Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:32])[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[C:33]([NH:35][CH2:36][C:37]12[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2)=[O:34].C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]2)=[O:32])=[CH:14][C:13]=1[C:33]([NH:35][CH2:36][C:37]12[CH2:38][CH:39]3[CH2:40][CH:41]([CH2:42][CH:43]([CH2:45]3)[CH2:44]1)[CH2:46]2)=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 66.2 %

Procedure:
To dimethyl sulphoxide (0.155 ml) in anhydrous dichloromethane (11 ml) at −78° C. was added oxalyl chloride (0.086 ml) and the mixture was stirred for 5min. at −78° C. A solution of 4-[[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]hydroxymethyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.47 g, Example 64) in anhydrous dichloromethane (3 ml) was added dropwise and the mixture was stirred for 15 min. at −78° C. Triethylamine (0.633 ml) was then added and the solution was warmed to room temperature. After 45 min. at room temperature, the reaction mixture was poured onto water and the layers were separated. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC eluting a gradient of 0-5% ethanol in dichloromethane to give the subtitle compound as a white foam (0.31 g).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH2:19](Br)[C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][C:20]#[CH:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(NC(=O)C(C)(C)C)c1C(=O)OC

Procedure:
A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 47, 4.57 g), propargyl bromide (80% solution in toluene, 2.03 mL) and potassium carbonate (3.74 g) in acetone (35 mL) was heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20% to give methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) as an oil which crystallised on standing to give a white solid.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[SH:18][CH2:19][CH2:20][OH:21]>CN(C=O)C.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[S:18][CH2:19][CH2:20][OH:21]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc([N+](=O)[O-])ccc1SCCO
Temperature: 60 °C
Yield: 95.9 %

Procedure:
To a stirred solution of 2-chloro-5-nitroaniline (1.0 g, 5.79 mmol) in DMF (10 mL) was added potassium carbonate (1.60 g, 11.59 mmol) followed by 2-mercaptoethanol (0.813 mL, 11.59 mmol). The resulting mixture was then heated at 60° C. for 2 hours and then at room temperature overnight. The mixture was then diluted with ethyl acetate and washed with water (3×), 1N NaOH, and brine. The organic phase was dried, filtered, and concentrated, giving a red/orange solid (1.19 g, 96%). 1H NMR (DMSO-d6) δ 7.52 (s, 1H), 7.42-7.33 (m, 2H), 5.79 (s, 2H), 4.99 (t, J=5.4 Hz, 1H), 3.55 (q, J=6.2 Hz, 2H), 3.02 (t, J=6.6 Hz, 2H); ESI-MS (m/z, %): 215 (MH+, 23), 169 (100), 111 (63).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2=[N+:6]([O-])[O:7][N:8]=[C:4]2[CH:3]=1.P(OCC)(OCC)OCC>C(O)C.CCCCCC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1
Reactant: [O-][n+]1onc2cc(Br)ccc21
Agent: CCOP(OCC)OCC
Solvent: CCO
Solvent: CCCCCC
Product: Brc1ccc2nonc2c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a stirred solution of 5-bromobenzo[c][1,2,5]oxadiazole 1-oxide (6.0 g, 28.436 mmol) in ethanol (60 mL) was added triethyl phosphite (6.2 mL, 34.123 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 60° C. for 1 h., cooled to RT, diluted with hexane (100 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-bromobenzo[c][1,2,5]oxadiazole (4.0 g, 71%) as a light yellow solid.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH3:12])[N:10]=[CH:11][C:4]=12)[NH2:2].C1N=CN([C:18](N2C=NC=C2)=[S:19])C=1.[CH3:25]N(C)C=O>>[CH3:12][N:9]1[C:5]2[N:6]=[CH:7][N:8]3[C:25]([S:19][CH3:18])=[N:2][N:1]=[C:3]3[C:4]=2[CH:11]=[N:10]1
Reactant: Cn1ncc2c(NN)ncnc21
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CN(C)C=O
Product: CSc1nnc2c3cnn(C)c3ncn12

Procedure:
3.08 g. of 4-hydrazino-1-methylpyrazolo[3,4-d]pyrimidine and 3.56 g. of 1,1-thiocarbonyldiimidazole in 100 ml. of dimethylformamide are stirred at 5° over a period of 16 hours. The 7-methyl-3-mercapto-7H-pyrazolo[4,3-e][1,2,4]-triazolo[4,3-c]pyrimidine which has been formed is filtered under suction, washed with water and recrystallized from a little dimethylformamide as yellowish crystals, m.p. 252°-254°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]N)=[CH:4][CH:3]=1.C[N:12](C1C=CC=CN=1)C.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25].Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:30]2[C:22]([O:21][CH3:20])=[C:23]([CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]([NH2:12])=[O:25])=[CH:6][CH:7]=1
Reactant: NCCc1ccc(F)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: COc1c(CCc2ccc(F)cc2)cc(Cl)cc1C(N)=O

Procedure:
1.39 g (10.0 mmol) of 4-fluoro-β-phenylethylamine are dissolved in 40 ml of pyridine, treated with a spatula tipful of dimethylaminopyridine and with a solution of 2.15 g (10.5 mmol) of 2-methoxy-5-chlorobenzoyl chloride. The reaction mixture is poured into cold dilute hydrochloric acid, and the precipitated product is filtered off with suction and dried. 4-Fluoro-β-phenylethyl-(2-methoxy-5-chlorobenzamide) is obtained as colorless crystals of melting point 85° C. The benzamide thus obtained is introduced into cold chlorosulfonic acid. After reaction is complete, the reaction mixture is poured onto ice, and the precipitate is filtered off with suction (melting point of the sulfonyl chloride: 118° C.) and dissolved in acetone. This solution is treated with excess, concentrated aqueous ammonia and, after the exothermic reaction has subsided, concentrated to a third of the original volume. The 2-methoxy-5-chloro-N-[5-(1-sulfonylamino-2-fluorophenyl)ethyl]benzamide forms colorless crystals which melt at 203° C. Heating of 2-methoxy-5-chloro-N-[5-(1-sulfonylamino-2-fluorophenyl)ethyl]benzamide in excess morpholine under reflux for three hours yields 2-methoxy-5-chloro-N-[5-(1-sulfonylamino-2-(4-morpholino)phenyl)ethyl]benzamide, which is isolated by column chromatography (silica gel 60, heptane/ethyl acetate gradient of 2:1 to 4:1). The product melts at 236° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]=[C:5]2B(O)O.[CH3:21][N:22]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]1=[O:28].O1CCOCC1>[Rh].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]=[C:5]2[CH:24]1[CH2:25][C:26](=[O:27])[N:22]([CH3:21])[C:23]1=[O:28]
Reactant: CC(C)(C)[Si](C)(C)n1cc(B(O)O)c2cc(Br)ccc21
Reactant: CN1C(=O)C=CC1=O
Agent: [Rh]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)CC(c2cn([Si](C)(C)C(C)(C)C)c3ccc(Br)cc23)C1=O

Procedure:
To an oven dried, argon purged flask fitted with magnetic stir-bar is charged 5-bromo-1-(tert-butyldimethylsilyl)-1H-indol-3-ylboronic acid 15 (141.6 mg, 0.400 mmol), N-Methyl maleimide 16 (22.2 mg, 0.200 mmol), Rhodium catalyst (0.05 equiv.), anhydrous dioxane (1 mL) and stirring begun. H2O (0.05 mL) added, and mixture heated in an oil bath as per the conditions outlined in Table 9 below. The reaction mixture was filtered through silica gel bed, and the solvent was evaporated to obtain crude product. The crude product was purified via chromatography on silica gel (20% Ethylacetate/80% Hexanes) to yield 3-(5-bromo-1-(tert-butyldimethylsilyl)-1H-indol-3-yl)-1-methylpyrrolidine-2,5-dione 17. The enantiomeric excess was determined with chiral HPLC.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OC)=O.[NH2:28][CH:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[N:32]([CH:41]([CH3:43])[CH3:42])[N:31]([CH3:44])[C:30]1=[O:45]>ClCCl>[CH3:44][N:31]1[C:30](=[O:45])[CH:29]([NH:28][C:13](=[O:15])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[N:32]1[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)N1C(=O)c2ccccc2C(N)C(=O)N1C
Agent: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of N-boc-(L)-valine (IV, 1.04 g, 4.8 mmol) in dichloromethane (100 mL) was added the N-methyl morpholine (0.56 g, 5.6 mmol) and methyl chloroformate (0.37 mL, 4.8 mmol) at 0° C. The resulting solution was stirred for 10 minutes before the addition of a solution of 5(R,S)-amino-2,3,4,5-tetrahydro-3-methyl-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione (IIIA, 1.0 g, 4.04 mmol) in dichloromethane (5 mL) and it was further stirred for another 1 h. The resulting mixture was washed with 1N hydrochloric acid (50 mL), sodium bicarbonate (50 mL), brine (50 mL) and dried over MgSO4, filtered and concentrated to afford the crude product. This product was purified further on flash (silica gel) chromatography (hexane/ethyl acetate, 3/2) to afford 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-[(1,1-dimethylethoxycarbonyl)amino]-3-methyl-1-oxobutyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione(1.5 g, 83%).
Reaction SMILES: C1(N=C=O)C=CC=CC=1.CC1(C)OC2C(N3C=NC4C3=NC=NC=4[NH:40][C:41]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:42])OC(C(NC3C=C(C=CC=3)C(O)=O)=O)C2O1>>[C:44]1([NH:43][C:41]([NH2:40])=[O:42])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC1(C)OC2C(C(=O)Nc3cccc(C(=O)O)c3)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Solvent: O=C=Nc1ccccc1
Product: NC(=O)Nc1ccccc1

Procedure:
Phenyl isocyanate was coupled with the amide product using a method similar to those described above, affording the intermediate phenylurea compound. MW calculated for C30H29N7O7 (MH+) 600, found 600 by LCMS.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26].[CH2:27]1[O:29][CH2:28]1>C1COCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH2:28][OH:29]
Reactant: C1CO1
Reactant: Cc1ccncc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCCc1ccncc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
Diisopropylamine (7.1 g, 70 mmol) is dissolved in THF (100 ml), and thereto is added a solution of n-butyl lithium in hexane (35.7 ml, 60 mmol) at −70° C., and the mixture is stirred for 15 minutes. Then, to the mixture is added a solution of 3-bromo-4-methylpyridine (8.6 g, 50 mmol) in THF (30 ml). Ten minutes thereafter, to the mixture is added ethylene oxide (2.6 g, 60 mmol), and the mixture is warmed to 0° C. over a period of time for one hour.” The reaction is quenched with a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (150 ml×2). The organic layer is washed with a saturated brine (100 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (8.5 g) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[Cl:8][C:7]1[C:2]([O:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Clc1cccnc1Cl
Reactant: Cc1nsc(N)n1
Product: Cc1nsc(Nc2ncnc3ccc(Oc4ncccc4Cl)cc23)n1

Procedure:
The compound of Example 86 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-dichloropyridine, 5-amino-3-methyl-[1,2,4]thiadiazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.Cl[N:12]1C(=O)[CH2:15][CH2:14][C:13]1=O.C(N)C#C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:15]=[C:14]([CH2:13][NH2:12])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(Cl)cc1
Agent: C#CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCc1cc(-c2ccc(Cl)cc2)no1
Yield: 110.2 %

Procedure:
1.56 g (10 mmol) of p-chlorobenzaldoxime was dissolved in 40 ml of dried dichloromethane in a erlenmeyer flask equipped with a magnetic stirrer, and 1.7 g (12 mmol) of N-chlorosuccinimide was added slowly. The reaction mixture was stirred until completely dissolved. The system was heated slightly for 20 min. Then, 0.56 g (10 mmol) of propargyl amine was introduced and 1.2 g (12 mmol) of triethylamine was added dropwise, which caused the emission of white smog. The reaction mixture was heated under reflux for 2 h, and then purified by column chromatography on silica gel using petroleum ether (b.p. 60-90° C.)—ethyl acetate (v:v=4:1) as eluant, to obtain 2.3 g of the product as yellow solid. The yield was 62%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[CH2:33][C:34]#[N:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1>CO.C1(C=O)CC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([C:33](=[CH:39][CH:40]3[CH2:42][CH2:41]3)[C:34]#[N:35])=[O:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
Into a 50 mL, round-bottom flask, was placed a solution of 3-[(2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (109 mg, 0.22 mmol, 1.00 equiv) in methanol (10 mL), cyclopropane-carbaldehyde (1 mL), and piperidine (1 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with ethyl acetate and the resulting mixture was washed with water and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 32 mg (25%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]+. 1H-NMR: (300 MHz, CDCl3, ppm): δ 8.38 (s, 1H), 7.74 (d, 2H), 7.18 (d, 2H), 7.08 (m, 2H), 6.92 (m, 1H), 6.81 (d, 1H), 5.54 (s, 2H), 4.82 (m, 1H), 4.68 (m, 2H), 3.65 (m, 1H), 3.51 (m, 1H), 2.02 (m, 3H), 1.20 (m, 3H), 0.88 (m, 3H).
Reaction SMILES: [CH:1]1([CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.CO>[Pd].C(OCC)(=O)C>[CH:1]1([CH2:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CN(c1cc(C=CC2CC2)cc(C(=O)O)c1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(c1cc(CCC2CC2)cc(C(=O)O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A mixture of 3-(2-cyclopropylvinyl)-5-[methyl(methylsulfonyl)amino]benzoic acid obtained in Reference Example 23 89 mg (0.30 mmol), 10% Pd/C (50% wet) 30 mg, methanol (1 mL) and ethyl acetate (1 mL) was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The reaction solution was filtered on Celite and the solvent was evaporated to give 89 mg (0.30 mmol, 100%) of the title compound (yield: 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:7]=2[CH:26]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=3[O-:35])[C:7]=2[CH:26]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccccn2)[C@@H]1O
Solvent: ClCCl
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2cccc[n+]2[O-])[C@@H]1O
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-2,2-bis(methoxymethyl)-4-(2-pyridylamino)-2H-1-benzopyran-3-ol (152 mg, 0.43 mmol) obtained in Example 42 was dissolved in dichloromethane (5 ml), and m-chloroperbenzoic acid (150 mg, purity 80%) was added under ice-cooling. The mixture was stirred for 1.5 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (methanol:chloroform=5:95) to give 94.5 mg of the title compound (59%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[N:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:26]([C:30]1[CH:54]=[CH:53][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[C:38]=2[CH3:52])=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:26]([C:30]1[CH:54]=[CH:53][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[O:19])=[CH:16][N:17]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)[C:38]=2[CH3:52])=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(c1ccc(Nc2cc(Cl)nn3ccnc23)nc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c2nccn2n1
Temperature: 170 °C
Reaction time: 3 h
Yield: 10.2 %

Procedure:
A mixture of crude [6-(6-chloro-imidazo[1,2-b]pyridazin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone (0.048 g, “0.133 mmol”), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.087 g, 0.23 mmol), potassium carbonate (0.056 g, 0.41 mmol), Pd(PPh3)4 (0.016 g, 0.014 mmol), 1 mL of toluene, 0.25 mL of ethanol and 0.25 mL of water under N2 was stirred at 170° C. in a microwave for 3 h. More Pd(PPh3)4 was added (0.025 g, 0.021 mmol) and the mixture was stirred for an additional 1 h at 170° C. in a microwave. The mixture was partitioned between 5 mL of water and 5 mL of ethyl acetate, and the aqueous layer was extracted with 5 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to 0.126 g of a yellow oil. Column chromatography (1st column: 0->10% MeOH/CH2Cl2; 2nd column: 0->5% MeOH/EtOAc) afforded 0.008 g (10%) of 4-tert-butyl-N-(2-methyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-phenyl)-benzamide as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(OC(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(C(=O)O)c(F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 120 %

Procedure:
To a mixture of methyl 2-fluoro-4-hydroxy-benzoate (2.1 g, 12.4 mmol), potassium carbonate (6.8 g, 49.5 mmol) in dry DMF (13 mL) was added 2-iodopropane (2.5 mL, 24.8 mmol) and the reaction mixture was heated at 60° C. for 2 hours. The reaction was cooled and diluted with ether (50 mL) and filtered over Celite®. The filtrate was washed sequentially with water (3×25 mL) and brine solution (25 mL). The organic layer was separated and dried over MgSO4 and solvent was concentrated in vacuo to give a residue which was purified by silica gel column chromatography using 5-45% EtOAc/hexanes to give methyl 2-fluoro-4-isopropoxybenzoate as a colorless oil (2.2 g, 83%). To a solution of methyl 2-fluoro-4-isopropoxybenzoate (2.2 g, 10.3 mmol) in THF (5.5 mL) was added a suspension of lithium hydroxide (0.9 g, 37.1 mmol) in water (5.5 mL). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the excess LiOH was removed by filtration. The filtrate was diluted with water (9 ml), and washed with ether (2×5 mL). The aqueous layer was separated and cooled to 0° C. and the pH was adjusted to pH 2 by addition of 6 M HCl solution. The aqueous layer was extracted with EtOAc (3×30 mL). The organics were separated and washed sequentially with water and brine. The organic layer was separated, dried and concentrated in vacuo to give 2-fluoro-4-isopropoxy-benzoic acid (2.45 g, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (t, J=8.8 Hz, 1H), 6.69 (ddd, J=15.1, 10.9, 2.0 Hz, 2H), 4.63 (dt, J=12.1, 6.0 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H).