Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](=O)[C:17](=[O:31])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>NN.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][C:17](=[O:31])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc3c2C(=O)C(=O)N3Cc2cccc(F)c2)CC1
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc3c2CC(=O)N3Cc2cccc(F)c2)CC1
Yield: 16.1 %

Procedure:
4-[1-(3-Fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (930 mg) was dissolved in 17 ml each of hydrazine and ethanol, and the solution was heated at 110° C. for 16 hours. The reaction was cooled and partitioned between water and ethyl acetate, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography to afford 146 mg of 4-[1-(3-fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperidine-1-carboxylic acid tert-butyl ester. MS: 423 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([NH:33][CH2:34][CH2:35][N:36]2[CH:39]2[CH2:41][CH2:40]2)=[CH:31][C:30]=1[F:42]>CCCCCCC.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32](=[CH:31][C:30]=1[F:42])[N:33]([C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=1[Cl:1])=[O:12])[CH2:34][CH2:35][N:36]2[CH:39]1[CH2:41][CH2:40]1
Reactant: Fc1cc2c(cc1Cl)N(C1CC1)CCN2
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2cc(Cl)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 7-chloro-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-quinoxaline and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (19%). MS (ESI): m/z=494.041 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.N1(C(N2C=CN=C2)=O)C=CN=C1.O>CN(C)C=O>[N:26]1([CH2:32][CH2:33][NH:34][C:23](=[O:25])[CH2:22][CH2:21][C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Reactant: NCCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C

Procedure:
3-[2-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (Compound VI) (1 g), 630 L of 2-morpholin-4-yl-ethylamine, and 530 mg of di-imidazol-1-yl-methanone, in 10 mL of N,N-dimethyl-formamide, were stirred at room temperature for 1 hr. The reaction mixture was poured into water. The precipitate was filtered and was suspended in hot ethanol. After the suspension was cooled to room temperature, the precipitate was filtered, was washed with ethanol, and was dried in an oven overnight to give N-(2-morpholin-4-yl-ethyl)-3-[2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide (Compound VII).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:18].[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[Br:19][C:3]1[C:2]([Cl:1])=[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]2[C:4]=1[C:5]([NH2:18])=[N:6][CH:7]=[N:8]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c(CN3CCOCC3)c(Cl)cc12
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CN3CCOCC3)c(Cl)c(Br)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 114.6 %

Procedure:
To a solution of 6-chloro-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.9 g, 3.36 mmol) in DMF (5 mL) at −20° C. was added 1,3-dibromo-5,5-dimethylhydantoin (0.43 g, 1.51 mmol) portion wise over 30 min. The reaction mixture was stirred for 20 minutes at that temperature. TLC analysis indicated that there was complete conversion of starting material. The reaction was quenched with distilled water (30 mL) as the solution warmed to rt. CH2Cl2 (30 mL) was added to the reaction and the solution was transferred to a separatory funnel and the organic layer was isolated while the aqueous layer was back extracted with CH2Cl2 (4×20 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated to dryness. The crude material was washed with diethyl ether (10 mL). The white precipitate was collected and dried under vacuum to yield 0.6 g of the above compound (1.73 mmol, yield 51%). 1H-NMR (CD3OD-d4) δ 7.94 (s, 1H), 3.79 (s, 2H), 3.05 (t, J=4.8 Hz, 4H), 2.39 (t, J=4.8 Hz, 4H); MS [M+H]+=347.7; LCMS RT=1.21 min.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[N:11]=2)=[CH:18][CH:17]=1
Reactant: Nn1nc(Cc2ccc(Cl)nc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Cc2ccc(Cl)nc2)c2ccccc2c1=O

Procedure:
The product from Example 30A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.33 (dd, J=7.9, 1.4 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.95-8.00 (m, 1H), 7.87-7.93 (m, 1H), 7.74 (dd, J=8.2, 2.5 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.05-7.21 (m, 3H), 4.39-4.40 (bs, 2H), 3.74 (s, 2H); MS (APCI) M/Z 441 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH2:38])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:38][CH2:36][CH3:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: CCN
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 100 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) were stirred in 2 ml of THF for 30 min. Another 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) was then added, and the mixture was stirred at RT for 2 h. About 15 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 81 mg (89% of theory) of the desired target compound.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[CH2:7]([N:14]1[C:18]2[NH:19][C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:21]C(=O)C=2[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[CH2:7]([N:14]1[C:18]2[N:19]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:21]=[C:1]([Cl:6])[C:2]=2[N:16]=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3)c2[nH]1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3)c2n1
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 114.2 %

Procedure:
DMF over MS(105 g, 110 ml, 1.43 mol, Eq: 2.56) was charged in the reactor followed by Dichlormethane (1.46 kg, 1.1 l). The solution was heated to 35° C. and oxalylchloride (144 g, 97.6 ml, 1.11 mol, Eq: 2) was added over 1 h. After 45 min, a fine suspension of 3-benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (161 g, 557 mmol, Eq: 1.00) in a mixture of dichlormethane (877 g, 662 ml) and DMF (41.8 g, 44.1 ml) was added over of 20 min. After 3 h, the reaction mixture was cooled to RT and slowly added to a cold (0-5° C.) half saturated aqueous NaHCO3 (1.76 l). The organic phase was separated and washed again with half saturated NaHCO3 (662 ml) followed by water (662 g, 662 ml). Then the org. phase was dried over MgSO4 and was concentrated under reduced pressure at 50° C./down to 10 mbar to give 192 g of a crude oil which does crystallize on standing. The crude 3-benzyl-5-tert-butyl-7-chloro-triazolo[4,5-d]pyrimidine was introduced in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](OC(=O)CC)(=O)[CH2:12][CH3:13]>>[CH2:12]([C:13]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:1]=1)[CH3:11]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCC(=O)OC(=O)CC
Product: CCc1nc2ncccc2c(=O)o1
Temperature: 120 °C
Yield: 86 %

Procedure:
A suspension of 2-aminonicotinic acid (1.0 g 7.24 mmol) in propionic anhydride (10 mL) of was heated to 120° C. for 1 h under nitrogen atmosphere. The temperature was increased to 167° C. to remove the propionic acid and propionic anhydride under reduced pressure. The resulting brown solid was triturated with hexane and dried to give the title pyrido-oxazine (16) (1.10 g, 86%) as a white solid:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:16][CH:17]=2)[N:11]=1.C1C(=O)N([Br:29])C(=O)C1.O>C(Cl)Cl>[Br:29][C:9]1[O:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:21])([CH3:19])[CH3:20])=[N:16][CH:17]=1
Reactant: CC(C)(O)c1ccc(-c2coc(-c3ccccn3)n2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)c1ccc(-c2nc(-c3ccccn3)oc2Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[5-(2-pyridin-2-yl-1.3-oxazol-4-yl)pyridin-2-yl]propan-2-ol from Step D (75 mg, 0.267 mmol) in DCM (1 mL) was added NBS (62 mg, 0.347 mmol). The reaction mixture was stirred at rt for 16 h. Water was added and the mixture extracted with DCM. The organics were dried (MgSO4), and concentrated to afford 2-[5-(5-bromo-2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol, which was used without further purification LCMS: m/z 360.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:33])[CH:28]=[CH:29][O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:33])[CH:28]=[CH:29][O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, 0.24 ml of trifluoromethansulfonic anhydride was added at 0° C. to 4 ml of pyridine solution with 180 g of 7-hydroxy-4H-chromen-4-one, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and then dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified with preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 83 mg of the above compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:27])=[CH:11][C:12]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:13]([CH:19]=1)[C:14]([O:16]CC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)(C)C.O>[CH2:1]([O:8][C:9]1[C:10]([F:27])=[CH:11][C:12]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:13]([CH:19]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Yield: 98.4 %

Procedure:
A mixture of 1.0 g of the compound obtained in Step 4.3 and 0.45 g of KOH in 16 ml of isopropanol and 4 ml of water is irradiated in a microwave field for 20 minutes at 130° C. The reaction medium is evaporated under reduced pressure. Water is added, the resulting mixture is acidified with aqueous 1N HCl solution to pH 3 and this mixture is extracted with EtOAc. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure to give 0.91 g of the expected product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6]N[CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>O>[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N:19]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)O
Solvent: O
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
1-Methylpiperazine (0.962 mL, 8.67 mmol) was added to a suspension of 2-methoxy-4,5-dinitrobenzoic acid (2.0 g, 8.26 mmol) in water (5 mL). The mixture was heated at 50° C. for 1.5 h then 75° C. for 3 h. A further 0.5 equivalents of 1-methylpiperazine was added and the mixture was heated overnight. The mixture was then allowed to cool and stand. A crystalline solid formed which was collected by filtration, washed with water and then dried on the filter to give the title compound (1.87 g, 77%) as a yellow crystalline solid; 1H NMR: 2.25 (3H, s), 2.45-2.49 (4H, m), 3.13-3.21 (4H, m), 3.93 (3H, s), 6.63 (1H, s), 8.32 (1H, s); m/z: ES+ MH+ 296.5.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16]([C:19](O)=[O:20])=[CH:15][C:14]3=[O:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:43][C:42]=1O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:2][N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16]([C:19]([NH:40][C:41]2[CH:42]=[CH:43][C:44]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[CH:45][CH:46]=2)=[O:20])=[CH:15][C:14]3=[O:22])[CH2:7][CH2:8]1
Reactant: Nc1ccc(N2CCOCC2)cc1O
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)O)oc23)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCOCC5)cc4)oc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) (400 mg, 1.23 mmol) was suspended in anhydrous N,N-dimethylformamide (20 ml) and triethylamine (0.69 ml, 4.92 mmol) was added to give a clear solution. The following were added in order: 1-hydroxybenzotriazole (HOBt (205 mg, mol)), O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-pentamethylene-uronium tetrafluoroborate (TBTU (435 mg, 3.1 mmol)) then 4-(dimethylamino)pyridine (25 mg). After stirring for 5 min at room temperature, 4-(4-morpholinyl)aniline (Reference Example 21) (220 mg, mmol). The reaction stirred overnight at room temperature. The solution was concentrated in vacuo, the remains were partitioned between chloroform/saturated sodium bicarbonate, extracted (×3) with chloroform, dried (MgSO4) and concentrated in vacuo to give the crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.O.[CH3:19]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH3:19])=[O:12]
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Reactant: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,4,6-trifluorobenzeneacetic acid (5.00 g, 26.3 mmol) in methanol (25 mL) was stirred at ambient temperature, and thionyl chloride (6 mL, ˜3 eq.) was added dropwise, causing the temperature of the reaction mixture to reach 60° C. The reaction mixture was allowed to cool to ambient temperature and was stirred for 3 h. Water (25 mL) was added with ice cooling. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (2×), with saturated aqueous sodium bicarbonate solution and with brine, and dried over MgSO4. Concentration provided the title product as a clear oil (5.38 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:20]1[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[S:23][CH:24]=1)=[CH2:19]>CN1C(=O)CCC1.O>[S:23]1[CH:24]=[C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1csc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2csc3ccccc23)CCN(C)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in NMP (1 mL) were added powdered KOH (392 mg, 7.0 mmol) and 3-vinyl-benzo[b]thiophene (320 mg, 2.0 mmol). The reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (3% MeOH-DCM) followed by reverse phase HPLC to yield 5-(2-benzo[b]thiophen-3-yl-ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.82 (d, 1H), 7.6 (d, 1H), 7.38 (m, 2H), 7.2 (m, 2H), 7.0 (d, 1H), 6.93 (s, 1H), 4.3 (t, 2H), 3.62 (s, 2H), 3.5 (s, 3H), 3.21 (t, 2H), 2.63 (t, 2H), 2.41 (m, 5H).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].C1N=C[N:23](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[CH:9]=[N:8]1)([CH3:6])[C:3]([NH2:23])=[O:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C(=O)O)n1cc(-c2ccnc3[nH]ccc23)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)n1cc(-c2ccnc3[nH]ccc23)cn1
Reaction time: 3 h
Yield: 26.2 %

Procedure:
A mixture of 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoic acid (23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CDI) (21 mg, 0.00013 mol) in 2 mL of DMF was stirred for 3 hours. An excess of solid NH4Cl and TEA was added to the mixture and this was stirred for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) followed by re-purification via preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanamide (6 mg, 26%). 1H NMR (400 MHz, d6-DMSO): 11.63 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS(ES): 270 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)=[CH:15][CH:14]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2ccc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a mixture of 4-bromoindole (1.96 g, 10 mmol), and 4-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 1.85 g (83%) of the product 44-Methoxy-phenyl)-1H-indole as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][CH2:23]OS(C)(=O)=O)[N:18]=2)[S:5][C:6]=1[C:7](=[O:16])[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:7]([C:6]2[S:5][C:4]([C:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][NH:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)[N:18]=3)=[N:3][C:2]=2[CH3:1])=[O:16])[CH:11]=1
Reactant: Cc1nc(-c2ccn(CCOS(C)(=O)=O)n2)sc1C(=O)NCc1cccnc1
Reactant: Nc1ccc(F)cc1
Product: Cc1nc(-c2ccn(CCNc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from methanesulfonic acid 2-(3-{4-methyl-5-[(pyridin-3-ylmethyl)-carbamoyl]-thiazol-2-yl}-pyrazol-1-yl)-ethyl ester and 4-fluoro-phenylamine as describe in Example 77 and isolated as a white solid (0.032 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.28-7.34 (m, 1H), 6.89 (t, J=8 Hz, 2H), 6.83 (d, J=2 Hz, 1H), 6.51-6.56 (m, 2H), 6.09 (bs, 1H), 4.65 (d, J=8 Hz, 2H), 4.47 (t, J=6 Hz, 2), 3.58-3.63 (m, 2H), 2.76 (s, 3H); MS (M+H)+=436.9; Rt=1.20 min; HRMS (M+H)+=437.12.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[CH3:7][C:8]1([CH3:26])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=O)[OH:14])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[CH3:7][C:8]1([CH3:26])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:14])[O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: OCC(F)(F)F
Reactant: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCC(F)(F)F

Procedure:
Using the procedure of Example 53, trifluoroethanol and the product of Step B of Example 57 were reacted to obtain benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+45° (c=0.6% in chloroform).