Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([Cl:19])=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27].C([BH3-])#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:27][CH2:26][C:25]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([Cl:19])=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)OC(=O)N1CCCC(=O)c2cc(Br)c(Cl)cc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A mixture of 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (0.98 g, 2.72 mmole), 3,5-bistrifluoromethyl benzyl amine (0.682 g, 2.72 mmol) and titanium(IV) isopropoxide (1.00 ml, 3.26 mmol) was stirred at room temperature overnight. To it was added sodium cyanoborohydride (0.684 g, 10.9 mmole) in MeOH (20.0 ml) and the reaction was continued at room temperature for 6 hours. The mixture was partitioned between ethyl acetate (50.0 ml) and water (50.0 ml). The precipitate was removed by filtration. The aqueous layer was extracted with more ethyl acetate (2×50.0 ml). The combined organics washed with brine (3×150 ml). Dried over Na2SO4, filtered and concentrated to provide the crude product (1.47 g, 88%), which was used directly for the next step without further purification. MS (ES+): 587, 589 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:32]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)c(Cl)c1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)c(Cl)c1

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chloro-4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid is (3.5 g) and 5-amino-2-[4-(2-hydroxyethyl)-piperazin-1-yl]benzonitrile (3.7 g), the title compound (1.0 g) was obtained, melting point: 191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=C[C:44]([O:47][CH2:48][CH2:49]CN(C)C)=[C:43]3C=2[C:40]2C=C(C)C=N[C:41]=2[NH:42]3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:40][CH2:41][N:42]1[CH2:43][CH2:44][O:47][CH2:48][CH2:49]1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCN3CCOCC3)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, Methanol-d4) δ 8.12 (s, 1H) 8.00 (m, 1H) 7.92 (m, 1H) 7.74 (t, J=7.84 Hz, 1H) 7.64 (s, 1H) 7.09 (m, 1H) 7.02 (m, 1H) 6.84 (s, 1H) 4.40 (t, J=5.0 Hz, 2H) 4.11 (br, 4H) 3.80 (br, 4H) 3.55 (t, J=5.0 Hz, 2H) 3.30 (q, J=7.32 Hz, 2H) 1.27 (t, J=7.32 Hz, 3H). [M+H] calc'd for C25H27ClN3O4S, 500; found, 500.
Reaction SMILES: [I:1]I.O[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[I:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1
Reactant: II
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(I)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
Iodine (17.6 g, 69.2 mmol) was added dropwise as a solution in THF (40 mL) over 1 hour to an ice cold solution of benzyl 4-hydroxypiperidine-1-carboxylate (15.5 g, 65.9 mmol), imidazole (4.71 g, 69.2 mmol), and triphenylphosphine (18.2 g, 69.2 mmol) in THF (40 mL). This resulting red solution was stirred overnight with warming to room temperature, then cooled back to 0° C. before being quenched with 10% aqueous sodium sulfite. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography (10% EtOAc/hexane) to give benzyl 4-iodopiperidine-1-carboxylate as a colorless oil (9.50 g, 42% yield).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21](O)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH2:34][OH:35])[NH:31][C:30]=2[CH:36]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]5[CH:27]=[CH:28][C:29]6[N:33]=[C:32]([CH2:34][OH:35])[NH:31][C:30]=6[CH:36]=5)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCCC1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc5nc(CO)[nH]c5c4)nn23)c1)N1CCCC1

Procedure:
(6-{7-[3-(Pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-1H-benzoimidazol-2-yl)-methanol was prepared from 7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1052a. Product isolated as a yellow foam (57 mg, 40%). LCMS (m/e) 490 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.23-12.01 (m, 1H), 9.47-9.35 (m, 1H), 9.05-8.99 (m, 1H), 8.77-8.61 (m, 1H), 8.35-8.26 (m, 1H), 7.91-7.70 (m, 3H), 7.62-7.37 (m, 2H), 7.32-7.24 (m, 1H), 7.01-6.94 (m, 1H), 5.67-5.58 (m, 1H), 4.70-4.62 (m, 2H), 3.22-3.12 (m, 4H), 1.69-1.60 (m, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:11])[S:9][CH:10]=1)=[O:5])C.[Li+].[OH-]>CO.O>[Br:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1csc(Br)n1
Reaction time: 4 h

Procedure:
To a solution of 2-bromo-thiazole-4-carboxylic acid ethyl ester (Combi-Blocks, Inc., San Diego, Calif.; 5 g, 21.2 mmol) in MeOH (25 mL) and water (25 mL) was added LiOH (0.56 g, 23.3 mmol). After stirring for 4 h at reflux temperature, MeOH was evaporated in vacuo. To the residue was added more water, the mixture was acidified to pH 2 with concentrated HCl (3 mL), and extracted with EtOAc. The combined extracts were evaporated to give 2-bromo-thiazole-4-carboxylic acid which was used without further purification. The compounds of the present invention were preferably prepared by methods A to F:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[Br:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:10][C:8]1[CH:7]=[CH:6][C:5]([Br:11])=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 100 %

Procedure:
A mixture of methyl-2-bromo-5-hydroxybenzoate (1.0 g, 4.33 mmol), benzyl bromide (0.62 mL, 5.19 mmol), and K2CO3 (780 mg, 5.63 mmol) in anhydrous DMF (8 mL) was stirred at room temperature for 21 h under nitrogen atmosphere. The mixture was poured into equal volumes of water and EtOAc (1:1, 20 mL), then the layers were separated. The aqueous layer was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give methyl 5-(benzyloxy)-2-bromobenzoate (1.39 g, 100%).
Reaction SMILES: Cl[C:2]1[CH2:3][CH2:4][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C:7]=1[CH:8]=O.C(N(CC)CC)C.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:23][SH:24].[OH-].[K+]>N1C=CC=CC=1.O>[S:24]1[C:2]2[CH2:3][CH2:4][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C:7]=2[CH:8]=[C:23]1[C:22]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)N1CCC(Cl)=C(C=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(s1)CCN(C(=O)OCC)C2
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-chloro-5-formyl-3,6-dihydropyridine-1(2H)-carboxylate (1 eq) obtained from step II in pyridine was added triethyl amine (1.5 eq.), ethyl thioglycolate (1 eq.) at 0° C. and the reaction mixture was stirred for overnight. A solution of KOH (1.5 eq) in water was added at 0° C. and further stirred at room temperature for 1 h Water was added and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired diethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate.
Reaction SMILES: [NH2:1][CH:2]([C:12]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:19])[C:15]([OH:29])=[C:14]([OH:30])[N:13]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:38][CH2:39][CH:40]=O.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH2:5]([O:4][CH2:3][CH:2]([C:12]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:19])[C:15]([OH:29])=[C:14]([OH:30])[N:13]=1)[NH:1][CH2:40][CH2:39][Cl:38])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(COCc1ccccc1)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Reactant: O=CCCl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1nc(C(COCc2ccccc2)NCCCl)nc(O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of compound of Step 3 in dry trimethylortoformiate, triethylamine (1.3 eq.) and 1.1 eq. of α-chloroacetaldehyde (1.1 eq.) were added. The resulting solution was aged for 2 hours at room temperature, the solvent was removed by rotary evaporation to afford a residue that was dissolved in MeOH, treated with acetic acid (pH=5) and NaBH3CN (1.1 eq.). The mixture was stirred overnight at room temperature then the solvent was removed by rotary evaporation and the resulting residue was taken in dry toluene and concentrated. This material was used without any purification for the next step. MS (ES) C23H24ClFN4O4 requires 474. Found: 475.
Reaction SMILES: [Li+].[Cl-].[Br:3][C:4]1[CH:5]=[N:6][C:7]([F:18])=[C:8]([C:16]=1[F:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Br:19]C(Br)(F)C(F)(F)F>C1COCC1>[Br:3][C:4]1[C:5]([Br:19])=[N:6][C:7]([F:18])=[C:8]([C:16]=1[F:17])[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)c1c(F)ncc(Br)c1F
Reactant: FC(F)(F)C(F)(Br)Br
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(F)nc(Br)c(Br)c1F
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
Into a solution of TMPMgCl LiCl (1.0 M×6.8 mL, 6.8 mmol) in THF (5.0 mL) at −45° C. was added dropwise a solution of tert-butyl 5-bromo-2,4-difluoronicotinate (1.32 g, 4.5 mmol) in THF (5.0 mL). The mixture was stirred for 15 min then dibromotetrafluoroethane (1.0 mL, 6.8 mmol) was added. After 15 min at −45° C., the temperature was allowed to rise to room temperature. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by silica chromatography (0-10% ethyl acetate in hexanes) to give tert-butyl 5,6-dibromo-2,4-difluoronicotinate (1.29 g, 77%).
Reaction SMILES: Br[CH:2]([C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)(C)C>[NH2:19][C:17]1[S:18][C:2]([CH2:3][C:4]([OH:6])=[O:5])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:16]=1
Reactant: O=C(O)CC(Br)C(=O)c1ccc(F)cc1
Reactant: NC(N)=S
Solvent: CC(C)O
Product: Nc1nc(-c2ccc(F)cc2)c(CC(=O)O)s1

Procedure:
A mixture of 10 grams of β-bromo-β-p-fluorobenzoyl-propionic acid and 2.77 grams of thio-urea in 60 c.c. of isopropyl alcohol is refluxed for 1 hour. After cooling, the precipitated solid is filtered off and recrystallised from isopropyl alcohol, m.p. 267°-268°C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[N-:13]=[N+:14]=[N-:15].[Na+].[Cl-].[Li+].O>COCCO>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[C:1]1[NH:15][N:14]=[N:13][N:2]=1
Reactant: N#Cc1ccc2ccccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: c1ccc2cc(-c3nnn[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
A mixture of 10 g of 2-cyanonaphthalene, 10.61 g of sodium azide, and 7.67 g of lithium chloride was placed in a reaction vessel, and 240 ml of 2-methoxyethanol serving as a solvent was added thereto. The above mixture was refluxed with stirring for 80 hours. The mixture was cooled to room temperature, and 500 ml of water was added to the mixture.
Reaction SMILES: [S:1]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].[CH3:11]OC(OC)OC>CO>[CH3:11][O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: COC(OC)OC
Reactant: NS(=O)(=O)CCCC(=O)O
Solvent: CO
Product: COC(=O)CCCS(N)(=O)=O
Temperature: 60 °C
Reaction time: 19 h
Yield: 99 %

Procedure:
A mixture of 4-sulfamoylbutyric acid (2.53 g, 15.1 mmol), methanol (25 ml), trimethylorthoformate (10 ml, approx 5 eq) and polystyrene-bound toluenesulfonic acid (0.58 g) was stirred at 60° C. After 19 h the mixture was decantated from the catalyst and concentrated to yield 2.70 g (99%) of the title ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:25][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NN1CCOCC1
Product: O=C(NN1CCOCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-morpholin-4-ylisonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.81 mmol of morpholin-4-ylamine LC/MS [8.25 min; 443 (M+1)]
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([C:12]2[N:16]3[CH:17]=[CH:18][N:19]=[C:20]([CH3:21])[C:15]3=[C:14]([Br:22])[N:13]=2)[CH2:9]1.C([BH3-])#N.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[Br:22][C:14]1[N:13]=[C:12]([CH:10]2[CH2:9][N:8]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH2:11]2)[N:16]2[CH:17]=[CH:18][N:19]=[C:20]([CH3:21])[C:15]=12
Reactant: Cc1nccn2c(C3CNC3)nc(Br)c12
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nccn2c(C3CN(C4CCOCC4)C3)nc(Br)c12
Yield: 5.8 %

Procedure:
To tetrahydro-4-h-pyran-4-one (3.74 mmol, 0.346 ml) in dichloromethane (5 ml) and acetic acid (0.306 ml) was added 3-(azetidin-3-yl)-1-bromo-8-methylimidazo[1,5-a]pyrazine (1.872 mmol, 500 mg) in dichloromethane (10 ml) and after stirring for 20 minutes under a nitrogen atmosphere at room temperature sodium cyanoborohydride (3.74 mmol, 235 mg) was added in portions. After one hour the reaction mixture was quenched with water, a saturated aqueous sodium hydrogencarbonate solution was added (pH of reaction mixture ˜7) followed by 2M sodium hydroxide until the pH reached 11 and extracted three times with dichloromethane. The organic layers were combined, filtered through a phase separation filter and concentrated in vacuo. Purification by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) gave 1-bromo-8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)imidazo[1,5-a]pyrazine (38 mg).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[C:49]([F:52])([F:51])[F:50]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:44]=[CH:45][C:40]([F:39])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:42]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(F)c(C(F)(F)F)c2)c1

Procedure:
5-(tert-Butyl)-4′-fluoro-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-fluoro-3-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[O:29]1[C:33]2[CH:34]=[CH:35][C:36](B(O)O)=[CH:37][C:32]=2[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH2:27][CH3:28])=[CH:37][C:32]=2[CH2:31][CH2:30]1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.56 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.09 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.95 g, 87%) as a colorless solid.
Reaction SMILES: Cl.[NH:2]1[CH2:9][CH2:8][CH2:7][CH:3]1[C:4]([NH2:6])=[O:5].CCN(CC)CC.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CC#N.C(Cl)Cl>[C:4]([CH:3]1[CH2:7][CH2:8][CH2:9][N:2]1[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1)(=[O:5])[NH2:6]
Reactant: NC(=O)C1CCCN1
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)C1CCCN1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A solution of dl-prolinamide hydrochloride (2.5 g, 21.8 mmol) in CH3CN (35 mL) was treated with Et3N (7.45 mL) and 4-chlorobenzyl chloride (3.88 g, 24.1 mmol). The reaction mixture was stirred at 70° C. for 4 h and then at 25° C. for 16 h. The resulting mixture was diluted with CH2Cl2 (20 mL) and was washed with water (3×30 mL). The organic phase was dried (MgSO4) and concentrated. Chromatography (SiO2, 1% CH3OH—CH2Cl2) afforded 2-carbamoyl-1-(4-chlorobenzyl)pyrrolidine (5.21 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([F:19])[CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1cccc(F)c1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(F)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (m, 1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz).