Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:4]2[CH2:3]1.[C-]#N.[K+]>CO>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
285 mg (1 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 66 mg of potassium cyanide are heated to boiling under reflux for 24 hours in 10 ml of methanol. Then, the mixture is concentrated on a rotary evaporator, the residue is partitioned between water and chloroform, extracted twice with chloroform, the chloroform phase is dried over magnesium sulphate and evaporated. There is obtained methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 212°-214° C. This product is uniform according to thin-layer chromatography.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: OCCN1CCNCC1
Reactant: Clc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: OCCN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-8-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 8-chloro-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:40]=2)[C:38]#[N:39])O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH3:24])=[C:2]([C:33]4[CH:34]=[N:35][CH:36]=[C:37]([CH:40]=4)[C:38]#[N:39])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cncc(C#N)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (first peak from Example 167, step 4 chiral separation, 106 mg, 0.25 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (70.0 mg, 0.31 mmol, from Combi-Blocks Catalog, item # PN-8893), sodium carbonate (43 mg, 0.41 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (33 mg, 0.041 mmol) in acetonitrile (2 mL)/water (0.6 mL) was degassed with N2 and then stirred at 95° C. for 2 h. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product (95 mg, 87%) was purified by chromatography eluting with CH2Cl2/MeOH (max. MeOH 5%). LCMS calculated for C22H21ClN7O (M+H)+: m/z=434.2; Found: 434.2.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16]Br)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCc1sc2c(c1CCBr)CCN(C(C)=O)C2
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: CCc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C(C)=O)C2
Yield: 62 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.5 g of 6-acetyl-3-(2-bromoethyl)-2-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 2.2 g of 6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 191°-201° C. as oxalate 1/2hydrate thereof.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=O)[NH:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C(#N)C>[S:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[S:20])[NH:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NCSc2ccsc21
Solvent: CC#N
Product: S=C1NCSc2ccsc21

Procedure:
(aae) 19.6 g of 2,3-dihydro-4H-thieno[2,3-e][1,3]-thiazin-4-one were heated under reflux together with 23.1 g of Lawesson reagent in 200 ml of acetonitrile until all of the starting material reacted. The reaction mixture was cooled and the crystallized-out product was removed by filtration. By recrystallization from ethyl acetate there was obtained pure 2,3-dihydro-4H-thieno[2,3-e][1,3]thiazine-4-thione of m.p. 136°-138°. Additional material can be obtained by evaporation of the mother liquor and recrystallization.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:24]([OH:26])=[O:25])=[CH:16][CH:17]=[C:18](SC)[C:19]=2C#N)=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1.ClS(C(C)C)(=O)=O.[OH-].[Na+]>CO.ClCCl.CO.C(Cl)Cl>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:9][CH:10]=2)[C:15]([C:24]([OH:26])=[O:25])=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CSc1ccc(C(=O)O)c(-c2ccc(-c3ccccc3N)cc2)c1C#N
Agent: CC(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
Mix 2″-Amino-6-cyano-5-methylsulfanyl-[1,1′;4′,1″]terphenyl-2-carboxylic acid (0.195 g, 0.521 mmol) and dichloromethane (6 ml) then cool to 0° C. Next add DBU (0.33 ml, 2.162 mmol), and ClSO2CH(CH3)2 (0.13 ml, 1.128 mmol) drop wise to the solution and stir for 16 hours. If TLC shows remaining SM, add DBU (0.3 ml) and ClSO2CH(CH3)2 (0.1 ml) and stir for 16 hours. Dilute the reaction with CH2Cl2 (50 ml) and wash with H2O, satd aq. sodium chloride, dry with Na2SO4, and concentrate under reduced pressure. Analyze by TLC and if reaction has remaining SM add MeOH (2 ml) and 1N NaOH (1 ml, 1 mmol). Heat to reflux for 6 hours. Add 1N HCL (1 ml, 1 mmol) and extract into dichloromethane. Purify the reaction by flash chromatography (Silica gel -dichloromethane then up to 10% MeOH/dichloromethane), to give 6-Cyano-5-methylsulfanyl-3″-propane-2-sulfonylamino)-[1,1′;4′,1″]terphenyl-2-carboxylic acid (0.008 g). MS (m/e): 467(M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10]Br.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=2)=[O:22])=[CH:16][C:15]=1[C:35]([F:38])([F:37])[F:36])#[N:13]>CN(C=O)C>[F:36][C:35]([F:37])([F:38])[C:15]1[CH:16]=[C:17]([N:20]2[CH2:10][CH2:9][CH2:8][N:23]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[C:26]([F:34])[CH:25]=3)[C:21]2=[O:22])[CH:18]=[CH:19][C:14]=1[C:12]#[N:13]
Reactant: BrCCCBr
Reactant: CNC(=O)c1ccc(NC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCCN(c3ccc(C#N)c(C(F)(F)F)c3)C2=O)cc1F
Temperature: 90 °C

Procedure:
K2CO3 (109 mg, 0.79 mmol) and 1,3-dibromopropane (32 mkl, 0.32 mmol) were added to a solution of 4-[4-cyano-3-(trifluoromethyl)-phenylcarbamoylamino]-N-methyl-2-fluorobenzamide (100 mg, 0.26 mmol) 2 in DMF (2 ml). Mixture was stirred at 90° C. In 18 h another portion of K2CO3 (109 mg) and 1,3-dibromopropane (32 mkl) were added and stirring was continued at the same temperature. Addition was repeated by 2 more times. After the reaction was completed the mixture was evaporated in vacuo, the residue was dissolved in chloroform, washed with water, dried over Na2SO4, the solvent was evaporated. The product was isolated by colomn chromatography on SiO2 (eluent—AcOEt). LCMS (M+H)+ 421. 1H NMR (DMSO-d6, 400 MHz): 8.17 (br. m, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.83 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 7.62 (t, J=8.4 Hz, 1H), 7.38 (dd, J1=12.4 Hz, J2=2.0 Hz, 1H), 7.29 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 3.90 (t, J=5.8 Hz, 2H), 3.81 (t, J=5.8 Hz, 2H), 2.77 (d, J=4.8 Hz, 3H), 2.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:5]([CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[C:29]([O:33][C:34]([NH:36][C@H:37]([C:48](O)=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].ON1C(=O)CCC1=O>>[CH3:32][C:29]([O:33][C:34]([NH:36][C@H:37]([C:48]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C@H:4]([N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:3]([O:2][CH3:1])=[O:28])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:35])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COC(=O)[C@H](CCCCN)N(CC1CCCC1)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C1CCC(=O)N1O
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)N(CC1CCCC1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
The title compound was prepared in the same manner as in example 65 (step D) using Nα-cyclopentylmethyl-Nα-(4-methoxybenzenesulfonyl)-L-lysine methyl ester (this example, step B) and Nα-tert-butoxycarbonyl-L-tryptophan-N-hydroxysuccinimide as the starting materials. The yield of the two last reactions was 82%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:25](#N)C.O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC#N
Reactant: Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1F
Solvent: O
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)c(F)c2)c1

Procedure:
The title compound was prepared from 2-[5-[(3-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 93) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 2.28 (3H, s), 3.97 (3H, s), 5.21 (2H, s), 5.75 (1H, s), 7.09-7.21 (3H, m), 7.60 (1H, s), 7.79 (1H, d, J=4.8 Hz), 8.35 (1H, s), 8.73 (1H, s). LCMS (mobile phase: 20%-95% Acetonitrile-Water-0.1% NH4OH): purity is >95%, Rt=3.936 min. [M+H] Calc'd for C18H16FN3O3, 342. Found, 342.
Reaction SMILES: Cl.I[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[CH2:25]([NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([NH:27][C:28](=[O:29])[NH:30][C:31]1[N:32]=[CH:33][C:34]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C@@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]3=[O:24])=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[CH:36]=1)[CH3:26]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(C[C@@H]2CCNC2)c2ccc(I)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@@H]2CCNC2)cn1
Temperature: 82.5 °C
Yield: 82.9 %

Procedure:
A vial was charged with (R)-ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 97, 1.0 g, 2.16 mmol), 6-(3-ethylureido)-4-(4-trifluoromethylthiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 17, 940 mg, 2.61 mmol), and sodium bicarbonate (730 mg, 8.65 mmol) in dimethoxyethane (10 mL) and water (2 mL). The reaction mixture was purged with N2 for about 5 min, then trans-dichlorobis(triphenylphosphine)palladium (II) (160 mg, 0.228 mmol) was added. The reaction mixture was heated for 3 h at 80-85° C., then cooled to room temperature and water (10 mL) was added. The precipitated solid was collected by filtration to give (R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (1.1 g, 82.7%) as a light brown solid after drying under vacuum at 40° C. overnight.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:22][N:23](C=O)C>[Zn].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][C:16]1([CH3:18])[O:15][C:14](=[O:19])[NH:13][C:12]2[CH:20]=[CH:21][C:9]([C:4]3[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=3)[C:22]#[N:23])=[CH:10][C:11]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Temperature: 85 °C

Procedure:
A mixture of 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-2H-benz[d][1,3]oxazin-2-one (1 g, 2.8 mmol), zinc cyamide (0.2 g, 1.7 mmol), and tetrakis(triphenylphosphine)-palladium (0) (0.2 g, 0.17 mmol) in dry DMF (20 mL) was degassed to remove oxygen and was then heated at 85° C. under a blanket of nitrogen for 6.5 hours. The reaction solution was cooled to room temperature and poured onto a cold saturated aqueous ammonium chloride solution (100 mL). The white precipitate appeared and was collected on a filter. The white solid was washed with distilled water (3×20 mL) and dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL). The solution was applied on a pad of silica gel and eluted with a mixture of ethyl acetate and hexane (1:1). After solvent was removed, 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile was obtained as a white solid (0.7 g, 84%): mp 253–254° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H, D2O exchangeable), 8.13 (s, 1H), 7.92 (m, 1H), 7.82 (m, 1H), 7.73 (m, 2H), 6.98 (d, 1H, J=8.2 Hz), 1.68 (s, 6H); 19F-NMR (DMSO-d6) δ 112.25 (m, 1F); MS (EI) m/z 296(M+, 65%); Anal. Clc. For C17H13FN2O2: C, 68.91, H, 4.42, N, 9.45. Found: C, 68.85, H, 4.58, N, 9.14.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16](=[O:32])[CH2:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].Br[CH2:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[F:43].[I-].[Na+]>C1COCC1.CCOCC.CCCCC>[C:11]([O:15][C:16](=[O:32])[CH:17]([N:18]=[C:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[F:43])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ccc(F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: COc1ccc(F)c(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
LHMDS (92 mg, 0.55 mmol) was added to a solution of t-butylglycinate Schiff base 3 (136 mg, 0.46 mmol) in THF (1.5 mL) A mixture containing 2-fluoro-5-methoxy-benzyl bromide (35, 100 mg, 0.46 mmol) and sodium iodide (138 mg, 0.92 mmol) in THF (2.0 mL) was immediately added to the resulting enolate solution at −78° C. The combined mixture was warmed to room temperature, stirred for 2 h, diluted with 1:1 ether/pentane (25 mL), washed with brine (3×15 mL), dried (sodium sulfate) and concentrated to afford 40 as a crude yellow oil (108%). Once examined, the pure product was made in 97% yield (193 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:16])([F:15])[C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11].C[N:18](C=O)C>C(Cl)Cl>[F:7][C:8]([F:16])([F:15])[C:9]([CH3:14])([CH3:13])[C:10]([NH2:18])=[O:11]
Reactant: CN(C)C=O
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (140.8 mmol) was added dropwise to a solution of 3,3,3-trifluoro-2,2-dimethyl-propionic acid [889940-13-0] (128 mmol) in CH2Cl2 (128 mL) at 0° C. Added a few dr DMF until gas evolution was observed and then continued stirring for 30 min. After warming to rt and stirring overnight, the reaction mixture was concentrated (40° C., 00 mbar). The residue was dissolved in THF (128 mL), cooled to 0° C. and then slowly treated with a solution of concentrated aqueous ammonia (64 mL). After stirring at 0° C. for 30 min and then at rt for 4 h, the reaction mixture was concentrated to half its volume to give a thick white suspension. After filtering and drying, the title compound was obtained as a white solid. ESI-MS: [M+H]+ 156.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]3[O:27][CH:28]=[CH:29][N:30]=3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+].C(O)(=O)C>CO.O>[F:34][CH:32]([F:33])[O:31][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][CH:28]=[CH:29][N:30]=2)=[CH:22][CH:21]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-c2ncco2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-c2ncco2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
A solution of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-oxazol-2-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.73 g) in methanol (6.0 mL) and water (0.6 mL) was treated with 5.0 M aqueous lithium hydroxide solution (0.30 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified by the addition of glacial acetic acid, concentrated under reduced pressure, and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure, and then diluted with acetonitrile. The resulting precipitate was removed by filtration, washed with acetonitrile, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and glacial acetic acid (50:1:1 to 10:1:1 by volume). Further purification by preparative reverse-phase HPLC, and then column chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and glacial acetic acid (40:1:0.1 to 20:1:0.1 by volume) gave title compound as a white solid (0.082 g).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].Br[CH2:14][CH2:15][CH2:16][Cl:17]>>[Cl:17][CH2:16][CH2:15][CH2:14][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12]
Reactant: ClCCCBr
Reactant: CCC1C(=O)Nc2ccccc21
Product: CCC1(CCCCl)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-1,3-dihydro-2H-indol-2-one and 1-bromo-3-chloropropane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]4)[CH:20]=[N:21][CH:22]=3)=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.Cl>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:17]3[CH:18]=[C:19]([N:23]4[CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][CH2:28]4)[CH:20]=[N:21][CH:22]=3)=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5ccccc5F)nc34)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5ccccc5F)nc34)c2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 1-(5-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (125 mg, 0.195 mmol) in THF (3 mL) was treated with NaOH 10N (0.195 mL, 1.948 mmol). The reaction was heated to reflux at 80° C. After 4 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-5% MeOH/DCM), affording tert-butyl 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (69 mg, 73%). MS (ESI, pos. ion) m/z: 488.2 (M+1). A solution of tert-butyl 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (64 mg, 0.131 mmol) in MeOH (3 mL) and DCM (0.500 mL) was treated with HCl, 36.5-38.0% (0.109 mL, 1.313 mmol). The reaction was heated to 50° C. After 2 h 30 min, the reaction was cooled to 23° C. and concentrated. The residue (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(5-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-amine. MS (ESI, pos. ion) m/z: 388.3 (M+1).