC1
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: COC(=O)C1=C(S(=O)(=O)N=C=O)CCC1

Procedure:
In 75 ml of dry xylenes was placed 4.0 g of methy 2-(aminosulfonyl)-1-cyclopentene-1-carboxylate (VIII), 6.5 ml of n-butyl isocyanate, and 0.05 g of DABCO. The mixture was heated to reflux (ca 138°) then contacted with an excess of phosgene which was condensed into the mixture from a dry-ice condenser until the reflux temperature dropped to 126°. Over several hours the temperature increased to 135° and additional phosgene was condensed into the mixture, again, lowering the temperature to 129°. This process was repeated until no temperature increase could be observed, indicating complete consumption of the sulfonamide. The mixture was then cooled and the xylenes removed under reduced pressure to yield ca 5 g of an amber oil. An infrared spectrum (neat) exhibited a strong absorption at 2230 cm-1 indicating the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]=1)=[C:5]=[O:6]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:5](=[O:6])[NH:4][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]=1
Reactant: O=C=Nc1coc2ccccc2c1=O
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
A solution of anhydrous dimethylamine (7.5 g) in dry toluene (100 ml) is added rapidly to a solution of 3-isocyanatochromone (13 g) in toluene (50 ml). The temperature of the reaction mixture rapidly rises from 20° to 47° C. and crystallization then takes place. The mixture is stirred for a further 20 minutes until the temperature of the reaction medium drops to about 25° C. After filtration, recrystallization from isopropyl ether (1,000 ml) and drying, 3-(3,3-dimethylureido)-chromone (5.4 g), which melts at 148° C., is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:17]([C:23](=O)[CH2:24][CH2:25][CH3:26])[C:18](OCC)=[O:19])[CH3:16])=[CH:11][CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:18](=[O:19])[C:17]([CH:15]([C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)[CH3:16])=[C:23]([CH2:24][CH2:25][CH3:26])[N:40]4[N:41]=[CH:42][N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(C(=O)OCC)C(C)c1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A mixture of ethyl 2-[1-(2′-cyanobiphenyl-4-yl)ethyl]-3-oxohexanoate (4.80 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1.50 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight, allowed to cool and poured into 1 M hydrochloric acid (100 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed 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 a pale-yellow oil (1.50 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])=[CH:5]2.C(N(CC)CC)C.[CH3:35][C:36]([CH3:42])([CH3:41])[CH2:37][C:38](Cl)=[O:39].Cl>C1COCC1.C(OCC)(=O)C>[NH:21]([C:19]([C:6]1[N:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([NH:1][C:38](=[O:39])[CH2:37][C:36]([CH3:42])([CH3:41])[CH3:35])=[CH:10][CH:9]=2)=[O:20])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)Nc2ccccc2)cc2cc(N)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, 50 mg (0.14 mmol) of tert-butyl [5-amino-2-(anilinecarbonyl)-1H-indol-1-yl]acetate from Example LII and 15.23 mg (0.02 ml, 0.15 mmol) of triethylamine are added to 2 ml of THF. The mixture is cooled to 0° C., and a solution of 20.26 mg (0.02 ml, 0.15 mmol) of 3,3-dimethylbutyryl chloride in 0.2 ml of THF is added. The mixture is stirred at RT for 2 hours and, for work-up, added to dilute hydrochloric acid and ethyl acetate and extracted. The organic phase is washed with sat. sodium bicarbonate solution, dried with sodium sulphate, filtered and dried under reduced pressure. The resulting crude product is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][C:26]1([CH3:37])[N:31]([CH2:32][C:33]([NH:35][NH2:36])=[O:34])[CH2:30][CH2:29][O:28][CH2:27]1.C1COCC1.CCN(C(C)C)C(C)C>O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:36][NH:35][C:33](=[O:34])[CH2:32][N:31]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3([CH3:25])[CH3:37])=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC1(C)COCCN1CC(=O)NN
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCCN1CC(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To the solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.250 g, 0.7 mmol) and 2-(3,3-dimethylmorpholino)acetohydrazide (0.160 g, 0.85 mmol) in THF (2.5 mL) T3P (0.63 mL, 1.06 mmol) was added dropwise followed by DIPEA (0.18 mL, 1.06 mmol) at −60° C. The reaction mixture was stirred for 1 h, transferred into 25 mL iced-water, and extracted with ethyl acetate (2×25 mL). The combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product, which was purified by chromatography (0-4% MeOH:CH2Cl2) to give 0.05 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-(3,3-dimethylmorpholino)acetyl)acrylohydrazide (Yield: 13%). 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.81 (s, 1H), 9.62 (s, 1H), 8.56 (s, 2H), 8.29 (s, 1H), 7.49-7.51 (d, J=10.4 Hz, 1H)), 6.01-6.03 (d, J=10.4 Hz, 1H), 3.65-3.67 (m, 2H), 3.30-3.34 (m, 2H), 3.08 (bs, 2H), 2.55-2.58 (m, 2H), 0.96 (s, 6H). LCMS m/z 521.18 [M+H]+, tR 1.937 min
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CS(C)=O>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:24]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (130 mg, 0.35 mmol) and DIPEA (135.7 mg, 10.5 mmol) in DMSO (1.75 mL) was added dropwise MeSO2Cl (47.6 mg, 0.42 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed most of starting material was converted. The mixture was partitioned between brine (100 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-90 (30 mg, 18.9%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:25]1[C:34]([OH:35])=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:25]1[C:34]([OH:35])=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C1(O)c1cc2c(cc1O)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 4-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 4-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (86%): as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ9.05 (s, 1H), 7.42-7.28 (m, 10H), 6.98-6.87 (m, 3H), 6.68 (s, 1H), 6.33 (d, J=7.6 Hz, 1H), 6.16 (s, 1H), 4.22-4.16 (m, 4H).
Reaction SMILES: S(=O)(O)[O-].[Na+].[N+:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])([O-:8])=[O:7].CCOCC.[C-:22]#[N:23].[K+]>O.C1COCC1>[N+:6]([C:9]1[CH:10]=[C:11]([CH:12]([OH:13])[C:22]#[N:23])[CH:14]=[CH:15][CH:16]=1)([O-:8])=[O:7]
Reactant: [C-]#N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: N#CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 10 °C
Yield: 125.4 %

Procedure:
A mixture of a 10% solution of sodium bisulfite (24 g, 230 mmol) and 3-nitrobenzaldehyde (27 g, 178 mmol) was combined in a 1 L flask with 75 mL ether and 100 ml THF. The resulting reaction mixture was cooled in an ice-water bath to 10° C. and a solution of potassium cyanide (15 g, 130 mmol) in 75 mL water was added over a period of a half-hour while stirring. The reaction mixture was stirred at 15° C. for 1 hour. The organic layers were separated and the aqueous phase was extracted with ether (200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford (3-nitrophenyl)(hydroxy)acetonitrile as a yellow oil (29 g, 163 mmol), which was used without further purification in the next step.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[C:10](O)(=O)[CH3:11].[C:14]([O-])(=O)C.[NH4+]>CC(C)=O.[C].[Pd]>[C:1]([CH:3]([CH:10]([CH3:11])[CH3:14])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: CC(=O)O
Reactant: N#CCC(=O)NC(N)=O
Reactant: CC(=O)[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(C)C(C#N)C(=O)NC(N)=O
Reaction time: 1 h
Yield: 932.5 %

Procedure:
Cyanoacetylurea (25.8 g) was suspended in acetone (258 ml), and acetic acid (2.4 g) and ammonium acetate (1.5 g) were added. This suspension was subjected to catalytic hydrogenation in the presence of 5% palladium carbon (2.1 g, 50% wet product) under hydrogen pressure at 10 kg/cm2 and at 40° C. for 1 hour. The reaction mixture was refluxed under heating to dissolve an insoluble matter, and the catalyst was filtered off. The obtained filtrate was concentrated to a half. Water (130 ml) was added to the filtrate to allow precipitation of crystals. The crystals were collected by filtration to give crystals of N-(2-cyano-3-methylbutanoyl)urea (yield 30.7 g).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O>>[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: N#CC(C#N)=Cc1ccc(Cl)cc1Cl

Procedure:
This material was prepared from malononitrile and 2,4-dichlorobenzaldehyde according to the procedure of M. Boehringer et al., WO 03/068748.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:32][C:33]([NH2:36])([CH3:35])[CH3:34]>CS(C)=O.O>[C:33]([NH:36][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH3:35])([CH3:34])[CH3:32]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)(C)C)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol) in DMSO (10 mL) was added DIEA (163 mg, 1.26 mmol) and 2-methylpropan-2-amine (461.3 mg, 6.32 mmol) with stirring overnight at 90° C. in an oil bath. The reaction mixture was cooled to room temperature, diluted with H2O (150 mL), extracted with ethyl acetate (3×80 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give the residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 3-(tert-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a light yellow solid (115 mg, 51%).