Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])C.[OH-].[K+].Cl>C(O)C>[CH2:14]([O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:4]([OH:16])=[O:3])[CH3:15]
Reactant: CCOC(=O)c1ccc(OC)cc1OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(OC)ccc1C(=O)O
Yield: 83.5 %

Procedure:
2-Ethoxy-4-methoxybenzoic acid ethyl ester (13 g, 58 mmol) was suspended in ethanol (150 mL). This was treated with potassium hydroxide (40 mL, ˜4 M) and refluxed for 1 h. The reaction was cooled and poured into cold aqueous hydrochloric acid (300 mL, 2 M) and extracted into dichloromethane (3×200 mL). The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was evaporated to dryness to give 2-ethoxy-4-methoxybenzoic acid (9.5 g, white solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[Si:61]([O:68][C@H:69]1[CH2:73][N:72]([CH3:74])[C@H:71]([CH:75]=O)[CH2:70]1)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62]>O1CCCC1>[Si:61]([O:68][C@H:69]1[CH2:73][N:72]([CH3:74])[C@H:71](/[CH:75]=[CH:29]/[C:28]([NH:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][C:23]=2[O:39][CH2:40][CH3:41])[N:20]=[CH:19][C:18]([C:42]#[N:43])=[C:17]3[NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([Cl:1])[CH:3]=2)=[O:38])[CH2:70]1)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:62])[CH3:63]
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CN1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.1 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (418 mg, 0.67 mmol) was dissolved in 2.5 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1 mL, 1 mmol). After the mixture was stirred for 45 minutes, a solution of (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carbaldehyde 3e (326 mg, 1.34 mmol) in 2.5 mL of tetrahydrofuran was added, and stirred for another 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-3-[(2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidin-2-yl]-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]prop-2-enamide 3f (292 mg, yield 61.2%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH3:23].C1(C)C=CC=CC=1.[BH4-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:27][S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NCc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126b, 2.0 g, 6.09 mmol), ethanesulfonamide (1.33 g, 12.17 mmol) and toluene (250 mL), and titanium(IV) isopropoxide (2.59 g, 9.13 mmol) is added dropwise. The mixture is stirred at 120° C. overnight. The mixture is then concentrated in vacuo. The residue is taken up in DCM (150 mL) and MeOH (150 mL), and NaBH4 (0.461 g, 12.17 mmol) is added at 0° C. The mixture is stirred at 0° C. for 30 min. Water (50 mL) is added and the mixture is stirred for 5 min. The suspension is filtered through a pad of celite. The celite layer is washed with DCM (3×50 mL). The combined organic phase is dried over Na2SO4 and concentrated to give a residue is purified by silica gel flash chromatography (ethyl acetate). The resulting fractions containing the product are concentrated and repurified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 97:3). The concentrated product is redissolved in MeOH (500 mL) at 60° C. and concentrated in vacuo to give N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.3 Hz, 3H), 3.06 (q, J=7.3 Hz, 2H), 3.78 (s, 3H), 4.34 (d, J=6.3 Hz, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.77 (t, J=6.2 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8.80 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 389.0853 [(M+H)+ Calcd for C18H17ClN4O2S: 389.0839].
Reaction SMILES: [C:1]1([CH:7]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([O-])=[O:19].[Na+]>Cl.O>[N:18]([N:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:17])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19]
Reactant: O=N[O-]
Reactant: O=C1Nc2ccccc2NC1c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1c2ccccc2NC(=O)C1c1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A suspension of 3,4-dihydro-3-phenylquinoxalin-2(1H)-one (430 mg, 1.9 mmol) in 3N HCl (30 mL) was stirred at 5° C. Sodium nitrite (150 mg, 2.17 mmol) in water (1 mL) was added dropwise and stirring was continued for 1 h. The reaction mixture was extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain 475 mg of 3,4-dihydro-4-nitroso-3-phenylquinoxalin-2(1H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[CH3:20][S@@:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[NH:23])=[O:22].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:23]=[S@:21]([CH3:20])(=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9]
Reactant: C[S@@](=N)(=O)c1ccccc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[S@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a solution of 5-bromonicotinic acid (303 mg, 1.5 mmol), N,N-diisopropylethylamine (0.523 mL, 3.0 mmol), and (R)-(−)-S-methyl-S-phenylsulfoximine (233 mg, 1.5 mmol) in DMF (3.0 mL) cooled to 0° C. was added 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (859 mg, 1.65 mmol). The solution was stirred 10 minutes, the ice bath removed, and the reaction continued at room temperature for 2.5 hours. The mixture was taken up in EtOAc and washed with H2O, Na2CO3 solution, brine, AcOH solution, H2O, Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was chromatographed eluting with hexane/EtOAc to give the title compound as a yellow solid (478 mg, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])#[N:2].[OH2:11]>>[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]([OH:11])=[O:6])#[N:2]
Reactant: N#Cc1ccccc1C=O
Reactant: O
Product: N#Cc1ccccc1C(=O)O

Procedure:
Moreover, the present inventors have found that reaction of the cyanobenzaldehyde compounds as starting materials and a hypohalogenous compound in water or a mixed solvent of water and an aprotic polar solvent affords cyanobenzoic acid compounds in a high purity and in a high yield.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(Br)C=C.Cl>O1CCCC1.CCCCCC>[C:22]([O:21][C:19]([NH:18][CH2:17][CH:16]([CH2:3][CH:1]=[CH2:2])[C:15]([O:14][CH3:13])=[O:26])=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)CCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC(CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
Dissolve diisopropylamine (5.6 mL, 40 mmol) in anhydrous tetrahydrofuran, cool to -78° C. and place under nitrogen atmosphere. Treat with n-butyllithium (25 mL of a 1.6M solution in hexane, 40 mmol). Stir for 30 minutes and add, by dropwise addition, a solution of N-(t-butyloxycarbonyl)-β-alanine methyl ester (4.06 g, 20 mmol) in tetrahydrofuran (25 mL) over 20 minutes. Stir for an additional 30 minutes. Add allyl bromide (1.72 mL, 20 mmol) and allow the mixture to warm to room temperature with stirring until homogeneous. Cool to -78° C. and slowly warm to -20° C. over 30 minutes. Pour into 5% hydrochloric acid, extract into ether, wash with saturated sodium chloride, dry, and concentrate to yield 5.01 g yellow oil. Purify by silica gel chromatography (25% ethyl acetate/hexane) to yield 4.2 g (87%) of a racemic mixture of the title compound as a clear colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15](OCC)=[O:16])[CH3:11]>C(O)(=O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15](=[O:16])[N:7]2[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=[C:6]2[NH:9][CH:20]=1)=[O:24])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C3CC3)nn2c1=O
Temperature: 120 °C
Yield: 73.9 %

Procedure:
To a solution of 5-cyclopropyl-2H-pyrazol-3-ylamine (280 mg, 2.3 mmol, 1 eq) in acetic acid (3 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (500 μL, 2.5 mmol, 1.1 eq). The mixture was heated at 120° C. for 2 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol to afford the expected compound as white powder (420 mg, 75% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:37])C=CC=CC=1.C(O)(=O)C>O1CCCC1>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[C@H:25]([CH:26]1[CH2:27][CH2:28]1)[OH:37])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C(CC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](O)C1CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
A cooled (−78° C.) solution of sodium bis(trimethylsilyl)amide (0.6 M in toluene, 65 mL, 38.918 mmol) was diluted with anhydrous tetrahydrofuran (100 mL) and treated with a solution of (S)-4-benzyl-3-(2-cyclopropyl-acetyl)-oxazolidin-2-one (9.174 g, 35.380 mmol) in anhydrous tetrahydrofuran (50 mL). After stirring at −78° C. for 45 min, the mixture was treated with a solution of 2-benzenesulfonyl-3-phenyl-oxaziridine (11.064 g, 42.456 mmol) in anhydrous tetrahydrofuran (50 mL). After stirring at −78° C. for 55 min, the reaction was quenched with acetic acid (10.1 mL, 176.9 mmol) and allowed to warm to room temperature. The mixture was quenched with sodium bicarbonate solution (300 mL) and poured over dichloromethane/iso-hexanes (3:1, 400 mL). The aqueous layer was extracted with dichloromethane and the organics were combined, washed with saturated sodium thiosulfate, hydrochloric acid (1 M, 300 mL), water and filtered through a phase separator. The volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 7:3 followed by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (7.922 g, 81%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.42-0.65 (m, 4H), 1.25-1.38 (m, 1H), 2.88 (dd, J=13.4, 9.6 Hz, 1H), 3.35 (dd, J=13.4, 3.4 Hz, 1H), 3.44 (d, J=8.2 Hz, 1H), 4.25-4.37 (m, 2H), 4.67-4.72 (m, 1H), 4.80 (dd, J=8.0, 6.0 Hz, 1H), 7.21-7.41 (m, 5H). LCMS (m/z) 298.1 [M+Na], Tr=2.27 min.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[Li+].CC([N-]C(C)C)C.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([NH:23][C:24]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[Br:7])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1csc(Br)n1
Reactant: O=C=NCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccccc1)c1sc(Br)nc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a stirred solution of 2,4-dibromo-thiazole (4.95 g, 20.4 mmol) in THF at −78° C. was added LDA (1.8M in THF/hexanes, 13.6 ml, 24.5 mmol) slowly. The reaction was then stirred at −78° C. for 30 min., when benzylisocyanate (3.8 ml, 30.6 mmol) was added slowly. The mixture was then stirred at −78° C. for 30 min. before it was slowly warmed up to RT. Water was then added carefully to quench the reaction. The mixture was extracted with EtOAc and the combined extracts were dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (10% EtOAc/hexanes) to give 2,4-dibromo-thiazole-5-carboxylic acid benzylamide 26B as a white solid (5.05 g, 13.43 mmol, 66%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:20])([F:19])[C:9]1[NH:13][N:12]=[CH:11][C:10]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>C(#N)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:12]2[CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:8]([F:7])([F:19])[F:20])=[N:13]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cn[nH]c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(F)(F)F
Yield: 99.9 %

Procedure:
According to Scheme 1, Step 1: K2CO3 (11.5 mmol, 1.59 g) was added to a solution of ethyl 5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (7.69 mmol, 1.60 g) in acetonitrile (24 mL) followed by 1-(chloromethyl)-4-methoxybenzene (8.46 mmol, 1.15 mL) and the reaction mixture was heated under reflux for 4.5 hours. After evaporation of the solvent, the reaction mixture was diluted with brine and EtOAc. The aqueous phase was extracted with EtOAc. The organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield ethyl 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (7.68 mmol, 2.52 g, 100%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:34]Br>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:34][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(Cl)c2)C(=O)C1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) suspension of tert-butyl 3-oxopiperazine-1-carboxylate (2.0 g, 9.99 mmol) in DMF (20 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (10.69 mL, 10.69 mmol) was added and stirred at the temperature for 30 min. The resultant clear red brown solution was treated with 3-chloro-4-fluorobenzyl bromide (2.34 mL, 10.49 mmol), and stirred at 0° C. for 2 hours. The product mixture was concentrated under vacuum, and the residue partitioned between water and ethyl acetate. The organic extract was washed successively with 5% aq KHSO4, sat. NaHCO3, and brine. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0-100% gradient of ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the benzylated product.
Reaction SMILES: C(C1[C:4]([C:25](O)=O)=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12](N3C4C(=NC=CC=4)NC3=O)[CH2:11]C2)=NC=1)#N.[C:28]([C:30]1[C:31]([N:39]2[CH2:44][CH2:43][CH:42]([N:45]3[C:53]4[C:48](=[N:49][CH:50]=[CH:51][CH:52]=4)[NH:47][C:46]3=[O:54])[CH2:41][CH2:40]2)=[CH:32][C:33]([C:36]([OH:38])=O)=[N:34][CH:35]=1)#[N:29].N1C2C(=CC=CC=2)CC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:9]1([C:36]([C:33]2[N:34]=[CH:35][C:30]([C:28]#[N:29])=[C:31]([N:39]3[CH2:44][CH2:43][CH:42]([N:45]4[C:53]5[C:48](=[N:49][CH:50]=[CH:51][CH:52]=5)[NH:47][C:46]4=[O:54])[CH2:41][CH2:40]3)[CH:32]=2)=[O:38])[C:6]2[C:12](=[CH:11][CH:25]=[CH:4][CH:5]=2)[CH2:13][CH2:14]1
Reactant: N#Cc1cnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc1C(=O)O
Reactant: N#Cc1cnc(C(=O)O)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Product: N#Cc1cnc(C(=O)N2CCc3ccccc32)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C

Procedure:
0.11 mg (0.29 mmol) of an isomer mixture of 5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid and 5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylic acid, 34 mg (0.29 mmol) 2,3-dihydro-1H-indole and 90 μL (0.61 mmol) TEA were placed in 1.5 mL DMF. 0.10 g (0.32 mmol) TBTU were added. The reaction mixture was stirred over the weekend at RT. The purification and separation of the isomers were carried out by HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1>CC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([S:27][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Temperature: 90 °C

Procedure:
2-Bromo-6-phenyl-pyridine (13) (100 mg, 0.43 mmol), K2CO3 (117 mg, 0.85 mmol) in acetone (2 mL) was added 3-bromothiophenol and the reaction mixture was heated in a CEM Discover microwave for 1×30 minutes at 90° C., then 4×2 hours at 130° C., followed by 1×8 hours at 130° C. The crude product was partially purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound. Yield: 100 mg, 68%; LC-MS tr 1.97 min; HPLC Purity: 55%; MS (ES+) m/z 342, 344 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH3:11])[C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[C:17]([C:30](O)=[O:31])=[CH:16]2>>[CH3:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH:1][C:30]([C:17]3[N:18]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[C:19]4[C:15]([CH:16]=3)=[CH:14][C:13]([F:12])=[CH:21][CH:20]=4)=[O:31])[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: Cn1cnc2cc(N)cnc21
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: Cn1cnc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc21

Procedure:
Compound 7 is synthesized according to a process similar to that described in Example 1.2, starting with 6-amino-3-methyl-3H-imidazo[4,5-b]pyridine, described in the preceding step, and 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, described in step 1.1.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[N:31]1[CH:36]=[CH:35][C:34]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OB(O)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccncc1
Yield: 56 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and pyridin-4-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (56% yield); 1H-NMR (d6-DMSO) 1.11 (9H, s), 3.67 (2H, t), 4.13 (1H, t), 6.74 (1H, s), 7.18 (2H, m), 8.43 (2H, m); 13C-NMR (d6-DMSO) 27.7, 41.3, 66.9, 119.3, 134.7, 149.5; MS ES(+) 263.0 (M++1); HRMS m/z calcd for C14H18N2O3+H+ 263.1296 [M+H+]. Found 263.1402. IR λmax=1695 cm−1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Cc2ccccc2C(F)(F)F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Cc3ccccc3C(F)(F)F)cc2=O)n1
Yield: 61 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid (Intermediate 63) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionamide as an off-white solid (77 mg, 61%); ES+-HRMS m/e calcd for C27H32N5O3F3 [M+H+] 532.2530, found 532.2530. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.21-1.74 (m, 8H), 1.90 (m, 1H), 2.26 (m, 1H), 3.88 (s, 2H), 4.09 (s, 2H), 4.66 (s, 1H), 5.46 (dd, J=3.9, J=10.6 Hz, 1H), 6.29-6.42 (m, 2H), 7.38-7.59 (m, 3H), 7.70 (t, J=7.4 Hz, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([C:17]2[CH:18]=[N:19][C:20](S(CCC)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:19][CH:18]=2)[CH:3]=1
Reactant: C1CCNCC1
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Product: O=C(O)COc1ccc(Cl)cc1-c1cnc(N2CCCCC2)nc1

Procedure:
The title compound was prepared from the product of example 20 step (iv) and piperidine by the method of example 20 step (v).