Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([C:15]1[C:16]([C:50](O)=[O:51])=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([CH:29]3[C:42]4[C:41](=[O:43])[CH2:40][C:39]([CH3:45])([CH3:44])[CH2:38][C:37]=4[O:36][C:35]4[CH2:34][C:33]([CH3:47])([CH3:46])[CH2:32][C:31](=[O:48])[C:30]3=4)[C:22]=2[CH3:49])=[CH:19][CH:20]=1)[CH3:14].[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:13]([C:15]1[C:16]([C:50]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:51])=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([CH:29]3[C:30]4[C:31](=[O:48])[CH2:32][C:33]([CH3:47])([CH3:46])[CH2:34][C:35]=4[O:36][C:37]4[CH2:38][C:39]([CH3:45])([CH3:44])[CH2:40][C:41](=[O:43])[C:42]3=4)[C:22]=2[CH3:49])=[CH:19][CH:20]=1)[CH3:14]
Reactant: CS(N)(=O)=O
Reactant: CCc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)NS(C)(=O)=O
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
1,1′-Carbonyldiimidazole (104 mg, 0.64 mmol) was added to a solution of the 3-ethyl-6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 13 (267 mg, 0.49 mmol) in DMF (5.3 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 1.5 hours. Thereafter, methanesulfonamide (60.7 mg, 0.64 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.096 ml, 0.64 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 3 hours. Thereafter, an aqueous solution of citric acid (472 mg, 2.46 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). The solid thus obtained was washed with diethyl ether, followed by collection by filtration and drying, to obtain the title compound (128 mg, yield: 42%).
Reaction SMILES: [CH3:1][C:2](=[O:4])[CH3:3].C(O)C.[F:8][C:9]([F:13])([F:12])[S:10]Cl>ClCCl>[F:8][C:9]([F:13])([F:12])[S:10][CH2:1][C:2](=[O:4])[CH3:3]
Reactant: CC(C)=O
Reactant: FC(F)(F)SCl
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)CSC(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 69 %

Procedure:
A mixture of 2-propanone (0.25 mole), ethanol (0.49) and dichloromethane (75 ml) was introduced into a sealed and pressure tested vessel having a volume of about 500 ml under reduced pressure. Trifluoromethanesulfenyl chloride (0.22 mole) was then added to the cooled, evacuated vessel. The vessel was warmed to about 25°C and then rocked for five days. The vessel was vented through a cold gas trap (-78°C) to trap any unreacted trifluoromethylsulfenyl chloride gas and then through a scrubbing system to remove the vented hydrogen chloride gas. Residual liquid was transferred to a flask and distilled to give about 24 g of 1-trifluoromethylthio-2-propanone. The structure of the purified product (b.p. 51°-52°C/22 mm Hg) was confirmed by spectral and elemental analyses.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C@@H:10]1[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][CH:10]1[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: OC1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside (5 g, 10.75 mmol) is dissolved at 0° C. in a 9:1 mixture of trifluoroacetic acid and water (50 mL) (N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull Chem. Soc. Jpn 56, 2849 (1983)). The mixture is stirred overnight at 0° C. The solvents are evaporated under reduced pressure without heating. The residue is dissolved in ethyl acetate and washed successively with sodium bi-carbonate and brine. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure so as to afford an oil. Flash chromatography on silica gel and elution with a graded mixture of ethyl acetate and hexane will afford 2,3,6-tri-O-benzyl-D-galactopyranose as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:45](Cl)(=[O:50])[CH2:46][CH2:47][CH2:48][CH3:49]>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:45](=[O:50])[CH2:46][CH2:47][CH2:48][CH3:49])[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCC(=O)Cl
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
Amine (22) (23.5 mg, 40 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) and valeryl chloride (5 μL, 42 μmole, 1.05 eq) were added and the reaction stirred 30 minutes. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.21 (s, 1H), 7.62 (t, 1H), 7.36 (d, 2H), 7.25 (t, 2H), 7.18 (t, 1H), 4.42 (s, 2H), 3.30 (water), 3.00 (s, 2H), 2.74 (t, 2H), 2.48 (DMSO), 1.99 (t, 2H), 1.56 (m, 4H), 1.41 (m, 2H), 1.26 (m, 1H), 1.20 (m, 3H), 0.81 (t, 3H), 0.60 (m, 4H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:40][CH:39]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])=[CH:42][CH:43]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cc2ccccc2)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)OCC
Yield: 11.7 %

Procedure:
Ethyl 3-(3-benzyl-4-hydroxyphenyl)-2-ethoxypropanoate (2 g, 6 mmol), 2-{4-[(tert-butoxycarbonyl}amino]phenyl}ethyl 4-methylbenzenesulfonate (3.6 g, 9 mmol); was solved in 2-butanone (30 ml). PEG-400 (0.8 g) and potassium carbonate (2.6 g, 19 mmol) was added and the mixture was refluxed for 8 h. Water was added, the organic layer separated and evaporated. The residue was purified on silica gel using isooctane/ethylacetate 2:1 which yielded 0.38 g (0.7 mmol) of the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCc3ccccc3)cc2CC1
Yield: 100 %

Procedure:
7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (790 mg, 3 mmol), potassium carbonate (1.24 g, 9 mmol) and catalytic potassium iodide were suspended in 2-butanone (20 ml). Benzyl bromide (536 μL, 4.5 mmol) was added and the mixture heated at reflux for 24 hours. The solids were filtered and then washed with acetone. The filtrate was concentrated in vacuo and the crude oil purified by column chromatography, eluting with a mixture of ethyl acetate and hexane (1:4) to afford the title compound (D1) (1.06 g, 100%), 1H NMR (CDCl3) 7.44 (5H, m), 7.03 (1H, d, J=8.1 Hz), 6.77 (1H, s), 6.74 (1H, dd, J 8.1 & 2.4 Hz), 3.49 (4H, m), 2.84 (4H, m), 1.48 (9H, s).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]O)=[CH:5][CH:4]=1>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][Br:1])=[CH:5][CH:4]=1
Reactant: Br
Reactant: OCCc1ccc(Cl)cc1
Product: Clc1ccc(CCBr)cc1

Procedure:
reacting hydrogen bromide with 2-(4-chlorophenyl)ethanol to form 2-(4-chlorophenyl)ethyl bromide;
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C([O-])([O-])=O.[K+].[K+].C(O)CC>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.CCOC(C)=O.O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:28]5[CH:29]=[CH:30][S:26][CH:27]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: OB(O)c1ccsc1
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: [K+]
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccsc4)ccc32)n1)c1ccccc1

Procedure:
A stirred solution of 2-[(S)-1-phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine (EXAMPLE 271) (37 mg), 3-thiophene boronic acid (16 mg), K2CO3 (35 mg) and Pd(PPh3)4 (0.97 mg) in 1:1 n-propanol:water (4 mL) was stirred under N2 at 100° C. for 16 h. The reaction mixture was cooled and poured into 100 mL EtOAc and washed with water, then brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography eluting successively with 10% acetone/hexanes, 20% acetone/hexanes and 30% acetone/hexanes giving 25.3 mg of the title compound. Mass spectrum (ESI): 398.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[CH:17]1([C:2]2[CH:16]=[CH:15][C:5]3[NH:6][C:7]([CH:9]4[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]4)=[N:8][C:4]=3[CH:3]=2)[CH2:19][CH2:18]1
Reactant: OB(O)C1CC1
Reactant: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2[nH]c(C3CCNCC3)nc2cc1C1CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
The mixture of 5-bromo-2-piperidin-4-yl-1H-benzoimidazole (200 mg, 0.53 mol), cyclopropanylboronic acid (58.4 mg, 0.687 mmol), K3PO4 (391 mg, 1.85 mmol), Pd (OAc)2 (6.8 mg, 0.005 mmol) and tricyclohexylphosphine (14.9 mg, 0.053 mmol) in toluene (10 mL) and H2O (3 mL) was stirred at 90° C. under N2 for 12 h. Then it was poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 5-Cyclopropyl-2-piperidin-4-yl-1H-benzoimidazole (58 mg, 30%) as white solid.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])O.[Na+].Cl.Cl[CH2:15][C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:17].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:7][CH2:15][C:16](=[O:17])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:6]
Reactant: O=C(CCl)c1cccnc1
Reactant: CC(C)(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)OCC(=O)c1cccnc1
Yield: 92.1 %

Procedure:
Pivalic acid (5.3 g, 52 mmol), 8.8 g (104 mmol) of sodium hydrogen carbonate and 0.84 g (2.6 mmol) of tetrabutylammonium bromide were added to a solution of 5.0 g (26 mmol) of 3- (2-chloroacetyl) pyridine hydrochloride in 80 ml of THF at room temperature, and the mixture was refluxed for 2 hours. Water (100 ml) was added to the reaction mixture and the resulting mixture was extracted three times with 100 ml of ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and then dried over sodium sulfate. The solvent was distilled off under reduced pressure and the product was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 5.3 g (yield 92%) of the desired 2-oxo-2-pyridin-3-ylethyl 2,2-dimethylpropanoate.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)#[N:10].C(N(CC)CC)C>O1CCCC1.O>[CH2:1]([NH:8][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]#[N:10])[CH:12]=1)(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzylamine (1.17 g, 10 mmol) was added to a solution of 3-cyanobenzene sulphonyl chloride (2 g, 10 mmol) and triethylamine (3.45 ml, 25 mmol) in tetrahydrofuran (30 ml) and the mixture stirred at room temperature for 18 hours. The mixture was diluted with water (30 ml), and extracted with ethyl acetate (50 ml). The organic extract was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a solid, 2.53 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].FC1C=CC(C2C=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=2)=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Reactant: CC(=O)c1ccc(F)cc1F
Product: O=C(O)c1ccc(-c2ccc(F)cc2F)nc1

Procedure:
The title compound was prepared from 2′,4′-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][N:6]=1.[CH:17](OC)=[O:18]>COCCOC>[CH3:16][O:15][C:13](=[O:14])[C:12]([CH2:11][C:8]1[CH:9]=[N:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1)=[CH:17][OH:18]
Reactant: COC(=O)CCc1cnc(OC)nc1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C(=CO)Cc1cnc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a suspension of NaH (14.7 g, 367 mmol) in DME (216 mL) was added dropwise a mixture of methyl 3-[2-(methyloxy)-5-pyrimidinyl]propanoate (18 g, 92 mmol) and methyl formate (33.1 g, 550 mmol) in DME (216 mL) under N2 at 0° C. The reaction mixture was stirred at 25° C. overnight, then filtered through a pad of Celite. The filtrate was diluted with ether (500 mL), kept standing for about 2 h and re-filtered. The filtrated cake was washed with diethyl ether and dried to give the title compound (14 g, 51.7%), which was used into next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][C:7]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH:36]=1)[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.O.C(Cl)(Cl)Cl>[CH2:42]([O:41][C:37]1[CH:36]=[C:35]([O:34][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:40]=[CH:39][C:38]=1[C:10]([C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=1)=[O:12])[CH:43]([CH3:45])[CH3:44]
Reactant: COC(=O)Cc1cc(C(=O)O)ccc1OCC(C)C
Reactant: CC(C)COc1cccc(OCC(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
In 6 ml of methylene chloride is dissolved 0.62 g of 4-isobutoxy-3-(2-methoxy-2-oxoethyl)benzoic acid. After adding 0.25 ml of oxalyl chloride at ambient temperature, the mixture thus obtained is stirred at ambient temperature for one hour. Then, 0.62 g of aluminum chloride and 0.77 g of 1,3-diisobutoxybenzene are successively added at 5-10° C., and the mixture is stirred at ambient temperature for one hour. The reaction mixture is added to a mixture of chloroform and water, and the organic layer is separated. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography [eluent; n-hexane:ethyl acetate=95:5] to obtain 0.63 g of methyl 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]acetate as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:25](=[O:27])[CH3:26])[CH2:7][C:8]3[CH:15]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:4]=2[CH:3]=1.[CH3:30][O:31][C:32](=[O:49])[C:33]1[CH:38]=[C:37]([CH:39]=[O:40])[CH:36]=[CH:35][C:34]=1OS(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.O.CCO>[CH3:30][O:31][C:32](=[O:49])[C:33]1[CH:38]=[C:37]([CH:39]=[O:40])[CH:36]=[CH:35][C:34]=1[C:14]1[CH:13]=[CH:12][C:9]2[CH:10]=[CH:11][C:4]3[CH:3]=[C:2]([Cl:1])[CH:29]=[CH:28][C:5]=3[N:6]([C:25](=[O:27])[CH3:26])[CH2:7][C:8]=2[CH:15]=1
Reactant: CC(=O)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C=Cc2cc(Cl)ccc21
Reactant: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C=O)ccc1-c1ccc2c(c1)CN(C(C)=O)c1ccc(Cl)cc1C=C2
Temperature: 75 °C
Yield: 54.2 %

Procedure:
A 15 mL three necked oven dried round bottom flask was cooled under argon and charged with Example 21A (50 mg, 0.12 mmol), Example 236A (47 mg, 0.15 mmol) and toluene (2 mL)/EtOH (1 mL). The mixture was purged with argon for 30 minutes. Pd(PPh3)4 (14 mg, 0.012 mmol) and 2 M Na2CO3 (187 μl, 0.36 mmol were added and the reaction was heated at 75° C. for 2 hours. The resulting mixture was poured into water (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by radial chromatography (2 mm plate, 30% to 50% EtOAc/Hexanes) to give the desired product Example 236B (29 mg, 55%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[C:13]1([C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]1([C:19]2[CH2:24][CH2:23][N:22]([CH2:3][C:4]3[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=3)[CH2:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CC=C(c3ccccc3)CC2)c(N)n1
Reaction time: 5 h
Yield: 21.4 %

Procedure:
A suspension of 9.7 g (0.050 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride, 9.8 g (0.050 mol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 13.8 g (0.1 00 mol) of dry potassium carbonate in 125 ml of dimethylformamide was stirred vigorously at 80° for 5 hours. The mixture was cooled, suction filtered, completely freed from the solvents and the residue was triturated in water. The resulting crystals were filtered off under suction and recrystallized from ethanol/water. 3.0 g (21%) of 5-(4-phenyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-pyrimidin-4-ylamine were obtained as yellow crystals; m.p. 165°-166°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:29])[C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]([CH3:29])[C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCCCCCCOCCC#Cc1ccc(N(C)C(=O)C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCCCCCCOCCCCc1ccc(N(C)C(=O)C(F)(F)F)cc1
Yield: 99.1 %

Procedure:
A solution of Intermediate 54 (1.2 g, 2.9 mmol) in methanol was treated with palladium on carbon (10% w/w, 50 mg). Mixture was shaken under 50 psi of hydrogen gas for two hours and then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the title compound as an oil (1.2 g, 100%). ES/MS calcd. for C21H31F3NO4+ 418.2. Found m/z=418.3 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][C:8]2[C:9]([CH3:19])=[N:10][CH:11]=[N:12][C:13]=2[C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N:31]([C:34]1[C:35]([CH3:40])=[N:36][O:37][C:38]=1[CH3:39])=[C:32]=[O:33]>ClCCl>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][C:8]2[C:13]([C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:32]([NH:31][C:34]3[C:35]([CH3:40])=[N:36][O:37][C:38]=3[CH3:39])=[O:33])=[N:12][CH:11]=[N:10][C:9]=2[CH3:19])=[CH:5][CH:4]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: Cc1ncnc([C@H]2CCCN2)c1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncnc([C@H]2CCCN2C(=O)Nc2c(C)noc2C)c1Cc1ccc(Cl)cc1
Yield: 28.1 %

Procedure:
(R)-5-(4-chlorobenzyl)-4-methyl-6-(pyrrolidin-2-yl)pyrimidine hydrochloride (30 mg, 0.066 mmol) and N,N-diisopropylethylamine (0.041 mL) were dissolved in dichloromethane (2 mL). 4-isocyanato-3,5-dimethylisoxazole (15 mg, 0.11 mmol) was added while stirring. The reaction mixture was stirred for 16 h then evaporated to dryness. Purification by semi-preparative HPLC afforded the desired product (7.9 mg, 27.8%).