Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH2:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:22]=3[N:21]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH3:2].[BH4-].[Na+]>CO.O>[CH2:1]([C:3]1[C:4]([CH2:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:22]=3[N:21]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]([OH:18])[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: CCc1cc(C)c2[nH]cc(C(=O)C(F)(F)F)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cc(C)c2[nH]cc(C(O)C(F)(F)F)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-((5-ethyl-7-methyl-3-(2,2,2-trifluoroacetyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (60 mg, 0.114 mmol) in MeOH (10 mL) was added portionwise NaBH4 (21.6 mg, 0.572 mmol). The mixture was stirred at room temperature for 3 h, and then for 16 h at 60° C. The reaction mixture was diluted with H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography [CH2Cl2/(2M NH3 in MeOH)=94/6, isocratic] to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.50 (br. s., 1H), 7.83 (s, 1H), 7.54 (d, J=8.30 Hz, 1H), 7.47 (d, J=8.30 Hz, 1H), 7.42 (br. s., 1H), 6.95 (s, 1H), 5.56 (q, J=7.28 Hz, 1H), 4.78 (d, J=17.40 Hz, 1H), 4.64 (d, J=17.43 Hz, 1H), 2.74 (q, J=7.45 Hz, 2H), 2.45 (s, 3H), 1.12 (t, J=7.52 Hz, 3H). HRMS calcd. for C22H19F3N4O (M+H)+ 413.1584. found 413.1583.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH2:11][CH2:12][CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].C(=O)([O-])[O-:16].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]([OH:16])([CH2:11][CH2:12][CH3:13])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(O)(C(=O)O)C(=O)OCC
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Air was bubbled for 1 hour at room temperature through a suspension of 15.0 g (72.7 mmol) diethylpropylmalonate and 47.6 g (145 mmol) cesium carbonate in 120 ml dimethylformamide. At 10-20° C. 150 ml water were added and stirring was continued at room temperature for 3 hours. Most of the dimethylformamide was then removed by vacuum distillation at 35° C. bath temperature. 1 l water was added and extraction with diethylether yielded 11.7 g 2-hydroxy-2-propyl-malonic acid monoethylester, MS (m/e): 189.1 (M−H)−.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:19](=[O:32])[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[C:14]([CH:18]=1)[C:15](O)=[O:16])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:34]1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:18]=[C:14]2[C:13]([C:19]([OH:32])([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[NH:34][C:15]2=[O:16])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)c2ccc(OC(=O)c3ccccc3)cc2C(=O)O)cc(OC)c1OC
Reactant: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2(O)NC(=O)c3cc(OCc4ccccc4)ccc32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of 5-benzoyloxy-2-(3,4,5-trimethoxybenzoyl)benzoic acid 50 mg, 14.8M aqueous ammonia 50 μl, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimido hydrochloride 68 mg and 1-hydroxybenzotriazole 15.9 mg is dissolved under ice cooling in N,N-dimethylformamide 2 ml and the mixture is stirred overnight at room temperature. To the reaction mixture is added water. The mixture is extracted with ethyl acetate and the extract is washed with water and dried, followed by removal of the solvent. The residue is purified with silica gel chromatography (solvent: chloroform:ethyl acetate=1:1) and left to be crystallized. The crystals are triturated with diisopropyl ether-ethyl acetate to give 6-benzyloxy-3-hydroxy-3-(3,4,5-trimethoxyphenyl)-2,3-dihydroisoindol-1-one 46.7 mg.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C([O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1)=[O:35])(C)(C)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:39]3[CH:40]=[CH:41][C:36]([C:34]([OH:35])=[O:33])=[CH:37][CH:38]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cc1

Procedure:
The title compound was prepared from compound 2b and 4-(tert-butoxycarbonyl)phenylboronic acid pinacol ester using the methods described in Example 1, Step G, followed by the deprotection of the resulting product with TFA using the methods described in Example 6, Step B. Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H23N5O3: 478.2 [M+H]. found 478.1.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])Cl)=[C:6]([F:14])[C:5]=1[I:15]>C1COCC1>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:2][CH3:1])=[N:10][OH:11])=[C:6]([F:14])[C:5]=1[I:15]
Reactant: ON=C(Cl)c1ccc(Cl)c(I)c1F
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=NO)c1ccc(Cl)c(I)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine (33% wt solution in absolute ethanol, 1.9 mL, 18 mmol) was added dropwise to a solution of 4-chloro-2-fluoro-3-iodobenzoyl chloride oxime (0.600 g, 1.8 mmol) in anhydrous THF (10 mL) at 0° C. The reaction mixture was stirred at RT for 1 h. The volatile solvents were removed under reduced pressure. Flash chromatography on silica gel (dichloromethane:hexane 25:75) gave 4-chloro-2-fluoro-N′-hydroxy-3-iodo-N-methylbenzamidine as an amorphous white solid. MS (ESI, pos.ion) m/z: 330.9 (M+1)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:26]#[C:27]Br.N>CO>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C@H:2]3[CH2:3][O:4][C:27]([NH2:26])=[N:1]3)=[CH:8][CH:9]=2)=[CH:19][CH:18]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCc1ccc(Nc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1=N[C@@H](CCc2ccc(Nc3ccc(Cl)cc3)cc2)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
To a stirred suspension of (S)-2-amino-4-[4-(4-chloro-phenylamino)-phenyl]-butan-1-ol (210 mg) and sodium acetate (121 mg) in methanol (5 ml) was added dropwise a solution of cyanogen bromide (68 mg) in methanol (0.3 ml). The resulting pale yellow solution was then stirred at room temperature for 16 h. Aqueous ammonia solution (0.4 ml, 25%) was added dropwise and stirring was continued for a further hour. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to give (S)-4-{2-[4-(4-chloro-phenylamino)-phenyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine (74 mg, 48%) as a yellow solid. MS (ISP): 318.1 ([{37Cl}M+H]+), 316.1 ([{35Cl}M+H]+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[C:17]([O-])([O-])=[O:18].[K+].[K+].[OH-].[Na+]>CN(C=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH:14][OH:16])[CH:17]=[O:18])=[CH:11][CH:12]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=CC(=CO)c1ccc(Br)cc1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Cool to 4° C. phosphorous oxychloride (2.34 mL, 26.0 mmol) in a 100 mL flask. To this, add 5 mL of DMF and stir mixture for 5 min. Remove the flask from the cooling bath and heat at 75° C. Add (4-bromophenyl)acetic acid (2.00 g, 9.30 mmol) in one portion with an additional 5 mL of DMF and stir the mixture at 75° C. under Ar for 16 h. Pour the mixture into ice and neutralize by slow addition of K2CO3. Heat the solution at 75° C. and make strongly basic by the addition of 50% aq. NaOH resulting in an oil. Extract the oil from the aq. phase with 2×70 mL of CH2Cl2, dry with MgSO4, filter and concentrate to give 2.10 g, 99% of 2-(4-bromo-phenyl)-3-hydroxy-propenal.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:18]Br>O>[Br:18][C:8]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][NH:6][CH:7]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
A 1 L 3-neck flask equipped with a stir bar was charged with 3-nitro-1H-pyrazole (41.3 g, 365 mmol), sodium acetate (36.0 g, 438 mmol), and acetic acid (260 mL). The flask was fitted with a septum, addition funnel, and a temperature probe. Bromine (23 mL, 450 mmol) was added over 30 minutes via addition funnel to the reaction mixture; the temperature increased to 40° C. over the course of bromine addition. The heterogeneous reaction mixture became homogeneous as the reaction progressed, with the exception of a few chunks of solid. As the temperature of the reaction mixture fell, a precipitate formed. The reaction mixture was poured into 1.2 L of ice and water and stirred vigorously. After 15 minutes, the solids were collected by filtration and washed with several portions of water (500 mL total). The solids were dried under vacuum to afford the product as a tan powder (49.67 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL) was added ethyl chloroformate (26 mg, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give Ethyl 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidine-1-carboxylate as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.13 (s, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 6.28 (s, 1H), 4.30-4.26 (m, 2H), 4.14 (q, 2H), 2.99-2.96 (m, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.8-1.77 (m, 2H), 1.64-1.55 (m, 2H), 1.28 (t, 3H); ESMS m/z 488.2 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43]C)=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1>[OH-].[Na+].C1COCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of compound 6 (37 g) in NaOH (1N, 150 ml), THF (500 ml) and water (500 ml) was stirred at room temperature overnight. The organic solvent was evaporated. The aqueous concentrate was washed with DCM and acidified with HCl (1N, 150 ml). The solvent was evaporated. The residue was stirred in water, filtered off and dried, yielding 32 g (84%) of 6,11-dihydro- 11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylic acid (compound 7, mp. 174.2° C.).
Reaction SMILES: [CH:1](=[N:5][OH:6])[CH2:2][CH2:3][CH3:4].[CH3:7]/[C:8](/[C:11]([CH3:13])=O)=[N:9]\[OH:10]>CCOCC>[CH3:13][C:11]1[N+:5]([O-:6])=[C:1]([CH2:2][CH2:3][CH3:4])[N:9]([OH:10])[C:8]=1[CH3:7]
Reactant: CCCC=NO
Reactant: CC(=O)/C(C)=N/O
Solvent: CCOCC
Product: CCCc1n(O)c(C)c(C)[n+]1[O-]
Reaction time: 48 h

Procedure:
A mixture of butyraldoxime (8.7 g., 0.1 mole) and diacetyl monoxime (10.1 g., 0.1 mole) was warmed to obtain a homogeneous solution. After standing for 2 days at room-temperature, the mixture was heated on the steam-bath for 3 hr., and then diluted with ether (500 ml), the tan solid separated was removed by filtration (16.7 g.) and recrystallised from ethanol (95%) having a melting point 174°-175°C
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)n1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Yield: 92.1 %

Procedure:
Using the procedure of example 66, compound 13 (24 mg) and methanesulfonyl chloride (9.4 mg) were used to provide compound 67 (28 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 8.85 (d, 1 H), 8.52 (d, 1 H), 8.32 (d, 1 H), 8.28 (s, 1 H), 7.40 (dd, 1 H); 6.85 (d, 1H), 5.12 (m, 1 H), 3.90 (m, 1 H), 3.65 (s, 3 H), 2.15 (m, 2 H), 1.85 (m, 2 H), 1.65 (m, 2 H), 1.50 (m, 2 H), 1.35 (m, 2 H). MS (ESI) m/z: 372 (M+H)+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[CH2:26][CH:25]([CH2:27][CH2:28][CH2:29][OH:30])[O:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(OCC)C>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[CH2:26][CH:25]([CH2:27][CH2:28][CH:29]=[O:30])[O:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NOC(CCCO)C2)cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Reaction time: 6 h
Yield: 52.4 %

Procedure:
After dissolving pyridinium chlorochromate (PCC; 2.249 g, 10.435 mmol) and 70-230 mesh SiO2 (2.748 g) in 25 mL of methylene chloride, 3-[3-(3,4-dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propan-1-ol (1.374 g, 5.217 mmol) dissolved in 2 mL of methylene chloride was added. After the reaction was continued for about 6 hr, 10 mL of diethyl ether was added and the reaction mixture was filtered through a cellite bed. After removing all the solvent and purifying by column chromatography on silica gel (hexane/ethyl acetate=1.5/1, v/v), 0.72 g (51.6%) of the target compound was obtained.
Reaction SMILES: [C:1]([C:4]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2]>C(O)C.O>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:5]2[C:4]=1[C:1](=[O:2])[O:3][C:4]([C:1]([OH:3])=[O:2])=[CH:6]2
Reactant: Cc1cccc(C=O)c1C(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cccc2cc(C(=O)O)oc(=O)c12

Procedure:
8-Methylisocoumarin-3-carboxylic acid, mp. (EtOH-H2O) 236°-7°, (Found: C, 64.66; H, 3.95. C11H8O4 requires C, 64.70; H, 3.95), was prepared from 2-carboxy-3-methylbenzaldehyde by an analogous procedure to that described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:43][C:44]1[CH:68]=[CH:67][C:47]2[CH2:48][CH2:49][C:50]3[C:51]([C:64]([NH2:66])=[O:65])=[N:52][N:53]([C:55]4[CH:63]=[CH:62][C:58]5[O:59][CH2:60][O:61][C:57]=5[CH:56]=4)[C:54]=3[C:46]=2[CH:45]=1>CN(C=O)C>[O:59]1[C:58]2[CH:62]=[CH:63][C:55]([N:53]3[C:54]4[C:46]5[CH:45]=[C:44]([NH:43][C:5](=[O:7])[C:4]6[C:8]([Cl:11])=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=6)[CH:68]=[CH:67][C:47]=5[CH2:48][CH2:49][C:50]=4[C:51]([C:64]([NH2:66])=[O:65])=[N:52]3)=[CH:56][C:57]=2[O:61][CH2:60]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
2,5-Dichloroisonicotinic acid (1.65 g, 0.0086 mol), HATU (3.27 g, 0.0086 mol) and finally Et3N (2.32 mL, 0.0166 mol) were added to a solution of the title compound of step 4 of Example 161 (2 g, 0.00574 mol) in 29 mL of DMF. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of step 4 of Example 161 in LC/MS. The crude reaction mixture was concentrated to about 10 mL of DMF. Upon addition of water to this DMF residue, a white solid was formed. This white solid was triturated in water for 20 min and filtered. The solid was collected, dissolved in THF, and dried with MgSO4. Removal of the solvent afforded a brown solid that was triturated in warm CH3CN (80° C.) to give 2.2 g of the title compound (yield 73%). Mp: 292-293° C. 1H NMR (300 MHz, d6-DMSO): δ 2.90-2.92 (m, 4H), 6.09 (s, 2H), 6.94-7.04 (m, 2H), 7.12 (d, 1H, J=2 Hz), 7.26-7.38 (m, 4H), 7.51 (s, 1H), 7.81 (s, 1H), 8.61 (s, 1H), 10.54 (s, 1H). M+1=523.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[F:14][C:15]([F:31])([F:30])[C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:20]2[CH2:21][C@H:16]([C:15]([F:31])([F:30])[F:14])[CH2:17][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]2)=[C:3]2[CH2:13][CH2:12][CH2:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 150 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
To a mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (144.2 mg, 0.7260 mmol) and tert-butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (from MolBridge, 179.9 mg, 0.6706 mmol) was added 1-butanol (3.0 mL) followed by DIPEA (493.7 mg, 3.820 mmol). The mixture was stirred at 150° C. for 6 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (179.2 mg, 62%). LCMS calc. for C19H26F3N4O4 (M+H)+: m/z=431.2. found 431.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[N:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[C@@H:24]([CH3:25])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)(=[O:3])[NH2:2].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[CH3:18][N:16]1[CH:17]=[C:13]([C:11]2[N:12]=[C:6]3[C:5]([NH:19][C@H:20]4[C@@H:24]([CH3:25])[CH2:23][NH:22][CH2:21]4)=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=[N:8][N:7]3[CH:10]=2)[CH:14]=[N:15]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate in DCM (4.5 ml) at 0° C. was added TFA (526 μl, 6.83 mmol) dropwise. The reaction was stirred at 0° C. for 10 minutes and at room temperature for 1.5 h. The reaction solution was concentrated to yield a yellow oil, which was partitioned between ethyl acetate and water. The organic layer was washed with (sat.) sodium chloride, dried with sodium sulfate, filtered and concentrated to give 2-(1-methyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, 2 TFA (333.5 mg, 0.587 mmol, 86% yield) as a yellow solid. ESI-MS (analytical LCMS Method B): m/z 341.2 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 1.847 min.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15]>O>[Cl:1][S:2]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:6][C:7](=[O:15])[CH2:8]2)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: O
Product: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
To a 100 mL flask charged with 27 mL of chlorosulfonic acid was added slowly 13.3 g of 2-oxindole. The reaction temperature was maintained below 30° C. during the addition. After the addition, the reaction mixture was stirred at room temperature for 1.5 hr, heated to 68° C. for 1 hr, cooled, and poured into water. The precipitate was washed with water and dried in a vacuum oven to give 11.0 g of 5-chlorosulfonyl-2-oxindole (50% yield) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[C:18]([F:19])([F:21])[F:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Benzyloxy-3-trifluoromethyl-benzoic acid (CAB03046, 3.555 g, 12 mmol) in THF (20 mL) was added dropwise to a suspension of lithium aluminium hydride (1.0 g, 26.3 mmol) in THF (20 mL). The mixture was stirred for another 30 minutes at room temperature and then quenched by addition of 2N NaOH (5 mL). The white preciptate was filtered off and washed with dichloromethane (100 mL), the filtrate was dried over sodium sulphate and concentrated under reduced pressure. The resulting oil was crystallised from diethyl ether/hexane. Yield: 3.31 g (98%). 1H-NMR (400 MHz, CDCl3) δ=1.72 (t, J=5.9 Hz, 1H, —OH), 4.66 (d, J=5.9 Hz, 2H, —CH2OH), 5.21 (s, 2H, —CH2Ph), 7.02 (d, J=8.2 Hz, 1H), 7.30-7.48 (m, 6H), 7.61 (d, J=2.3 Hz, 1H). LRMS (FAB+): 91.1 (100), 265.2 (45), 282.2 (40, [M+H]+).