Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(=O)CC1C2C(=CC=CC=2OCCCP(=O)(O)O)N(CC2C=CC=C(Cl)C=2)C=1CC.C[O:33][P:34]([CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[N:47]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=1)[C:46]([CH2:59][CH3:60])=[C:45]2[CH2:61][C:62]([NH2:64])=[O:63])(=[O:37])[O:35]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[NH2:64][C:62](=[O:63])[CH2:61][C:45]1[C:44]2[C:48](=[CH:49][CH:50]=[C:42]([O:41][CH2:40][CH2:39][CH2:38][P:34](=[O:33])([OH:37])[OH:35])[CH:43]=2)[N:47]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=2)[C:46]=1[CH2:59][CH3:60]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1cccc(Cl)c1
Agent: CCc1c(CC(N)=O)c2c(OCCCP(=O)(O)O)cccc2n1Cc1cccc(Cl)c1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(O)O)ccc2n1Cc1cccc(Cl)c1
Reaction time: 0.75 h
Yield: 64.5 %

Procedure:
[3-[[3-(2-Amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]propyl]phosphonic acid. [[3-[[3-(2-Amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (99 mg, 0.2 mmol) and 0.21 mL (1.6 mmol) of trimethylsilyl bromide in 2 mL of methylene chloride was stirred for 16 hours, 5 mL of MeOH added, stirred 0.75 hours and concentrated at reduced pressure. The residue was crystallized from EtOAc/MeCN/HOAc/water to give 60 mg (65% yield) of [3-[[3-(2-amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-5-yl]oxy]propyl]phosphonic acid, mp, 203°-205° C.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:18]([OH:29])=[CH:19][C:20]4[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=4[CH:28]=3)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:18](=[CH:19][C:20]5[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=5[CH:28]=4)[O:29][CH2:37]3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: CN1C(=O)COc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Product: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′ (1′H,3H)-dione was obtained (32%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.23 (m, 11H), 7.19-7.10 (m, 1H), 7.07-6.98 (m, 1H), 6.88 (s, 1H), 6.72 (s, 1H), 6.64 (d, J=7.9 Hz, 1H), 6.20 (s, 1H), 4.93 (d, J=9.4 Hz, 1H), 4.82 (d, J=9.4 Hz, 1H), 4.57 (s, 2H), 3.01 (s, 3H); MS (ES+) m/z 489.0 (M+1).
Reaction SMILES: [CH:1](C1C=CC(CN(C)C(=O)OCC2C=CC=CC=2)=CC=1)=O.C(=NC1C=CC=C2C=1COC2=O)C1C=CC=CC=1.C[O-].[Na+].CO.[CH2:45]([O:52][C:53]([N:55]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[C:73](=[O:74])[C:72]3[C:71]([C:75]([O:77][CH3:78])=[O:76])=[CH:70][CH:69]=[CH:68][C:67]=3[NH:66][CH:65]2[C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)=[CH:60][CH:59]=1)[CH3:56])=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OCC)(=O)CC>[CH2:45]([O:52][C:53]([N:55]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[C:73](=[O:74])[C:72]3[C:71]([C:75]([O:77][CH2:78][CH3:1])=[O:76])=[CH:70][CH:69]=[CH:68][C:67]=3[NH:66][CH:65]2[C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)=[CH:60][CH:59]=1)[CH3:56])=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Reactant: CN(Cc1ccc(C=O)cc1)C(=O)OCc1ccccc1
Agent: C[O-]
Agent: O=C1OCc2c(N=Cc3ccccc3)cccc21
Agent: [Na+]
Solvent: CO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A mixture of benzyl 4-formylbenzyl(methyl)carbamate (566 mg, 2 mmol) and 4-(benzylideneamino) isobenzofuran-1-one (474 mg, 2 mmol) in ethyl propionate (15 mL) was cooled to 0° C. A solution of sodium methoxide in methanol [sodium (184 mg, 8 mmol) in methanol (15 mL)] was then added dropwise. After the addition, the mixture was stirred at 25° C. for 18 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 10:1) to give a mixture of methyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (220 mg, yield 20%) as a light yellow solid. LC-MS (ESI) m/z: 535 (M+1)+ and 549 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12]C)=[O:11].Br[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:16]1([S:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:14])[C:10]([OH:12])=[O:11])=[C:2]([F:1])[CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)C(C)c1ccc(S)cc1F
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(SC2CCCC2)cc1F
Yield: 95.4 %

Procedure:
A solution of compound (9) (0.53 g, 2.5 mmol), bromocyclopentane (0.32 mL, 3.0 mmol), and potassium carbonate (1.2 g, 8.8 mmol) in dry DMF (5 mL) was treated in the same manner as in Example 7. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional hydrolysis to give 0.64 g (90%) of compound (17) of interest as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[C:28]12([NH2:38])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>C(Cl)(Cl)Cl>[C:28]12([NH:38][C:12]([C:9]3[C:8](=[O:15])[N:7]4[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]4=[N:11][CH:10]=3)=[O:14])[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC34CC5CC(CC(C5)C3)C4)c(=O)n12
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
A mixture containing 4.08 (0.02 mole) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 3.1 ml (0.022 mol) of triethylamine in 120 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 2.52 ml (0.026 mol) of methyl chloroformate in 10 ml of chloroform is dropped to the above mixture at -15° C. during 10 minutes. After stirring for 5 minutes, 3.33 g (0.022 mol) of 1-adamantanamine dissolved in 20 ml of chloroform are dropped to the above solution at -15° C. during 15 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 4.4 g (65.2%) of the named product as pale yellow crystals after recrystallization from ethanol, m.p.: 190°-193° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=O)=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=[N:18][OH:19])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COc1cc(C=CC=O)ccc1OC(C)=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=CC=NO)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
4-Acetoxy-3-methoxycinnamaldehyde (2.0 g, 9.1×10-3M) is dissolved in methanol (100 ml) and cooled to 0° C. with an ice/water bath. Hydroxylamine hydrochloride (0.8 g, 1.2×10-2M) is added with sodium acetate (0.97 g, 1.2×10-2M) and stirred for one hour. The reaction mixture is concentrated to near dryness, and redissolved in ethyl acetate (150 ml). The residual organics are washed twice with water dried over sodium sulfate, filtered, evaporated to dryness, and chromatographed on flash silica using hexane:ethyl acetate 3:1 to afford 1.45 g of 4-acetoxy-3-methoxycinnamaldehyde oxime in 68% yield; mp=72°-74° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([NH2:27])=[N:23]1>C(O)C>[NH:22]1[CH:26]=[N:25][C:24]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])[N:3]=2)=[N:23]1
Reactant: Nc1nc[nH]n1
Reactant: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Cl)n1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Nc2nc[nH]n2)n1
Temperature: 160 °C
Yield: 4 %

Procedure:
A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (0.326 mmol) and 1H-[1,2,4]triazol-3-ylamine (0.651 mmol) in ethanol (3 mL) was heated at 160° C. and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160° C. for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol/dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1×25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography afforded IX-175 as a colorless oil (4% yield). 1H NMR (500 MHz, CDCl3) δ 9.18 (d, 1H), 8.82 (s, 1H), 7.90 (d, 1H), 7.85-7.75 (m, 3H), 7.71-7.62 (m, 3H), 7.60-7.55 (m, 2H), 4.42-4.35 (m, 1H). LC-MS (ES+) 356.16 (M+H); HPLC-Method D,—Rt 3.55 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[CH:11]=[N:10][CH:9]=[CH:8][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([NH:13][C:24]([NH:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=2)=[O:25])=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(F)(F)F)c2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1ccc(C(F)(F)F)c2cnccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a solution of 8-(trifluoromethyl)isoquinolin-5-amine (Description 93; 150 mg, 0.708 mmol) in CDCl3 (10 ml) was added [4-(trifiuoromethyl)benzyl]isocyanate (Description 58) [0.506M soln in DCM; 1.403 ml, 0.71 mmol) and the resulting mixture heated at reflux overnight. NMR analysis showed a deficit of the [4-(trifluoromethyl)benzyl]isocyanate in comparison to remaining 8-(trifluoromethyl)isoquinolin-5-amine so a further portion of [4-(trifluoromethyl)benzyl]isocyanate [0.506M solution in DCM] (1.403 ml; 0.71 mmol) was added and refluxing continued for 2 days. The cooled reaction mixture was evaporated to dryness and purified by column chromatography on silica elution with 1% MeOH in DCM+0.5% NH4OH. NMR showed the product was the bis acylated urea. This material was dissolved in methanol (5 ml) and K2CO3 (500 mg, 3.6 mmol) added and the mixture stirred at room temperature for 2.5 hours. The mixture was filtered and the residue purified by preparative TLC eluting with 10% MeOH in DCM+0.5% NH4OH to give the title compound (100 mg, 34%) as a white solid. m/z (ES+) 414 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:30]#[N:31])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:30]([C:13]1[CH:14]=[C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:10]=[CH:11][N:12]=1)#[N:31]
Reactant: CCOC(=O)C(C)Cc1ccncc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.6 %

Procedure:
Ethyl 2-methyl-3-(4-pyridyl)propionate (5.9 g, 30.5 mmol) was dissolved in ethyl acetate (25 ml) and 3-Chloroperbenzoic acid (ca. 77%, 7.5 g, 33.4 mmol) was added thereto. The reaction mixture was stirred at room temperature for 14 hrs and subjected to a silica gel (120 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (3:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (18 ml), and trimethylsilyl cyanide (4.5 g, 45.0 mmol) and N,N-dimethylcarbamoyl chloride (3.5 g, 32.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (3.7 g, 76%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.O.[NH2:14][NH2:15]>C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:12])[NH:15][N:14]=[C:8]2[CH3:9]
Reactant: CC(=O)c1cc(Br)c(F)cc1F
Reactant: NN
Solvent: OCCO
Solvent: O
Product: Cc1n[nH]c2cc(F)c(Br)cc12
Temperature: 160 °C
Reaction time: 26 h
Yield: 67 %

Procedure:
To a solution of 1-(5-bromo-2,4-difluorophenyl)ethanone (4.9 g) in ethylene glycol (15 ml) was added hydrazine monohydrate (1.2 g) at room temperature, and the mixture was stirred at 160° C. for 26 hr. The reaction mixture was cooled to room temperature, and the insoluble material was removed. The filtrate was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1.[I:15][C:16]1[CH:17]=[N:18][N:19]([CH:23]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24](O)=[O:25])[C:20](=[O:22])[CH:21]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:24](=[O:25])[CH:23]([N:19]3[C:20](=[O:22])[CH:21]=[C:16]([I:15])[CH:17]=[N:18]3)[CH2:27][CH:28]([CH3:30])[CH3:29])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(C)CC(C(=O)O)n1ncc(I)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(I)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4, 708.7 mg, 3.59 mmol) in N,N-dimethylformamide was added to 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid (Intermediate 86, 1.42 g, 4.23 mmol). At this point, the reaction was treated with 4-dimethylaminopyridine (21.9 mg, 0.18 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (823.7 mg, 4.31 mmol). The resulting reaction was stirred at 25° C. overnight. The reaction was then diluted with ethyl acetate (200 mL), was washed with water (200 mL) and a saturated aqueous sodium chloride solution (200 mL), filtered, and concentrated in vacuo onto silica gel. Chromatography (ISCO Combiflash, 10-60% ethyl acetate/hexanes) afforded 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white/yellow solid (950 mg, 51%); ES+-HRMS m/e calcd for C19H26N5O4I [M+Na+] 538.0921, found 538.0921. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83 (d, J=5.7 Hz, 3H), 0.85 (d, J=5.7 Hz, 3H), 1.23 (s, 3H), 1.29 (s, 3H), 1.35 (br. s., 1H), 1.76 (ddd, J=13.3, 9.4, 4.2 Hz, 1H), 2.03-2.21 (m, 1H), 3.71 (dd, J=8.4, 6.0 Hz, 1H), 3.98 (dd, J=8.4, 6.5 Hz, 1H), 4.03-4.18 (m, 2H), 4.33 (quin, J=6.0 Hz, 1H), 5.47 (dd, J=11.0, 4.1 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.59 (d, J=2.1 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][NH2:12])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[CH2:24][C:25]1[N:29]2[N:30]=[C:31]([C:34](=O)[CH3:35])[CH:32]=[CH:33][C:28]2=[N:27][CH:26]=1>>[CH2:1]([NH:8][C:9]([NH:11]/[N:12]=[C:34](/[C:31]1[CH:32]=[CH:33][C:28]2[N:29]([C:25]([CH2:24][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][C:14]=3[F:13])[N:21]=[CH:20][CH:19]=[CH:18]4)=[CH:26][N:27]=2)[N:30]=1)\[CH3:35])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNC(=S)NCc1ccccc1
Product: C/C(=N\NC(=S)NCc1ccccc1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 80 %

Procedure:
The title compound was prepared from N-benzylhydrazine carbothioamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 80% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1H), 9.30 (t, 1H), 8.86 (dd, 1H), 8.30 (m, 2H), 8.05 (d, 1H), 7.95 (d, 1H), 7.77 (d, 1H), 7.69 (s, 1H), 7.47 (q, 1H), 7.32 (m, 4H), 7.23 (m, 1H), 4.89 (d, 2H), 4.58 (s, 2H), 2.39 (s, 3H). LCMS (method C): [MH]+=484, tR=4.18 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([O:10]CC)=[O:9])#[N:2].O.O[Li].O.Cl>C1COCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)cnc1C(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(C(F)F)c(C(=O)O)c1
Reaction time: 0.83 h
Yield: 66.7 %

Procedure:
To a solution of ethyl 5-cyano-2-(difluoromethyl)nicotinate (1.2 g, 5.3 mmol) in THF: water (20 mL: 5 mL) was added LiOH.H2O (0.267 g, 6.3 mmol) at 0° C. and the reaction mass was stirred for 40-60 minutes. The reaction mass was acidified with dil. HCl and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.700 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.37-7.72 (t, J=53.7 Hz, 1H), 8.24 (s, 1H), 9.30 (s, 1H), 14.25 (br s, 1H); MS (m/z): 199.34 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][N:10]1[CH2:14][CH2:13]OC1=O.COCCOCCO.C(=O)=O>>[CH3:9][NH:10][CH2:14][CH2:13][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: CN1CCOC1=O
Agent: Cl
Agent: O=C=O
Solvent: COCCOCCO
Product: CNCCNc1ccccc1
Temperature: 170 °C
Reaction time: 17 h

Procedure:
A mixture of aniline hydrochloride (13.0 g, 0.10 mole), 3-methyl-2-oxazolidinone (11.0 g, 0.109 mole) and 35 ml of 2-(2-methoxyethoxy)ethanol was heated to 170° C. in an oil bath. The reaction mixture became homogenous and carbon dioxide evolution occurred on heating. After 17 hours, the reaction was allowed to cool to room temperature. After a workup procedure similar to that described in Example 1 and distillation at 105° C. to 110° C. (0.4 mm), an 81 percent distilled yield of the product was obtained as a clear liquid. Product confirmation was made by the use of spectra evidence.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]=2[N:4]=[CH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:46][C:47]1[CH:48]=[C:49]([NH:54][C:55](=[O:67])[C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([C:65]#[N:66])([CH3:64])[CH3:63])[CH:57]=2)[CH:50]=[CH:51][C:52]=1[CH3:53]>CN(C=O)C>[C:65]([C:62]([C:58]1[CH:57]=[C:56]([CH:61]=[CH:60][CH:59]=1)[C:55]([NH:54][C:49]1[CH:50]=[CH:51][C:52]([CH3:53])=[C:47]([NH:46][C:11]([C:9]2[S:10][C:5]3[N:4]=[CH:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:13])[CH:48]=1)=[O:67])([CH3:64])[CH3:63])#[N:66]
Reactant: O=C(O)c1cc2[nH]c(=O)cnc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2[nH]c(=O)cnc2s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 0.3 %

Procedure:
A solution of 2-oxo-1,2-dihydrothieno[3,2-b]pyrazine-6-carboxylic acid 84 (27 mg, 0.138 mmol), TBTU (48.6 mg, 0.151 mmol) and DIPEA (0.068 mL, 0.413 mmol) in DMF (1 mL) was stirred for 15 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (45.4 mg, 0.138 mmol) in DMF (1 mL) was added and stirred overnight at 50° C. Quenched with water and extracted with EtOAc. Organic layer was washed with water, dried and evaporated. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-oxo-1,2-dihydrothieno[2,3-b]pyrazine-6-carboxamide 85 (0.2 mg, 0.308%). (m/z)=472 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[CH:21]=[C:20]([CH3:29])[CH:25]=[CH:24][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Cc1cccc(B(O)O)c1
Product: COc1ccc2c(-c3cccc(C)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and m-tolylboronic acid to give (6-methoxy-1-m-tolyl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[S:17]([C:13]1[CH:12]=[C:11]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]3[CH:10]=[N:9]2)[CH:16]=[CH:15][CH:14]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: NS(=O)(=O)c1cccc(-n2ncc3c(I)ccnc32)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-n2ncc3c(B(O)O)ccnc32)c1
Temperature: 84 °C

Procedure:
To a 48 mL pressure bottle was added 3-(4-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)benzenesulfonamide, “dot” 2 1-methyl-2-pyrrolidinone complex (60 mg, 0.100 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (94.7 mg, 0.373 mmol), potassium acetate (24.4 mg, 0.249 mmol) and anhydrous DMSO (Volume: 2 mL). The reaction mixture was purged well with argon and treated with PdCl2(dppf).CH2Cl2 (12.5 mg, 0.017 mmol). The reaction mixture was then heated to 84° C. for 1 h to give the desired intermediate. LC/MS (Condition B): ret. T=2.4 min, (M+H)+ 318.98.