Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH3:25])([CH3:24])[C:21]#[C:22][CH3:23]>>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:23][C:22]#[C:21][Si:20]([CH3:25])([CH3:24])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#C[Si](C)(C)C
Reactant: ClCc1nc2ccccc2n1Cc1ccccc1
Product: C[Si](C)(C)C#CCCc1nc2ccccc2n1Cc1ccccc1
Yield: 102.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from of 1-benzyl-2-(chloromethyl)-1H-benzo[d]imidazole (500 mg, 1.9 mmol) and trimethyl(prop-1-ynyl)silane (262 mg, 2.34 mmol). 1-benzyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (647 mg, Yield: 100%) was obtained as a brown oil which was used in the next step without purification.
Reaction SMILES: O.O.[F-].[K+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9](B2OCCCO2)=[C:8]([F:18])[C:7]=1[O:19][CH3:20].[NH2:21][C:22]1[C:27]([F:28])=[C:26](Br)[N:25]=[C:24]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH:23]=1.CC#N>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.O>[NH2:21][C:22]1[C:27]([F:28])=[C:26]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[C:7]([O:19][CH3:20])[C:8]=2[F:18])[N:25]=[C:24]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH:23]=1
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(Br)n1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Temperature: 69 °C
Reaction time: 1 h

Procedure:
In a 50 mL three-neck round bottom flask was charged potassium fluoride dihydrate (12.0 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (5.40 mmol), isopropyl 4-amino-6-bromo-5-fluoropicolinate (4.0 mmol), MeCN (15 mL), and H2O (5 mL). The resulting mixture was sparged with N2 for 15 min then Pd(PPh3)2Cl2 (0.006-0.08 mmol) was added. The resulting suspension was sparged for 20 min then heated to 68-70° C. After 1 h of stirring, an aliquot (1-2 μL) was taken and diluted with MeCN (2 mL). The aliquot was analyzed by HPLC by monitoring the consumption of starting material 4-(acetylamido)-5-fluoropicolinate ester. After the reaction was deemed complete the heating mantle was removed and the mixture was cooled to ambient temperature and was diluted with MeCN/toluene/H2O (75 mL, 3/1/1); if needed, extra volume of the solvent mixture was added to dissolve the solids. The layers were then separated using a reparatory funnel. The product assay was then determined using an internal standard (hexanophenone): mp=177-179° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, JF-H=6.8 Hz, 1H), 7.47 (dd, J=8.4, 1.6 Hz, 1H), 7.29 (dd, J=8.4, 7.2 Hz, 1H), 6.70 (s, 2H), 5.12 (p, J=6.4 Hz, 1H), 3.93 (s, 3H), 1.30 (d, J=6.4 Hz, 6H); 13C NMR (100.6 MHz, DMSO-d6) δ 163.6, 154.4, 151.2, 148.0, 145.5, 144.0 (dd, JF-C=38.3, 4.2 Hz), 143.7 (d, JF-C=2.9 Hz), 139.0 (d, JF-C=13.6 Hz), 128.2 (d, JF-C=3.1 Hz), 126.0 (d, JF-C=3.4 Hz), 125.4 (d, JF-C=3.5 Hz), 123.9 (dd, JF-C=14.2, 3.5 Hz), 112.5 (d, JF-C=5.1 Hz), 68.5, 61.5 (d, JF-C=4.0 Hz), 21.6; 19F {1H} NMR (376.5 MHz, DMSO-d6) δ −129.4 (d, JF-F=25.6 Hz), −142.8 (d, JF-F=25.6 Hz); MS Calcd. for C16H15ClF2N2O3: 356.1. Found: 356 (M+), 270.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:15]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrC1CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3CCCC3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), cyclopentyl bromide (46 mg, 0.31 mmol, Aldrich, Cat. No. C115207), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 hours. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 40 mg of the product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=263.3
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[C:14]([CH2:15][OH:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:3][C@H:4]([C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:14]([CH2:15][OH:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[N:28]=[CH:27][N:26]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(CO)c2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(CO)c2n1-c1ccccc1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
To a solution of [2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-yl]methanol dihydrochloride (159 mg, 0.45 mmol) in IPA (5 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (69 mg, 0.45 mmol) and DIPEA (228 μL, 1.33 mmol) and the reaction mixture heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 353 as a white solid (87 mg, 49%). 1H NMR 400 MHz δ (d6-DMSO): 7.78 (1H, s), 7.65-7.56 (2H, m), 7.55-7.38 (5H, m), 7.16 (2H, br s), 7.05 (1H, dd, J=10.6, 8.8 Hz), 5.15 (1H, quin, J=6.9 Hz), 4.51 (1H, t, J=5.0 Hz), 3.97 (2H, d, J=5.0 Hz), 1.43 (3H, d, J=6.9 Hz)
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C1COCC1>[C:25]([O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: O=Cc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc2c1-c1ccc(C=O)cc1C2=O
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a stirred suspension of 1.53 g (6.83 mmol) of 4-hydroxy-7-formyl-fluoren-9-one, prepared in Step G of Example 43, in 25 mL THF at 0° C. was added 1.24 mL (8.88 mmol) of triethylamine and 0.58 mL (8.2 mmol) of acetyl chloride. The mixture was stirred further for 0.5 hour and then partitioned between EtOAc, ice, 1N HCl, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by chromatography on silica gel using methylene chloride as eluant gave 1.46 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:10]([OH:22])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:23][C:24]([F:25])([F:26])[F:27])[C:10](=[O:22])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(NC(=O)C(O)C(CC(F)(F)F)NC(=O)OC(C)(C)C)c(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(=O)C(CC(F)(F)F)NC(=O)OC(C)(C)C)c(C)c1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A mixture of 360 mg (0.92 mmol) of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxy-2′,4′-dimethylvaleranilide and 424 mg (1 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one in 10 ml of dichloromethane was stirred under a nitrogen atmosphere for 1 hour. The solution was extracted with a solution of 2.5 g of sodium thiosulphate in 10 ml of saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel using 25% ethyl acetate in petroleum ether for the elution. The solid obtained was triturated with petroleum ether to give 222 mg of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2′,4′-dimethyl-2-oxovaleranilide as a white solid, 1H NMR (250 MHz, CDCl3) δ:1.4 (s,9H), 2.25 (s,3H), 2.3 (s,3H), 2.8-3.1 (m,2H), 5.2-5.3 (m,1H), 5.4-5.5 (d,1H), 7.0-7.1 (m,2H), 7.7-7.8 (d,1H), 8.4-8.5 (br.s,1H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:15]([NH:17][C@H:18]([C:24]([OH:26])=[O:25])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[C:11]([CH2:10][C@H:9]([C:15]([NH:17][C@H:18]([C:24]([OH:26])=[O:25])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[NH2:8])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)C[C@H](NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C[C@@H](N)C(=O)N[C@@H](CC(C)(C)C)C(=O)O
Reaction time: 0.5 h

Procedure:
N-(tert-Butoxycarbonyl)-3-tert-butyl-D-alanyl-3-tert-butyl-L-alanine (4.5 g, 12.1 mmol, example 10A) is predissolved in dioxane (3 ml). At RT, a 4 N solution of hydrogen chloride in dioxane (30.2 mmol, 120 mmol, 10 equivalents) is added dropwise. The reaction mixture is stirred for 30 min, evaporated in vacuo and dried under high vacuum. The title compound is obtained as a solid (3.5 g, 99% of theory).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]#[N:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1.N1C=CC=CC=1>ClCCl>[C:25]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([C:9]1[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=1)[CH2:22][C:21]2([CH3:24])[CH3:23])#[N:26]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(C)(=O)=O)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 52.1 %

Procedure:
Methanesulfonyl chloride (93 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide as off-white solid (100 mg, Yield: 52.1%). MS (ESI+APCI) M+1=356.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][C:8]([CH2:10]O)=[N:9][C:5]=2[CH:4]=1.S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:10][C:8]1[NH:7][C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2[nH]c(CO)nc2c1
Solvent: ClCCl
Product: COc1ccc2[nH]c(CCl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5-Methoxy-1H-benzoimidazol-2-yl)-methanol (221, 0.5 g, 3 mmol) was combined with 30 mL dichloromethane. Thionyl chloride (0.51 mL, 7 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated. Ethyl acetate was added and washed with sodium bicarbonate saturated solution and brine. The organic portion was dried over anhydrous sodium sulfate, filtered through Celite and evaporated to dryness. The resulting desired compound was used without further purification. MS (ESI) [M+H+]+=197.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:13]([NH:14][C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:18]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Product: COc1ccc(Nc2ccc(C#N)nc2)c(C(F)(F)F)c1
Yield: 97.4 %

Procedure:
Analogously to Example 1a) 5-bromo-pyridine-2-carbonitrile was reacted with 2-trifluoromethyl-4-methoxy-aniline. After chromatographic purification through silica gel (petroleum ether with 10 to 30% ethyl acetate) the 4-(4-methoxy-2-trifluoromethyl-phenyl-amino)-benzonitrile was obtained in a yield of 97.4% of theory.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][CH2:32][C:33](=O)[CH3:34])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:15]([CH2:14][CH2:13][CH2:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=3)[C:33]([CH3:34])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCc1ccc(CCCN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 75 %

Procedure:
A solution of 3-(4-pentylphenyl)propylamine (1.8 g, 8.8 mmol) and 1-(4-benzyloxyphenyl)-1,4-pentanedione (2.43 g, 8.7 mmol) and p-toluenesulfonic acid monohydrate (200 mg) in toluene (30 ml) was refluxed for 12 hours under heating and the solvent was removed under reduced pressure. The residue was silica gel chromatography (hexane:ethyl acetate=9:1) to give the object compound as an oily substance. 2.99 g, (yield 75%)
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH+:10]=[C:9]([CH3:14])[C:8]2([CH3:16])[CH3:15])([OH:4])=[O:3].[CH3:17][N:18]([CH3:29])[C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1>C(#N)C>[CH3:17][N:18]([CH3:29])[C:19]1[CH:28]=[CH:27][C:22]([C:23]2[CH:24]=[CH:25][N+:10]3[C:11]4[C:7]([C:8]([CH3:16])([CH3:15])[C:9]=3[CH:14]=2)=[CH:6][C:5]([C:2]([O-:4])=[O:3])=[CH:13][CH:12]=4)=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C=CC=O)cc1
Reactant: CC1=[NH+]c2ccc(C(=O)O)cc2C1(C)C
Agent: [Cl-]
Solvent: CC#N
Product: CN(C)c1ccc(-c2cc[n+]3c(c2)C(C)(C)c2cc(C(=O)[O-])ccc2-3)cc1
Temperature: 60 °C

Procedure:
A suspension of 5-carboxy-2,3,3-trimethyl-3H-indolium chloride (14.5 g, 60.5 mmol) and 4-dimethylamino cinnamaldehyde (10.6 g, 60.5 mmol) in 200 ml of acetonitrile was heated to 60° C. for 24 h. The solvent was removed under vacuum and the resulting residue was subjected to silica gel chromatography twice. Then, recrystallization from methanol and ether afforded 10 g of target compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([Cl:12])[CH:5]=[C:6]([F:11])[C:7]=1[O:8][CH2:9][CH3:10].Cl.Cl[Sn]Cl.O>C(O)C>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH2:13]
Reactant: CCOc1c(F)cc(Cl)c([N+](=O)[O-])c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOc1c(F)cc(Cl)c(N)c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To a solution of 30-4 (22.9 g, 77 mmol) in ethanol (100 mL) at room temperature was added concentrated HCl (74 mL) and SnCl2 (44 g, 231 mmol). The mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 mL), the organic layer was combined and was concentrated under vacuum to get a crude product which was purified on silica gel column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to afford 30-5 (16 g, 78%) as a white solid. LRMS: calc 266.9 and found: 267.9 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([NH:7][CH3:8])=O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([CH3:8])[N:32]=[N:31][N:30]=2)[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cn1nnnc1-c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution of 3-bromo-N-methyl-5-nitro-benzamide (0.6 g) in DCM (15 ml) at −15° C. was added triflic anhydride (0.6 ml) and the reaction stirred for 30 min. Sodium azide (226 mg) was added and the reaction allowed to warm to room temperature and stirred further overnight. NaHCO3(aq) was added to neutralise the reaction and the mixture extracted into EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (9:1 to 2:8 cyclohexane:EtOAc) to give the title compound (290 mg). R1=0.51 (3:2 cyclohexane:EtOAc).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 79 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of p-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 1.3 g (80%) of 1-benzyl-piperidin-4-yl 4-methyl-benzoate was obtained as white crystals; m.p. 73°-74°.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:7](=[NH:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:23][C:19]=1[C:20](O)=[O:21].CCN(CC)CC.C(P(=O)(OCC)OCC)#N>C1COCC1>[NH2:28][S:27]([C:24]1[CH:25]=[CH:26][C:18]([F:17])=[C:19]([CH:23]=1)[C:20](/[N:16]=[C:7]1/[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15]2)[N:9]([CH3:10])[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]/1)=[O:21])(=[O:30])=[O:29]
Reactant: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(S(N)(=O)=O)ccc2F)n1CC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To a solution of Example 113C (0.43 g, 1.9 mmol) and 2-fluoro-5-sulfamoylbenzoic acid (Enamine, 0.47 g, 2.1 mmol) in THF (10 mL) was added Et3N (0.68 mL, 4.9 mmol) followed by diethyl cyanophosphonate (0.44 mL, 2.9 mmol). The mixture was stirred at ambient temperature for 2 hours then concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (0.26 g, 0.62 mmol, 32% yield). MS (DCI/NH3) m/z 423 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6](C(OCC2C=CC=CC=2)=O)[C@H:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][C@H:3]1[CH2:24]/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(O)=O.[Pd]>[O:1]=[C:2]1[NH:6][C@H:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][C@H:3]1[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](C/C=C/c2ccccc2)C(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](CCCc2ccccc2)C(=O)N1
Reaction time: 0.75 h
Yield: 97.5 %

Procedure:
The protected pyroglutamate 8b (370 mg, 0.850 mmol) was partially dissolved in 1:1 EtOAc/hexanes (20 mL) and 100 □L AcOH. To this mixture, was added 10% Pd-C (50 mg). The mixture was evacuated and flushed with H2 (5×), then stirred under an atmosphere of H2 for 45 min. The reaction mixture was filtered and concentrated to afford 251.4 mg (98%) of 8c.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.OS([O-])=O.[Na+]>CC(N(C)C)=O>[F:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:17]([C:16]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=1)[N:6]=[C:4]2[OH:5]
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2nc(O)c3cc(F)ccc3n2)cc(OC)c1OC
Temperature: 140 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 2-amino-5-fluorobenzamide (13.02 g, 84.47 mmol, 1.00 equiv) in dimethylacetamide (200 mL), 3,4,5-trimethoxybenzaldehyde (17.97 g, 91.59 mmol, 1.08 equiv) and NaHSO3 (8.85 g). The resulting solution was stirred overnight at 140° C. in an oil bath. The reaction was then quenched by the addition of 400 mL of water/ice. The solids were collected by filtration. This resulted in 28 g (crude) of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol as a brown solid. MS (ESI) m/z 331 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17](Cl)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([C:33]#[N:34])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(Cl)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(C#N)c1=O
Temperature: 150 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
A mixture of {1-[5-chloro-4-(4-cyano-3-fluoro-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (460 mg, 1 mmol), Zn(CN)2 (175 mg, 1.5 mmol) and Pd(PPh3)4 (116 mg, 0.0.1 mmol) in DMF (5 mL) was stirred 4 h at 150° C. under N2 atmosphere. The mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo, and the residue purified by preperative HPLC to give 150 mg of the title product as a yellow solid (33%). [M+H] Calc'd for C23H25FN6O3, 453. Found, 453.