Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][C:22]1([CH3:28])[CH2:24][CH:23]1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH:8][C:25]([CH:23]1[CH2:24][C:22]1([CH3:28])[CH3:21])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC1C(=O)Cl
Reactant: CCCCC(N)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(NC(=O)C1CC1(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N. R. James, British Patent No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5 N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl, then with 2×200 ml of 0.5 N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52°->65°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[C:14](#[N:16])C.[C-]#N>C1(C)C=CC=CC=1.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([C:14]#[N:16])=[O:7]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC#N
Agent: [Cu]
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)C#N)cc1OC
Reaction time: 0.5 h

Procedure:
A well stirred mixture [paddle stirrer] of 3,4-dimethoxybenzoyl chloride [AcrosOrganics] (14.05 g; 0.070 mol), dry toluene (32 cm3), dry acetonitrile (8.0 cm3), copper I cyanide (8.5; 0.095 mol) and Celite (5 g) was heated under reflux until no acid chloride remained (˜1.5 hrs). The dark reaction mixture was cooled to ˜70° and diluted with toluene (150 cm3). After stirring for an additional ˜30 minutes, the resulting slurry was filtered through a bed of chromatographic silica gel (˜2.5 cm) and the pale yellow filtrate evaporated in vacuo to constant weight to give the title compound as a lemon yellow solid. Yield=11.41 g (85.3%), Mpt=143-145° C. The product was used directly in next stage.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27](C(O)=O)[CH2:28][CH2:29]2)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([N:38]([CH2:41]C)CC)C.CC[O:45]C(C)=O>C1(C)C=CC=CC=1>[N:38]([CH:27]1[CH2:28][CH2:29][CH:30]2[N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[CH:26]1[CH2:32][CH2:31]2)=[C:41]=[O:45]
Reactant: CCOC(C)=O
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C2CCC(C(=O)O)C1CC2
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC(N=C=O)C1CC2
Temperature: 100 °C

Procedure:
Diphenylphosphoryl azide (890 mg, 3.23 mmol) was added into a solution of 8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid (0.75 g, 2.94 mmol) and triethylamine (595 mg, 5.88 mmol) in toluene (10 ml). The reaction solution was heated at 100° C. for 5 h. EtOAc (50 ml) was added and the resulting solution was washed with water (10 ml). The organic layer was separated, and dried over sodium sulfate. The solution was filtered, concentrated, and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([NH:10][S:11]([C:14]2([CH2:17]C=C)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C:5]([F:9])=[CH:6][C:7]=1[F:8].C[N+]1([O-])CC[O:33]CC1.CCO[C:40]([CH3:42])=[O:41]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[OH:33][CH:42]([CH2:40][OH:41])[CH2:17][C:14]1([S:11]([NH:10][C:4]2[C:5]([F:9])=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])(=[O:13])=[O:12])[CH2:16][CH2:15]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCC1(S(=O)(=O)Nc2c(F)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F)C1(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
1-Allyl-cyclopropanesulfonic acid [3,4,6-trifluoro-2-(2-fluoro-4-iodo-phenyl amino)-phenyl]-amide (110 mg, 0.21 mmol) and 4-methylmorpholine N-oxide (24.6 mg, 0.21 mmol) was dissolved in THF (8 mL). Osmium tetroxide was added at room temperature (0.021 mmol, 0.153 mL, 4% in H2O) and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, the organic phase was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified over silica gel chromatography (eluants: EtOAc/MeOH) to obtain the titled product (0.89 g, 75%). 1H NMR (CDCl3, 300 MHz): δ 7.39 (dd, J=1.5 & 10.6 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.28 (s, 1H), 6.97 (s, 1H), 6.76 (m, 1H), 6.49 (m, 1H), 4.13 (m, 1H), 3.66 (dd, J=3.7 & 11.4 Hz, 1H), 3.53 (dd. J=6.7 & 11.2 Hz, 1H), 2.50 (dd, J=10.0 & 16.1 Hz, 1H), 1.6 (m, 1H), 1.46 (m, 1H), 1.28 (m, 1H), 1.20 (m, 2H), 0.92 (m, 2H); m/z=559 [M−1]−.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([CH3:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:25]>O1CCCC1.O.C(#N)C>[Li+:25].[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH:4]([CH3:22])[C:3]([O-:23])=[O:2])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: COC(=O)C(C)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)[O-]
Yield: 76.2 %

Procedure:
3-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-2-methyl-propionic acid methyl ester (623 mg; 1.89 mmol, prepared in accordance with Example 62) and lithium hydroxide (60 mg; 2.50 mmol) are suspended in a mixture of tetrahydrofuran (4 mL) and water (1 mL). The resulting mixture is irradiated in a mono-mode microwave oven for 50 minutes at 100° C. The mixture is then diluted with acetonitrile until precipitation occurs. The solid formed is then filtered and dried under high vacuum to afford the desired product (465 mg; 1.44 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C[C:16]1C=CC=[C:18](C)[C:17]=1[N+:23]([O-])=O.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([NH:23][CH:17]([CH3:18])[CH3:16])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Reactant: Cc1cccc(CC(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(CC(=O)NC(C)C)c1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To a slurry of 3-methyl-2-nitrobenzeneacetic acid (prepared by the method of H. Rapoport et al., J. Org. Chem., 1954, 77, 670-675 from 1,3-dimethyl-2-nitrobenzene, 0.70 g, 3.6 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.41 mL, 4.7 mmol) and two drops of N,N-dimethylformamide. The reaction mixture was stirred for 20 minutes, resulting in a solution. The volatiles were removed with a rotary evaporator. The residue was dissolved in 10 mL of dichloromethane. Half of this material was added dropwise at 0° C. to isopropylamine (1 mL) in 5 mL of dichloromethane. The reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution was added, and the reaction mixture was passed through a Celite® diatomaceous filter aid cartridge. The solvent was removed with a rotary evaporator to afford the title compound as an orange solid (0.40 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:16]([NH:19][CH2:20][C:21](O)=[O:22])(=[O:18])[CH3:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)C(C)C)(C)C>[C:16]([NH:19][CH2:20][C:21]([N:5]([CH2:4][CH:3]([O:14][CH3:15])[O:2][CH3:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:22])(=[O:18])[CH3:17]
Reactant: CC(=O)NCC(=O)O
Reactant: COC(CNCc1ccc(F)cc1)OC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(C)=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)amine (366.5 g, 1.72 mol), N-acetylglycine (213.7 g, 1.83 mol), EDC (350.0 g, 1.83 mol), and HOBt (29.1 g, 0.19 mol) in anhydrous DMF (2.5 L), N,N-diisopropylethylamine (˜250 mL) was added until the solution is about pH 8. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between dichloromethane (4 L) and water (1 L). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: C=CC.C1OC1.[C:7]([O:22]CCCC)(=[O:21])[C:8]1[C:9](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([O:12]CCCC)=[O:11]>C1(C)C(C)=CC=CC=1>[CH2:7]([OH:21])[CH2:8][CH2:9][CH2:10][OH:11].[C:10]1(=[O:12])[O:22][C:7](=[O:21])[C:8]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:9]12
Reactant: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Solvent: Cc1ccccc1C
Solvent: C1CO1
Solvent: C=CC
Product: O=C1OC(=O)c2ccccc21
Product: OCCCCO

Procedure:
320 parts of a 40% xylene solution of dihydroxyethylenepropylene copolymer (molecular weight; 8,000, propylene content; 50%, prepared by hydroxyethylating both terminals of the ethylene-propylene copolymer as produced by known living anionic polymerization with ethyleneoxide) and 460 parts of a 40% dibutyl phthalate solution of polyester obtained from 1,4-butanediol and phthalic anhydride (equivalent weight ratio; 41/40, molecular weight; 8,000) were fed into a four-mouthed reaction vessel fitted with a powerful stirrer, a temperature sensor, a condenser and a material charging inlet and stirred for one hour at 100° C. for homogenization. Afterwards, 4.3 parts of hexamethylene diisocyanate was added thereto and stirred for one hour at 120° C., and 0.02 part of dibutyl tin dilaurate was further added thereto and reacted until the NCO content became 0.05 or less (generally, for five hours) to obtain a 40% solvent solution of component (2)(i).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[O:5][C:6]=1[C:7](OC)=[O:8].[CH:15]([NH2:17])=O>>[N:1]1[C:2]2[C:3]3[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=3[O:5][C:6]=2[C:7](=[O:8])[NH:17][CH:15]=1
Reactant: COC(=O)c1oc2ccccc2c1N
Reactant: NC=O
Product: O=c1[nH]cnc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
A solution of methyl 3-aminobenzo[b]furan-2-carboxylate (0.28 g, 1.36 mmol) in formamide (5 mL) is heated at 135 C. for 4 h, then the temperature is raised to 170 C. After 4 h the reaction is cooled to 25° C. and a dark purple solid precipitates. The solid is collected by vacuum filtration and air dried to give 3H-benzofurano[3,2-d]pyrimid-4-one (118 mg, 46.6%). 1H NMR (DMSO) δ13.0 (1H, brs), 8.25 (1H, s), 8.05 (1H, d, J =8.1 Hz), 7.84 (1H, d, J=8.3 Hz), 7.68 (1H, t, J=7.7 Hz), 7.51 (1H, t, J=7.7 Hz).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
94 mg (0.346 mmol) of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in dichloromethane (3.4 mL), and 70 μL (0.676 mmol) of benzylalcohol and 98 mg (0.511 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride were added, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and subsequently the residue was diluted with ethyl acetate and washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=3/1) to afford 41.2 mg of the title compound (yield 33%). Enantiomeric excess: 99.8% ee (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 33.2 min.).
Reaction SMILES: [OH:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>>[OH:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[Br:11])=[O:20]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(F)c(F)c1O
Product: O=C(Nc1ccccc1Br)Nc1ccc(F)c(F)c1O

Procedure:
The urea was prepared from 2-hydroxy 3,4-difluoro aniline(0.290 g, 2 mmol) and 2-bromophenylisocyanate(0.4 g) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS m/z 343(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[C:36]([O:41][CH2:42][CH2:43]O)=[N:37][CH:38]=[CH:39][N:40]=2)[CH2:31][CH2:30]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[N:32]1([C:35]2[C:36]([O:41][CH2:42][CH2:43][O:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[N:37][CH:38]=[CH:39][N:40]=2)[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]1
Reactant: Oc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cccc(F)c1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared according to the procedure of Example 77 starting from 2,6-difluorophenol (239 mg, 1.84 mmol), TMAD (384 mg, 2.25 mmol), 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (600 mg, 1.86 mmol; prepared in Example 52, Step 2), and triphenylphosphine (969 mg, 3.69 mmol) to give 279 mg (45%) of a solid: mp 101-102° C. HRMS m/z calcd for C16H18F2N4O2(M)+336.1398, found 336.1403.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([NH:45][C:14]([NH:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[C:10]([C:23]([F:24])([F:25])[F:26])[CH:11]=2)=[O:22])[CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 79 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (184 mg, 79%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.79 (s, 1H), 8.69 (d, 1H), 7.79 (s, 1H), 7.68 (m, 2H), 7.46 (m, 4H), 7.42 (s, 1H), 7.35 (s, 1H), 7.27 (d, 1H), 6.87 (s, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 585 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:4]=1)=O.[CH:37]([NH2:40])([CH3:39])[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:37]([NH:40][CH2:1][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:4]=1)([CH3:39])[CH3:38]
Reactant: CC(C)N
Reactant: CCOC(=O)CCCCCCn1cc(C=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCn1cc(CNC(C)C)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 7-(7-formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Intermediate C)(50 mg, 0.103 mmol) in DCE (1 ml) was treated with iso-propylamine (0.027 ml, 0.310 mmol) and stirred at RT for 30 minutes. Sodium triacetoxyborohydride (65.7 mg, 0.310 mmol) was added and stirring continued at RT for 16 hours. The mixture was extracted with DCM (30 ml) and the organic extract was washed with water (×2) and concentrated under reduced pressure to afford the titled compound as an orange oil;
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:8]([O:10]CC(Cl)(Cl)Cl)=O)=O.[C:24]1([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:24]1([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][N:38]([C:8]([NH:7][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:37][CH2:36]3)[S:33][CH:34]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1cccnc1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 27.7 %

Procedure:
A mixed solution of bis(2,2,2-trichloroethyl)pyridin-3-ylimidodicarbonate (359 mg, 0.810 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (396 mg, 1.62 mmol) and diisopropylethylamine (0.281 ml, 1.62 mmol) in dimethyl sulfoxide (2.7 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 82.0 mg (27.8%) of the desired product as a solid. mp 74-75° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][N:11]3[CH:19]=2)=[CH:4][CH:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:20]([NH:24][C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:19]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc2nc(-c3ccc(F)cc3)cn2c1
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: CC(C)(C)NC(=O)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Yield: 100.9 %

Procedure:
2-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic acid (example 45; 40 mg, 0.14 mmol), tert-butylamine (73.1 mg, 0.0.27 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; 57.2 mg, 0.15 mmol) and triethylamine (56.8 μl, 0.41 mmol) in 3 ml DMF were stirred at room temperature for 2 hours. The mixture was evaporated. ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 44 mg (99%) of the desired product. MS: M+H+=312.15.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Yield: 21.2 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carboxamide (Intermediate 13) (30 mg, 0.072 mmols), 3-fluorophenyl boronic acid (30 mg, 0.216 mmols), potassium carbonate (60 mg, 0.433 mmol), and Pd(PPh3)4 (8 mg, 0.0072 mmol) in dioxane (2 mL) and water (1 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (6.57 mg, 21%)
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C([NH:43][C:44]1C=C[C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1)=O>>[O:50]1[CH2:48][CH2:47][CH2:46][C@@H:45]1[CH2:44][NH:43][C:29]([C:26]1[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: O=C(NC[C@H]1CCCO1)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting (R)-(tetrahydrofuran-2-yl)methamine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.85 (t, J=6.1 Hz, 1H), 8.32 (d, J=9.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 7.41-7.28 (m, 4H), 5.00-4.71 (m, 4H), 4.04 (p, J=6.2 Hz, 1H), 3.85-3.74 (m, 1H), 3.70-3.58 (m, 1H), 3.44-3.33 (m, 3H), 1.99-1.71 (m, 2H), 1.69-1.54 (m, 1H); MS (ESI(+)) m/e 368 (M+H)+.