Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O.CCOCC>[OH:12]/[N:11]=[C:3](/[C:2](=[O:1])[CH2:9][CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)/C(=N\O)C(=O)CC
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
A solution of ethyl 3-oxopentanoate (50 g) in acetic acid (66 ml) was cooled to 0° C. and treated dropwise with 2/3 portion of a solution of sodium nitrite (52.6 g) in water (170 ml). After dropping (40 minutes), the reaction mixture was diluted with water (170 ml) and stirred for 1.5 hours. The mixture was treated with the residual solution of sodium nitrite at room temperature and stirred for more 1.5 hours. The reaction mixture was diluted with ether and quenched by aqueous sodium bicarbonate. The organic phase was washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure to afford ethyl 2-(Z)-hydroxyimino-3-oxopentanoate (43.77 g).
Reaction SMILES: Br[C:2]1[C:3]([C:24]#[N:25])=[CH:4][C:5]([F:23])=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:7]=1.[NH2:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=1.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([C:3]1[C:2]([NH:26][C:27]2[O:31][N:30]=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=2)=[CH:7][C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:5]([F:23])[CH:4]=1)#[N:25]
Reactant: Nc1cc(-c2ccccc2)no1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Br)c(C#N)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cc(-c3ccccc3)no2)c(C#N)cc1F
Yield: 20.3 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(5-bromo-4-cyano-2-fluorophenylamino)cyclohexylcarbamate (165 mg, 0.400 mmol), 5-amino-3-phenylisoxazole (96 mg, 0.600 mmol), sodium phenoxide trihydrate (136 mg, 0.800 mmol), xantphos (30 mg, 0.051 mmol) and Pd2(dba)3 (30 mg, 0.032 mmol) in dioxane (2 mL) was degassed with Ar, then was heated at 170 C for 30 min by microwave. It was concentrated in vacuo. The residue was purified by HPLC to give tert-butyl (1S,2R)-2-(4-cyano-2-fluoro-5-(3-phenylisoxazol-5-ylamino)phenylamino)cyclohexylcarbamate (40 mg).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][P:24]([C:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][C:35]=1[Br:42])([F:33])[F:32])(=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])([CH3:21])[CH3:20]>>[Br:42][C:35]1[CH:36]=[C:37]([CH2:40][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][N:9]=2)[CH:38]=[CH:39][C:34]=1[C:31]([P:24](=[O:30])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[O:23][C:19]([CH3:22])([CH3:20])[CH3:21])([F:32])[F:33]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1Br
Reactant: c1ccc(Cc2noc(-c3ccccc3)n2)cc1
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(c2ccccc2)c2noc(-c3ccccc3)n2)cc1Br

Procedure:
Starting with 3-benzyl-5-phenyl-1,2,4-oxadiazole and di(tert-butyl)[[2-bromo-4-(bromomethyl)phenyl](difluoro)methyl]phosphonate, the title compound was prepared as an oil by using the same procedure described in Step 3 of Example 4.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([OH:18])=O.CN(C)C=O.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH2:33]>ClCCl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[Cl:7]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cccnc1N
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1NC(=O)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
Oxalyl chloride (0.14 ml) was added dropwise to a solution of (2,4-dichloro-phenyl)-acetic acid (270 mg) in dichloromethane (10 ml) at ambient temperature. A drop of N,N-dimethylformamide (“DMF”) was added to initiate the reaction. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to give a colourless oil which was dissolved in dichloromethane (3 ml). The mixture was added dropwise to a cooled (−5° C.) slurry of 2-amino-nicotinic acid methyl ester (200 mg) (Example 1.1), 4-dimethylaminopyridine (“DMAP”) (32 mg) and pyridine (0.19 ml) in dichloromethane (5 ml). The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between dichloromethane and aqueous hydrochloric acid (2M). The phases were separated. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: acetone/iso-hexane ratio 1:9 to 2:8) to give 2-[2-(2,4-dichloro-phenyl)-acetylamino]-nicotinic acid methyl ester as a light yellow gum (197 mg). 1H-NMR (400 MHz, CDCl3): 10.81 (bs, 1H), 8.59-8.60 (m, 1H), 8.29-8.31 (m, 1H), 7.42-7.44 (m, 1H), 7.34-7.36 (m, 1H), 7.23-7.27 (m, 1H), 7.07-7.11 (m, 1H), 4.08 (s, 2H), 3.90 (s, 3H) ppm.
Reaction SMILES: N1C=[CH:5][C:4]([CH2:7][S:8][C:9]2[NH:14][C:13](=[O:15])[N:12]3[N:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[C:11]3[N:10]=2)=CC=1.C(S[C:33]1[NH:38]C(=O)N2N=C(C3C=CC=CC=3)C=C2[N:34]=1)C1C=CC=CC=1>>[NH:34]1[CH:5]=[C:4]([CH2:7][S:8][C:9]2[NH:14][C:13](=[O:15])[N:12]3[N:16]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=[C:11]3[N:10]=2)[N:38]=[CH:33]1
Reactant: O=c1[nH]c(SCc2ccncc2)nc2cc(-c3ccccc3)nn12
Reactant: O=c1[nH]c(SCc2ccccc2)nc2cc(-c3ccccc3)nn12
Product: O=c1[nH]c(SCc2c[nH]cn2)nc2cc(-c3ccccc3)nn12

Procedure:
2-(4-pyridylmethyl)thio-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one; 2-benzylthio-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one; 3-benzyl-2-methylthio-7-phenyl pyrazolo [1,5-a]-1,3,5-triazine-4-one 2-(2-enzimidazolyl methylthio)-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one; and 2-(4-imidazolylmethylthio)-7-phenylpyrazolo [1,5-a]-1,3,5-triazine-4-one are prepared in analogous fashion by making appropriate modifications of the above-described procedures.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.O.[OH-].[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[C:20]1([NH:19][C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cncc(Nc2ccccc2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 5 ml of dimethylsulfoxide, 4.55 ml of aniline was added, and the mixture was heated for 17 hours at 80°-90 ° C. Water and 10%-sodium hydroxide aqueous solution were added to the reaction mixture, and the aqueous alkaline solution was washed with chloroform. The aqueous layer was filtered, and the filtrate was adjusted with 10%-hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and ethanol affording 0.80 g of the desired compound as yellow needles, m.p. 290°-293.5° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]I)=[CH:4][CH:3]=1.[C-:12]#[C-:13].[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:12]#[CH:13])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCCI)cc1
Reactant: [C-]#[C-]
Agent: [Na+]
Product: C#CCCCc1ccc(Cl)cc1

Procedure:
The title compound was synthesized using 3-(4-chlorophenyl)-1-iodopropane and sodium acetylide by conducting the reactions similar to those mentioned in Reference example 29.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[CH2:28]([C:30]1[C:38]2[C:37]([NH2:39])=[CH:36][CH:35]=[CH:34][C:33]=2[N:32]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[N:31]=1)[CH3:29]>ClCCl.CN(C)C=O>[CH2:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[NH:39][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[N:32]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[N:31]=1)[CH3:29]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(N)c12
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Yield: 26.9 %

Procedure:
To a stirred suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (36.5 mg, 0.225 mmol) in dichloromethane (0.6 mL) was added N,N-dimethylformamide. Oxalyl chloride (84.5 μL, 0.169 mmol) was added and the mixture was stirred in a sealed vessel with ice cooling. The cooling was removed and the mixture was stirred for 3 hours with occasional venting to allow gases to escape. Diisopropylethylamine (21.6 μL, 0.124 mmol) and 3-ethyl-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (30 mg, 0.113 mmol) were added. The mixture was stirred for 30 minutes and then concentrated under reduced pressure. The material was purified using preparative thin layer chromatography, eluting with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide solution. A second purification eluting with 5% methanol in ethyl acetate containing 0.5% ammonium hydroxide solution was carried out to provide N-(3-Ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (12.5 mg). MS (APCI), positive scan, m/z=411.3 (M+H).
Reaction SMILES: [O:1]1[C:6]2C=CC=CC=2C=CN1.C=O.[OH-].[Na+].[N:15]1[C:22]([NH2:23])=[N:21][C:19]([NH2:20])=[N:18][C:16]=1[NH2:17].NO.NC(N)=O>>[CH2:6]([NH:17][C:16]1[N:18]=[C:19]([NH2:20])[N:21]=[C:22]([NH2:23])[N:15]=1)[OH:1]
Reactant: C1=Cc2ccccc2ON1
Reactant: Nc1nc(N)nc(N)n1
Agent: C=O
Agent: NC(N)=O
Agent: NO
Product: Nc1nc(N)nc(NCO)n1
Temperature: 70 °C
Reaction time: 0.9 h

Procedure:
In this version of the synthesis of the benzoxazine polymer composition, 462.4 grams of 50% formalin and 0.59 grams of 25% sodium hydroxide solution were added to the reaction flask so that the pH after mixing was 8.59. Then, 157 grams of the resole of example 1 and 141 grams of melamine were added. Under mixing, the contents of the reaction flask were heated to 70° C. and allowed to exotherm to 80° C. The flask contents were clear when 80° C. was reached. When the temperature dropped to 79° C. further heating was used to bring the flask contents to 103.5° C. and atmospheric reflux was established. The flask contents were then allowed to react under atmospheric reflux until an HPC time of 83 seconds was reached. The time under atmospheric reflux was 54 minutes. The free formaldehyde of the flask contents at this point was measured at 9.2% by the hydroxylamine method. To further reduce the free formaldehyde, 40 grams of urea was added. Next, water and volatile components were removed by vacuum distillation at a reduced pressure of about 22 inches of mercury and a temperature of about 65° C. The vacuum distillation was continued until the second HPC time of 54 seconds was reached. The free formaldehyde at this point was 1.0 percent.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:30]B(O)O.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.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:30])=[CH:10][CH:9]=2)=[O:4]
Reactant: CB(O)O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
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: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), methylboronic acid (200 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg), potassium carbonate (280 mg), toluene (6 ml) and THF (3 ml) was stirred at 100° C. under a nitrogen atmosphere for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and the residue was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (210 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.O=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:12].Br>C(O)(=O)C>[CH3:15][C:14]1([CH3:16])[CH:13]=[C:11]([CH3:12])[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:9]1
Reactant: COc1cccc(N)c1
Reactant: CC(=O)C=C(C)C
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC(C)(C)C=C2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
273 g (2.2 mol) m-anisidine and subsequently 221 g (2.2 mol) mesityl oxide were added dropwise at 15-20° C. to 25 ml glacial acetic acid. Then the solution was stirred for ca. 18 hours at room temperature. Subsequently 500 ml hydrobromic acid was added dropwise at 20-30° C. After stirring for 1 h at room temperature the precipitate was filtered. The precipitate which was still wet, was suspended in ca. 1 l acetone, filtered and dried. 200 g 2,2,4-trimethyl-7-methoxy-1,2-dihydro-quinoline hydrobromide was resuspended in a mixture of 1 l water and 500 ml chloroform. The suspension was then neutralized with 10% sodium hydroxide solution. The organic phase was subsequently washed with water, dried over sodium sulfate and evaporated to dryness in a rotary evaporator. The green coloured oil solidified after a short time. The solid was recrystallized from hexane. Colourless crystals formed in a yield of 39% with a melting point of 67° C.-69° C.
Reaction SMILES: [N:1]1[C:2]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@@:29]([CH:43]4[CH2:46][CH2:45][CH2:44]4)([CH3:42])[C:30]([O:32]CC4C=CC(OC)=CC=4)=[O:31])[CH2:18]3)[CH2:12][CH2:11]2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[N:1]1[C:2]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@@:29]([CH:43]4[CH2:44][CH2:45][CH2:46]4)([CH3:42])[C:30]([OH:32])=[O:31])[CH2:18]3)[CH2:12][CH2:11]2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COc1ccc(COC(=O)[C@@](C)(C2CCC2)N2C[C@H](CN3CCC(c4cn5ccccc5n4)CC3)[C@@H](c3cccc(F)c3)C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@](C(=O)O)(C1CCC1)N1C[C@H](CN2CCC(c3cn4ccccc4n3)CC2)[C@@H](c2cccc(F)c2)C1
Yield: 104.3 %

Procedure:
The title compound was prepared from 19 mg of α-(R)-(3-(S)-((4-(imidazo[1,2-a]pyridin-2-yl)-piperidine-1-yl)methyl)-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-cyclobutylpropanoic acid, 4-methoxy-benzyl ester (from Step C), 2 mL of TFA and 0.2 mL of anisole, using a procedure analogous to that described in Example 235, Step D to provide 16 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD): δ1.45-1.64 (m, 6H), 1.83-2.04 (m, 6H), 2.30(t, J=14.2 Hz, 3H), 2.68-3.85(m, 12H), 6.93 (t, J=6.3 Hz, 1H), 7.27 (d, J=6.7 Hz, 2H), 7.35 (t, J=6.7 Hz, 1H), 7.45 (dd, J=13.6, 6.3Hz, 1H), 7.49 (d, J=13.5 Hz, 1H), 7.67 (s, 1H), 8.38 (d, J=6.9 Hz, 1H). ESI-MS 505 (M+H); HPLC A 2.21 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN1CCOCC1.[C:24]1([CH2:30][CH2:31][C:32]([N:34]2[CH2:41][CH2:40][CH2:39][C@H:35]2[C:36](O)=[O:37])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:36](=[O:37])[C@@H:35]1[CH2:39][CH2:40][CH2:41][N:34]1[C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: -25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To L-proline benzyl ester hydrochloride (0.98 g) in dichloromethane (20 ml) were added N-methylmorpholine (0.49 ml), N-(3-phenylpropionyl)-L-proline (1.00 g) and HOBt (0.60 g) under ice-cooling. After cooling to -25° C. , DCC (0.92 g) was added, and the mixture was stirred at a temperature between -25° C. and 0° C. for 2 hours, and then at room temperature for 14 hours. The reaction mixture was treated and purified as in Example 7-A) to give 1.39 g of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([C:9]1[CH:10]=C(S(O)(=O)=O)C=C[CH:14]=1)([O-])=O.OCC(CO)O.[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[O:33][CH3:34]>O>[Br:25][C:26]1[CH:32]=[C:31]2[C:29](=[CH:28][C:27]=1[O:33][CH3:34])[N:30]=[CH:10][CH:9]=[CH:14]2
Reactant: COc1cc(N)ccc1Br
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: OCC(O)CO
Product: COc1cc2ncccc2cc1Br
Temperature: 140 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
In a 100 mL round-bottom flask, a solution of concentrated sulfuric acid (2.1 mL, 39.6 mmol) in water (2.4 mL) was treated with 3-nitrobenzenesulfonic acid (2.06 g, 10.1 mmol) and glycerol (2.5 mL, 34.8 mmol) to give a thick grey suspension. The mixture was heated to 110° C. (oil bath) and 4-bromo-3-methoxyaniline (1.952 g, 9.66 mmol) was added portion-wise, resulting in an immobile slurry. Additional portions of water (3 mL), glycerol (3 mL), and concentrated sulfuric acid (3 mL) were added and the temperature increased to 140° C. After three hours the mixture had become a homogeneous dark brown solution, and LCMS analysis indicated reaction completion. The solution was cooled to RT, poured onto ice, and the pH was adjusted to 8 by addition of concentrated (30%) aqueous ammonium hydroxide. The mixture was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated to a brown liquid. Purification by flash column chromatography (24 g silica gel, gradient of 0-20% ethyl acetate in dichloromethane over 25 column volumes) provided 6-bromo-7-methoxyquinoline (1.18 g, 46.2%) as a light brown fluffy solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.86 (dd, J=4.0, 1.5 Hz, 1H), 8.01-8.12 (m, 2H), 7.53 (s, 1H), 7.34 (dd, J=8.1, 4.5 Hz, 1H), 4.07 (s, 3H). NMR indicates the presence of about 10% 7-methyoxyquinoline. The mixture was taken on without further purification.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:15])([F:14])[C:7]1[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([C:33](OC)=[O:34])[CH:27]=2>C1(C)C=CC=CC=1>[F:15][C:6]([F:5])([F:14])[C:7]1[N:12]=[CH:11][C:10]([NH:13][C:33]([C:28]2[CH:27]=[C:26]3[C:31]([CH:32]=[C:24]([C:18]4[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=4[Cl:16])[NH:25]3)=[CH:30][CH:29]=2)=[O:34])=[CH:9][CH:8]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To 4 mL of ice-cold toluene was added 0.28 mL of 2 M trimethylaluminum in toluene then 6-trifluoromethyl-pyridin-3-ylamine (84 mg, 0.5 mmol) was added in one portion and the yellow solution was stirred for 30 min. To this was added a solution of methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate (150 mg, 0.47 mmol) in toluene (5 mL) dropwise and the resulting solution was heated at 100° C. for 18 h. A second aliquot of trimethylaluminum was added and the mixture heated another 18 h, after which it was cooled to ambient temperature, quenched with 1N HCl. Water was added and the mixture was extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed using methylene chloride then 20% EtOAc/methylene chloride as eluent to give 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid (6-trifluoromethylpyridin-3-yl)-amide as a purple glass. MS (m/z) 449.9 (M+1); retention time=1.63 min (Method 10).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:24])[C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[N:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:26]=[O:27].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:26](=[O:27])[NH:25][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:30][CH:29]=2)[CH:3]=1)[C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])=[N:17][C:12]2=[CH:11][CH:10]=1
Reactant: CN(c1cccc(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of N-{5-[(3-aminophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (100 mg, 0.295 mmol) produced in Example 8(x) in N,N-dimethylformamide (1.0 mL) was added 1-isocyanato-4-(trifluoromethoxy)benzene (53 μL, 0.354 mmol), and the mixture was stirred at room temperature for 1 hr. Aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitate was collected by filtration, and recrystallized from hexane/tetrahydrofuran to give the title compound (101 mg, 63%) as a colorless powder.