Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:17]/[C:18](/[CH3:25])=[CH:19]/C(OCC)=O)C>CO>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9](/[C:12](/[CH3:13])=[CH:19]/[C:18](=[O:17])[CH3:25])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: CC(=O)c1ccc(C2CCCC2)cc1
Solvent: CO
Product: CC(=O)/C=C(\C)c1ccc(C2CCCC2)cc1
Yield: 51 %

Procedure:
(E)-4-(4-cyclopentyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 4'-cyclopentyl-acetophenone and ethyl (E)-3-ethoxy-crotonate with a yield of 51% of theory. B.p. 143°-147°C at 0.05 mm Hg. M.p. 33°-33.5°C (from methanol).
Reaction SMILES: [C:1](Br)(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)=O.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:8]=[C:7]1[NH:9][C:2]([C:1]([NH:12][CH:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19])=[O:10])=[CH:3][C:4](=[O:5])[NH:6]1
Reactant: O=C(Br)c1cc(=O)[nH]c(=O)[nH]1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)CC(NC(=O)c1cc(=O)[nH]c(=O)[nH]1)C(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the orotoyl bromide solution, 5.90 g (45 mmol) of Leucine is suspended, with stirring, in 50 mL of dry DCM. To this suspension a catalytic amount (˜0.1 mmol) of DMAP is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of about −15° C. When the target temperature is reached the drop wise addition of orotoyl bromide is commenced. Addition of orotoyl bromide continues, with constant cooling and stirring, until all of the orotoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant agitation. The solution is then filtered to remove any remaining Leucine and the volatile DCM is removed from the filtrate under reduced pressure, the remainder is then purified by flash chromatography (ethyl acetate/hexanes; 1/5), yielding 2-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-4-methylpentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH:10]([S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])=[CH2:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]=[CH:10][S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: C=CS(=O)(=O)C=C
Solvent: ClCCl
Product: C=CS(=O)(=O)C=CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Fifty grams of 4-chlorophenylsulfenyl chloride was added slowly to 33.0 g of divinyl sulfone in 150 ml of dichloromethane with cooling to remove the heat of reaction. After a few hours of standing at ambient temperature, the solvent was stripped and the crude adduct was dissolved in 200 ml of benzene. Thirty-one g of triethylamine was added slowly with cooling to maintain ambient temperature. After standing for one hour, the triethylamine hydrochloride was removed by filtration. After washing with water and drying over magnesium sulfate, the solvent was stripped to give 64 g of crude product. This was purified by chromatography over silica gel to give 48 g of vinyl 2-(4-chlorophenylthio)vinyl sulfone; calculated for C10HgCl02S2 :S, 24.6; found: S, 24.4.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-])[CH:8]=[CH:9][C:10]=3[N+:16]([O-:18])=[O:17])[C:5](=[O:20])[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:23])=[CH:9][C:10]=3[N+:16]([O-:18])=[O:17])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc[n+]([O-])c12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-bromo-4-nitro-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide (90 mg, 0.267 mmol) in 1 mL of dry DMF was added dropwise to a solution of phosphorus oxychloride (44.0 μL, 0.481 mmol) in 0.2 mL of DMF and 0.5 mL of toluene at 0° C. After stirring at 0° C. for 0.5 h, the reaction was quenched with saturated NaHCO3 and extracted with ethyl acetate (5×5 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=100:3) gave 8-bromo-2-chloro-4-nitro-10H-chromeno[3,2-b]pyridin-10-one as a light yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:38]5[CH2:39][CH2:40][N:35]([C:30]6[N:31]=[CH:32][CH:33]=[CH:34][N:29]=6)[CH2:36][CH2:37]5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(c5ncccn5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In THF (7 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 1-(2-pyrimidyl)piperazine (190 mg). The mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-[4-[1-(2-pyrimidyl)-4-piperazinylmethyl]-phenyl]-3,4-dihydronaphthalene-2-carboxamide (Compound 42) (166 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH2:10][CH3:11])[CH:3]=1.P(Br)(Br)[Br:13]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:13])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CO
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol (7.9 g, 36.7 mmol) in anhydrous CHCl3 (122 mL) was added PBr3(4.2 mL, 44.1 mmol). The resulting mixture was stirred at room temperature for 2 hours before it was quenched by the addition of water. The organic layer was washed with NaHCO3, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was filtered through a pad of silica gel with 20% EtOAc in hexanes. The solvent was removed in vacuo to afford the desired product (8.4 g, 83%). 1H NMR (300 MHz, CDCl3): δ 1.29 (t, J=7.5 Hz, 3 H), 2.71–2.78 (m, 2 H), 4.48 (s, 2H), 7.17–7.20 (m, 1H), 7.29–7.32 (m, 1 H), 7.36–7.38 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46](Cl)=[N:45][CH:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(OCC)(=O)C>[CH:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32])=[CH:22][CH:21]=3)=[N:45][CH:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(NC1CCCCC1)OCc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(COC(=O)NC3CCCCC3)s2)cc1

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with (2-chloro-1,3-thiazol-5-yl)methyl cyclohexylcarbamate (138 mg, 0.5 mmol). The crude residue was stirred in ethyl acetate for 16 hours before being filtered, mixed with water and the aqueous removed using a Varian Chem Elut Column (CE1010). The resulting solution was concentrated and purified by flash chromatography on silica, eluting with methanol/dichloromethane (0-30%) to give the title compound; Mass Spectrum: M+H+ 551.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH3:23])[C:7]([N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>C1COCC1.C(O)C>[Cl:31][C:32]1[N:37]=[C:36]([NH:1][C:2]2[CH:25]=[CH:24][C:5]3[N:6]([CH3:23])[C:7]([N:9]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[N:8][C:4]=3[CH:3]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(N)ccc21
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(Nc3ccnc(Cl)n3)ccc21
Temperature: 75 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
To a solution of tert-butyl 5-amino-1-methyl-1H-benzimidazol-2-yl(phenyl)carbamate (1.03 g, 3.0 mmol) in THF (3 ml) and ethanol (9 ml) was added NaHCO3 (0.76 g, 9.0 mmol) and 2,4-dichloropyrimidine (0.89 g, 6.0 mmol) and the reaction was heated to 75° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. The crude material was purified on silica gel to give the title compound as a white foam (0.98 g, 73%). 1H NMR (300 MHz, d6-DMSO) δ 10.00 (s, 1H), 8.10 (d, J=5.7 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.36-7.39 (m, 5H), 7.24-7.34 (m, 1H), 6.70 (d, J=6.0 Hz, 1H), 3.73 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:5][C:6]([C:16]1[CH:17]=[CH:18][C:13]([CH3:19])=[CH:14][CH:15]=1)=[O:7]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Add slowly tert-butylacetyl chloride (2 g, 14.858 mmol) to an ice-cold stirred solution of aluminum trichloride (2.972 g, 22.28 mmol) in anhydrous toluene (40 mL). Stir the reaction mixture at ambient temperature overnight. Add slowly ice-cold water and extract the mixture twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the desired intermediate (2.82 g, 100%) that was used without any further purification. GC-MS m/z: 190 (M4).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:30]I>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([N:25]([C:26](=[O:29])[CH:27]=[CH2:28])[CH3:30])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(=O)N(C)c1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h
Yield: 6.4 %

Procedure:
Sodium hydride (0.050 g, 26 mmol) was added in one portion to a stirred solution of 4-(4-acryloylamino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.25 mmol) in THF (1 ml). The reaction was stirred at room temperature for 5 minutes before methyl iodide (0.05 g, 0.25 mmol) was added in one portion and stirring continued for 1 hour. After this time, the reaction mixture was concentrated under vacuum and the resulting residue purified by prep HPLC to give the title compound (6.6 mg, 7% yield) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[NH2:9][C:10]1N(C2C=CC=C(I)C=2)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1>>[NH2:9][C:10]1[N:6]([C:5]2[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=2)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1
Reactant: Nc1ccc(I)cc1
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Product: Nc1nc2ccccc2n1-c1ccc(I)cc1

Procedure:
1-(2-Amino-1-benzimidazolyl)-4-iodobenzene (mp 212°-214° C. ) was prepared from 4-iodoaniline via 4-iodo-2'-nitrodiphenylamine (mp 174°-175° C.) and 4-iodo-2'-aminodiphenylamine (mp 127°-128° C.), in analogy with the sequence used in the preparation of 1-(2-amino-1-benzimidazolyl)-3-iodobenzene.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:6][C:5]([CH3:14])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:3]=1.[CH2:28](B(O)O)[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([C:2]1[C:7]([O:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:6][C:5]([CH3:14])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:3]=1)[CH3:29]
Reactant: CCB(O)O
Reactant: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(C)cc1OC(CC)CC
Temperature: 25 °C

Procedure:
Pd(PPh3)4 (12 mg, 0.01 mmol) is added to a solution of compound 45 (41 mg, 0.1 mmol) in toluene (0.6 ml), followed by ethylboronic acid (73 mg, 1 mmol) and Na2CO3 (1M, 0.2 ml, 0.2 mmol). The resulting mixture is heated to reflux overnight, and then cooled to room temperature. The toluene layer is separated. The aqueous layer is extracted with EtOAc. The combined organic layers are combined, washed with water, brine, dried, filtered and evaporated. The crude product is purified by chromatography (eluted with 6% EtOAc in hexane) to give the product as a white crystalline solid. 1H NMR (CDCl3) δ 1.00 (t, J=7.6 Hz, 6H), 1.23 (t, J=7.6 Hz, 3H), 1.73 (m, 4H), 2.09 (s, 3H), 2.84 (q, J=7.6 Hz, 2H), 3.87 (s, 3H), 4.16 (m, 1H), 6.78 (s, 1H), 6.89 (dd, 1H), 6.92 (s, 1H), 7.27 (d, J=8.4 Hz, 1H). LCMS 398.34 (M+1).
Reaction SMILES: [N:1]1([C:7]([NH2:9])=[NH:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:12]=1[CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16]>>[NH2:18][CH2:17][C:14]1[C:15]([NH2:16])=[N:8][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:9][C:13]=1[C:12]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:11]=1[Cl:10]
Reactant: N=C(N)N1CCOCC1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(N2CCOCC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=353.9 (M+), was prepared from morpholine-4-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[O:26])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].CNC.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Agent: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CO)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound. LCMS: 491.25 (M+1)+; HPLC: 99.58% (@ 254 nm) (Rt; 3.984; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.75 (s, 1H), 8.19 (t, 1H), 8.05 (d, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.41 (s, 1H), 7.24 (s, 1H), 5.86 (s, 1H), 5.44 (t, 1H, J=5.6 Hz), 4.59 (d, 2H, J=5.6 Hz), 4.28 (d, 2H, J=4 Hz), 3.85 (d, 2H, J=10.4 Hz), 3.32 (2H merged in solvent peak), 3.03 (m, 1H), 2.64 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.61 (bs, 4H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=2[O:7][CH2:6][CH2:5]1.[C:20]1([C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([SH:31])[C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([S:31][CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=3[O:7][CH2:6][CH2:5]2)[C:27]([F:28])([F:29])[F:30])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)COc1cccc2c1OCCN2CCO
Reactant: FC(F)(F)C(S)(c1ccccc1)c1ccccc1
Product: COC(=O)COc1cccc2c1OCCN2CCSC(c1ccccc1)(c1ccccc1)C(F)(F)F
Yield: 84.6 %

Procedure:
The same process as Example 1 was repeated except that methyl (4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (375 mg) and 1,1-diphenyl-2,2,2-trifluoroethanethiol (385 mg). were used to obtain the object compound (614 mg, yield 85%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCOCC1.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]>[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Yield: 64 %

Procedure:
Into a 500 mL single-neck flask fitted with a stirrer and thermometer, 10.0 g. of 4′-iodoacetophenone, 1.0 g. of PdCl2(dppf), and 17 mL triethylamine were placed in Dioxane (160 mL) and stirred at room temperature under a nitrogen atmosphere. This solution was then degassed with nitrogen for 15 minutes, followed by the addition of 8.8 mL pinacol borane syringe wise. Addition was exothermic and the solution turned dark immediately. The reaction was then heated at 85° C. for 6 h. The mixture was then cooled to room temperature and poured into H2O and the desired product was extracted with ether. This organic layer was washed with H2O, dried over MgSO4, and concentrated under reduced vacuum to yield a white solid. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with hexane/ethyl acetate 19:1 to yield intermediate title compound, acetophenone derivative, (6.4 g, 64%) as a white powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([C:16]2[C:17]([Cl:32])=[C:18]([NH:24]C(=O)OC(C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=2)[CH2:13][CH2:12][O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:24][C:18]1[CH:19]=[C:20]([CH:21]=[C:16]([N:14]2[CH2:13][CH2:12][O:11][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:15]2)[C:17]=1[Cl:32])[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCOC(CO[Si](C)(C)C(C)(C)C)C2)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCC1CN(c2cc(C#N)cc(N)c2Cl)CCO1
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a round bottom flask charged with (+/−)-tert-butyl (3-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-2-chloro-5-cyanophenyl)carbamate (1.2321 g, 2.56 mmol) in Dichloromethane (12.78 ml) and cooled to 0° C. was added 2,6-lutidine (0.595 ml, 5.11 mmol). Trimethyl trifluoromethanesulfonate (0.924 ml, 5.11 mmol) was added drop wise over several minutes. The reaction mixture was stirred at 0° C. 2 h and warmed to room temperature ON. The reaction mixture was poured into a separatory funnel containing 1:1 dichloromethane: saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on the ISCO system (40 g, 0-50% EtOAc/CH2Cl2). (+/−)-3-Amino-5-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-4-chlorobenzonitrile (0.860 g) was isolated as a yellow sticky solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][C:46](=[CH2:49])[CH2:47][NH2:48]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:48][CH2:47][C:46]([CH3:49])=[CH2:45])=[O:22])=[CH:16][CH:15]=1
Reactant: C=C(C)CN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=C(C)CNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-methylallylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-N-(2-methylallyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[C:5]([Br:20])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(-c2cc(=O)c3c(N)cccc3o2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)ccc(Br)c3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
2.50 g (11.9 mmol) of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one (EP-A-374789) was dissolved in 75 ml of dioxane, 1.86 g (13.1 mmol) of N-bromosuccinimide was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with a mixed solution of chloroform and methanol. The extract was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/acetone=40:1) to give 767 mg (20%) of Compound 5.