Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-chloro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M44) (0.79 g, 1.24 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (350 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([NH2:7])=O>O.CC#N.Cl[Pd]Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1cc(Br)cc(C=O)c1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(Br)cc(C=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
To a solution of 3-bromo-5-formylbenzamide (1.5 g, 6.58 mmol) in H2O (50.0 mL) and MeCN (50.0 mL) was added PdCl2 (117 mg, 0.658 mmol). The mixture was stirred for 72 h at room temperature and another portion of H2O (100 mL) and MeCN (100 mL) was added followed with addition of PdCl2 (100 mg, 0.56 mol). The mixture was stirred for another 12 hr and concentrated. The residue was dissolved in EtOAc (200 mL), washed with brine (3×50.0 mL), dried over Na2SO4 and concentrated, and then was purified by chromatography (10% EtOAc in hexanes) to give 550 mg of 3-bromo-5-formylbenzonitrile (40%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[I:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: O=S(=O)(c1ccc(I)cc1)N1CCOCC1

Procedure:
The title compound was prepared from morpholine and 4-iodobenzenesulfonyl chloride using a similar procedure to that described for Description 30.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[CH:16]=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[C:13]([F:12])[CH:18]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCOc1ccccc1F
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1F

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and 2-fluorophenetole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([CH2:24][N:25]([CH3:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:15][N:16](C3CCCCO3)C=2)[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.C(O)(C(F)(F)F)=O.CC#[N:47]>Cl>[CH:9]([O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:13]2[C:14]([CH2:24][N:25]([CH3:36])[CH2:26][CH2:27][NH2:28])=[CH:15][NH:16][N:47]=2)=[CH:5][C:6]=1[CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1cc(-c2cn(C3CCCCO3)cc2CN(C)CCNC(=O)OC(C)(C)C)cc(C)c1OC(C)C
Reactant: CC#N
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(-c2n[nH]cc2CN(C)CCN)cc(C)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of tert-butyl N-[2-[([4-[3,5-dimethyl-4-(propan-2-yloxy)phenyl]-1-(oxan-2-yl)-1H-pyrrol-3-yl]methyl)(methyl)amino]ethyl]carbamate (650 mg, 1.30 mmol, 1.00 equiv) in 3N hydrochloric acid (20 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 50 mmol CF3COOH and CH3CN (10.0% CH3CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm to give 269 mg (38%) of N1-((3-(4-isopropoxy-3,5-dimethylphenyl)-1H-pyrazol-4-yl)methyl)-N1-methylethane-1,2-diamine as a light yellow oil. 1H-NMR (300 MHz, D2O): δ 7.88 (s, 1H), 7.17 (s, 2H), 4.42 (s, 2H), 4.35-4.26 (m, 1H), 3.30-3.10 (m, 4H), 2.57 (s, 3H), 2.23 (s, 6H), 1.23 (d, J=6.3 Hz, 6H) ppm. LCMS (method J, ESI): RT=1.57 min, m/z=317.1 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5](Cl)=[O:6].[NH2:8][C:9]1[S:13][N:12]=[C:11]([Br:14])[C:10]=1[C:15](=[O:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([C:10]1[C:11]([Br:14])=[N:12][S:13][C:9]=1[NH:8][C:5]([C@@H:3]1[CH2:4][C@H:2]1[CH3:1])=[O:6])(=[O:17])[CH3:16]
Reactant: C[C@@H]1C[C@H]1C(=O)Cl
Reactant: CC(=O)c1c(Br)nsc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1c(Br)nsc1NC(=O)[C@@H]1C[C@H]1C
Yield: 82 %

Procedure:
Add a freshly prepared 1.93M solution of (1R,2R)-2-methyl-cyclopropanecarbonyl chloride (5.52; mol) in dichloromethane over 15; min to a suspension of 1-(5-amino-3-bromo-isothiazol-4-yl)-ethanone (1.17; kg, 4.93; mol) and triethylamine (859; mL, 6.16; mol) in dichloromethane (5.86; L) at room temperature and stir 4; hours. Quench the reaction with water (1; L) and separate the layers. Dry the organic layer over magnesium sulfate, filter, concentrate and purify the residue by short column silica gel chromatography (3500; g of SiO2) gradient eluting from 100:0; to 40:60 using n-hexane and ethyl acetate to give the title compound as a white solid (1230; g, 82%). MS (m/z): 303, 305; (M+1).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[N:8]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17]([C:31]#[N:32])[N:16]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:2][N:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[N:18]=[C:17]([C:31]#[N:32])[N:16]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCCNCC2)n1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Reaction time: 2 h

Procedure:
4-[1,4]Diazepan-1-yl-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (Example 13; 30 mg) and formaldehyde (6 mg, 37% wt aqueous) were stirred at room temperature in methanol (500 μl) for ten minutes. Sodium triacetoxyborohydride (17 mg) was added to the reaction and stirring continued for two hours. Solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography on silica yielded product 4-(4-methyl-[1,4]diazepan-1-yl)-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (10 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[N:8]([CH2:18][CH:19]=[CH2:20])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[N:8]([CH2:18][CH:19]=[CH2:20])[C:9]2[C:14]([C:15]=1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: C=CCn1c(=O)c(C(=O)OCC)c(Cl)c2ccc(C)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCn1c(=O)c(C(=O)OCC)c(N2CCCC2)c2ccc(C)nc21

Procedure:
A stirred mixture of 0.49 g. (0.0016 mole) of 1-allyl-4-chloro-1,2-dihydro-7-methyl-2-oxo-1,8-naphthridine-3-carboxylic acid ethyl ester, 0.11 g. (0.0016 mole) of pyrrolidine and 0.16 g. (0.0016 mole) sodium carbonate in 20 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was diluted with water to the cloudy point. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 0.2 g. of the title compound, m.p. 97°-103° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C@@H:6]([CH3:19])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[O:4].[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH3:22][N:5]([C@@H:6]([CH3:19])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)[C:3](=[O:4])[C:2]([F:20])([F:21])[F:1]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(=O)C(F)(F)F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a stirred solution of methyl (S)-4-[2-(trifluoroacetamido)-1-propoxy]benzoate (695 mg, 2.28 mmol) and K2CO3 (630 mg, 4.56 mmol) in DMF (10 ml) was added MeI (210 ml, 3.37 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with H2O and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with EtOAc—CHCl3 (1:19, v/v) as eluent to give methyl (S)-4-[2-[(N-methyl)trifluoroacetamido]-1-propoxy]benzoate (720 mg, 99%) as a white solid. mp 73-75° C.; 1H-NMR (CDCl3) 1.36-1.39 (m, 3 H), 2.96 and 3.10 (each s, total 3 H), 3.89 (s, 3 H), 3.99-4.14 (m, 2 H), 4.84-4.92 (m, 1 H), 6.88-6.92 (m, 2 H), 7.98-8.00 (m, 2 H); MS (FAB) m/z 320 (M++1); Anal. Calcd. for C14H16F3NOf: C, 52.67; H 5.05; F, 17.85; N, 4.39. Found: C, 52.76; Et 5.09; F, 17.53; N, 4.32.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].C(O)[C@H]([C@@H]([C@H]([C@@H](CO)O)O)O)O.C(O)[C@@H]([C@@H]([C@@H]([C@@H](CO)O)O)O)O.C(O)[C@@H](O)C(O)[C@H](O)CO.C(O)[C@@H]([C@@H]([C@@H](CO)O)O)O>>[CH2:10]([OH:11])[C@@H:8]([C@H:6]([C@H:4]([C@@H:2]([CH2:1][OH:12])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@@H](O)C(O)[C@H](O)CO
Agent: OC[C@@H](O)[C@@H](O)[C@@H](O)CO
Agent: OC[C@@H](O)[C@@H](O)[C@@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO

Procedure:
talitol; iditol; allitol; altritol; guilitol; arabitol; ribitol;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cccc(N)c2)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(/C=C\c2cccc(N)c2)c1
Reaction time: 2 h
Yield: 43.6 %

Procedure:
Into a reaction flask were added tert-butyl {5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbamate (0.45 g, 1.4 mmol) (prepared in Example C19, step A), methanol (15 mL) and 100 mg of Lindlar's catalyst. The reaction mixture was hydrogenated at 35 psi for 2 h. After removal of the solvent, the crude was purified by silica gel column chromatography to give the desired product as a white powder (0.19 g, 42%). LCMS for C18H22N3O2 (M+H)+: m/z=312.0.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([NH:23][C:24]1[CH:36]=[C:35]([CH:37]=[CH2:38])[CH:34]=[CH:33][C:25]=1[C:26]([O:28]C(C)(C)C)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:15]([NH:23][C:24]1[CH:36]=[C:35](/[CH:37]=[CH:38]/[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[CH:34]=[CH:33][C:25]=1[C:26]([OH:28])=[O:27])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1cccc(I)c1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(/C=C/c2cccc(O)c2)ccc1C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 56.2 %

Procedure:
54 mg of 3-iodophenol, 81 mg of cesium carbonate, 12 mg of tetrabutylammonium bromide and 19 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 1.0 mL of toluene solution containing 40 mg of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room, temperature, 19 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) was added and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 40-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 25 mg of 2-(benzamido)-4-((E)-2-(3-hydroxyphenyl)vinyl)benzoic acid as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:33]1[CH:38]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:36]=[N:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:37]6[CH:38]=[N:33][CH:34]=[N:35][CH:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2cncnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cncnc5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.074 g, 0.55 mmol, 1.2 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT (0.054 g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The Organic layer was separated, washed with water, concentrated and the crude product was purified by Prep. TLC (20 mm thickness) using 5% methanol/DCM as an eluent. Yield: 50 mg (20%) 1HNMR (400 MHz, DMSO-d6): δ 1.33-1.36 (m, 2H), δ 1.42-1.45 (m, 2H), 2.29 (s, 3H), 2.81-2.82 (d, J=4.4 Hz, 3H), 3.96 (s, 3H), 7.14 (s, 1H), 7.33 (dd, J=1.6, 8.4 Hz, 1H), 7.40 (t, J=8.8, 2H), 7.50 (d, J=1.2 Hz, 1H), 7.52 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.97-8.01 (m, 2H), 8.47 (q, J=4.4 Hz, 1H), 8.67 (s, 2H), 8.91 (s, 1H), 9.00 (s, 1H) LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]3[N:11]([CH:31]=2)[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=2)[C:14]=3[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]3[N:11]([CH:31]=2)[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][CH:19]=2)[C:14]=3[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1)(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3cccc(N)c3)[nH]c12
Product: C=CC(=O)Nc1cccc(-c2cn3nc(-c4ccc(Oc5ccccc5)cc4)c(C(N)=O)c3[nH]2)c1

Procedure:
The desired product was prepared from 2-(3-aminophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (400 MHz, CD3OD-d4) δ 8.06 (s, 1H), 7.83 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.52-7.38 (m, 5H), 7.15 (t, J=7.6 Hz, 1H), 7.09-7.05 (m, 4H), 6.49-6.37 (m, 2H) and 5.80 (dd, J=4.0, 8.8 Hz, 1H). MS (ESI) m/e [M+1]+ 463.9.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1>>[F:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:17]=1[F:18])[NH:19][C:1](=[O:8])[C:2](=[O:4])[NH:20]2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(F)c(F)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound (Sarges, R. et al., J. Med. Chem. 33:2240 (1990)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (1.11 g, 7.63 mmol and 4,5-difluoro-1,2-diaminobenzene (110 mg, 0.763 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid was collected by vacuum filtration, rinsed with hexanes, and air dried. This gray brown solid was recrystallized from 20 mL of EtOH and the brown-white crystals collected by vacuum filtration and the crystals further dried under vacuum (0.5 torr, 25° C.) to yield 45.3 mg (30.0%); mp>360° C. (lit.>310° C.); 1H NMR (d6 -acetone) δ7.19 (t, 2H, ArH, JH-F =9.3), 10.9 (br s, 2H, NH).
Reaction SMILES: [CH2:1]([In:6](CC(C)(C)C)[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl-:17].[In+3].[Cl-].[Cl-]>C(OCC)C>[Cl-:17].[CH2:7]([In+:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CC(C)(C)C[In](CC(C)(C)C)CC(C)(C)C
Agent: [Cl-]
Agent: [In+3]
Solvent: CCOCC
Product: CC(C)(C)C[In+]CC(C)(C)C
Yield: 61.6 %

Procedure:
6.56 g (20.0 mmol) of trisneopentyl indium was reacted with 2.21 g (9.99 mmol) of indium chloride in refluxing diethyl ether for 48 hours to form bisneopentyl indium chloride. The resulting solution was filtered and then reacted with 30 mmol of methyl lithium (17.6 ml, 1.7M solution of diethyl ether) at 0° C. The methyl lithium solution was slowly added with stirring over a 10 minute time period. After the reaction mixture had stirred for 2 hours, the diethyl ether was removed by vacuum distillation. The product methyl bisneopentyl indium was separated from lithium chloride by extraction and filtration using 30 ml of pentane. Removal of pentane left a clear liquid product. In order to insure that the last traces of solvents (diethyl ether or pentane) and been removed, the sample was continuously evacuated for 3 hours at room temperature. Further purification was achieved by a vacuum distillation using a bath temperature of 80° C. and a head temperature of 55° C. The final purified product methyl bisneopentyl indium (3.35 g, 12.3 mmol) was isolated in 61.6% yield based on trisneopentyl indium.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:61]3[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CCl)cc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)N[C@H]3CC[C@@H](Oc4ccc5nnc(N6CCCCC6)n5c4)c4ccccc43)cc2)CC1
Temperature: 50 °C
Yield: 7.3 %

Procedure:
To a solution of Intermediate 106b (0.25 mmol) in THF (2.5 mL) was added DIPEA (130 μL, 0.75 mmol) followed by N-methylpiperazine (83 μL, 0.75 mmol). The reaction mixture was heated at 50° C. for 18 h in a sealed tube, then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by HPLC (C, 18 X-select column, 10-98% gradient MeCN in H2O, 0.1% HCO2H), to give the title compound (13 mg, 7%). LCMS (Method 5): Rt 3.44 min, m/z 717 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.57-1.66 (2H, m), 1.68-1.77 (4H, m), 1.79-1.95 (2H, m), 1.98-2.19 (5H, m), 2.22-2.46 (8H, m), 3.14 (4H, t, J=5.3 Hz), 3.49 (2H, s), 4.76-4.85 (1H, m), 5.54 (1H, t, J=4.4 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=9.8, 2.2 Hz), 7.25-7.47 (8H, m), 7.59-7.65 (2H, m), 8.11 (1H, s).
Reaction SMILES: [OH:1][C@H:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4](OC)=[O:5].[CH3:13][NH2:14]>>[CH3:13][NH:14][C:4](=[O:5])[CH2:3][C@H:2]([OH:1])[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN
Reactant: COC(=O)C[C@H](O)c1cccs1
Product: CNC(=O)C[C@H](O)c1cccs1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
23 g of methyl (3S)-3-hydroxy-3-(2-thienyl)propanoate from experiments described in the Examples 1 and [lacuna] were initially introduced, and 130 ml of a 2-molar methanolic solution of methylamine were added. This mixture is stirred at 60° C. for 4 h, cooled and then concentrated in vacuo. 24 g (purity 87%; 90% of theory) are obtained in this way. The crude product can be used as such for the next step or else recrystallized from methylene chloride and hexane. This yielded 18 g of N-methyl-(3S)-3-hydroxy-3-(2-thienyl)propanamide (75% of theory) in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([Cl:8])=[N+:6]([O-:18])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Cl)ncc1Br
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)[n+]([O-])cc1Br
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-chloro-4-methylpyridine (1.0 eq.) and meta-chloroperbenzoic acid (mCPBA) (2.5 eq.) in chloroform (0.1 M) was stirred at 50° C. overnight. After cooling to room temperature, Ca(OH)2 (2.5 eq.) was added to the reaction mixture. The precipitate was filtered and washed with 5% methanol in dichloromethane and ethyl acetate. The filtrate was washed with saturated aqueous Na2S2O3 solution and saturated aqueous NaHCO3 solution. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo into a pale solid that was carried onto the next step without further purification.