Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2]N.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:20]=[C:21]([C:22](/[N:24]=[CH:25]/[N:26](C)C)=O)[C:16]=2[N:15]=[C:14]1[CH3:35].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:20]=[C:21]([C:22]3[N:24]=[CH:25][NH:26][N:2]=3)[C:16]=2[N:15]=[C:14]1[CH3:35]
Reactant: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
Hydrazine monohydrate (2 mL) was added to a solution of 1-[(2,3-dichlorophenyl)methyl]-N-[(1E)-(dimethylamino)methylidene]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxamide (220 mg, 0.46 mmol) in acetic acid (5 mL) and stirred at 130° C. for 20 min. The reaction mixture was cooled to rt and poured into saturated NaHCO3 solution (15 mL). The mixture was extracted with DCM (30 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluted with DCM:MeOH=30:1 to give the desired product (110 mg, 53%), as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.50 (s, 3H), 3.12 (t, 4H, J=4.8 Hz), 3.75 (t, 4H, J=4.8 Hz), 5.62 (s, 2H), 6.36 (d, 1H, J=8.1 Hz), 7.21 (s, 1H), 7.27 (t, 1H, J=8.1 Hz), 7.54 (s, 1H), 7.61 (d, 1H, J=8.1 Hz), 8.08 (s, 1H), 13.80 (s, 1H); LC-MS: m/e=443 [M+1]+.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:18][C:17](=[O:33])[C@@H:16]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39])=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C@H:16]1[C:17](=[O:33])[O:18][C@H:19]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:15]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCCCCCl)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@H](c2ccccc2)[C@H](c2ccccc2)N[C@H]1CCCCCCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of TFA in DCM (20%, 60 mL) is added at 0° C. to (3S,5S,6R)-3-(5-chloro-pentyl)-2-oxo-5,6-diphenyl-morpholine-4-carboxylic acid tert-butyl ester (8.0 g, 17.5 mmol). The reaction mixture is slowly warmed up to room temperature and stirred for 4 hours. The reaction mixture is poured into a saturated K2CO3 solution, the two phases are separated and the water phase is extracted with DCM twice. The combined organic phases are dried over anhydrous Na2SO4 and removal of the solvent under reduced pressure affords 6.0 g of (3S,5S,6R)-3-(5-Chloro-pentyl)-5,6-diphenyl-morpholin-2-one trifluoroacetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10](O)([CH3:11])[CH2:9][CH2:8][N:7]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5])[CH3:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:11])=[CH:9][CH2:8][N:7]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:14])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1N(S(=O)(=O)c2ccc(C)cc2)CCC1(C)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1C(C)=CCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
The pyrrolidine oil 82 (10.5 g, 32.11 mmol) was dissolved in pyridine (86 mL). POCl3 (7.48 mL, 80.27 mmol) was added dropwise and the resulting mixture stirred overnight at room temperature. The mixture was poured over ice, extracted with ether and washed with 5% aq. HCl, 5% sodium bicarbonate solution and water. The ether layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the crude solid 83 (8.80 g, 88%). 1H-NMR (400 MHz, CDCl3): δ 1.28 (t, 3H), 1.69 (m, 3H), 2.43 (s, 3H), 4.10 (m, 1H), 4.20 (q, 2H), 4.21 (m, 1H), 7.31 (d, 2H), 7.75 (d, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ 13.58, 14.10, 21.56, 54.64, 61.62, 70.55, 110.02, 122.51, 127.51, 129.73, 169.87 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 13.58, 14.10, 21.56; CH2 carbons: 54.64, 61.62; CH carbons: 70.55, 122.51, 127.51, 129.73 ppm. LC/MS: 100%, m/z=309.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:27]1([C:33]2[CH:37]=[C:36]([CH2:38][NH2:39])[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)CCC>[Cl:17][C:4]1[N:3]=[C:2]([NH:39][CH2:38][C:36]2[O:35][N:34]=[C:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:37]=2)[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=1
Reactant: NCc1cc(-c2ccccc2)no1
Reactant: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2cc(-c3ccccc3)no2)n1
Temperature: 90 °C
Reaction time: 30 h
Yield: 60.9 %

Procedure:
To a solution of 2,6-dichloropyrimidin-4-yl-(5-cyclopropyl-1H-pyrazol-3-yl)-amine (19.3 g, 71.7 mmol) in 1-butanol (200 mL) was added diisopropylethylamine (23.7 mL, 143 mmol) and 3-phenylisoxazol-5-ylmethylamine (15.0 g, 86.1 mmol). The mixture was stirred at 90° C. for 30 h, then concentrated on a rotary evaporator. The residue was taken up in 100 mL of methanol and boiled until the volume reached around 50 mL. The solution was allowed to cool to room temperature and then placed in the refrigerator overnight. The solid that formed was collected by filtration, while the filtrate was dissolved in dichloromethane and sonicated. The solid that formed was collected and combined with the first recrystallized crop to give the desired product (17.8 g, 61%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9]C#N)=[CH:5][CH:4]=1.Cl.O.[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][C:16]([OH:17])=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCCC#N)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OCCC(=O)O)cc1
Temperature: 100 °C
Yield: 86.04 %

Procedure:
A 945 g (5.34 mol, 1 eq.) sample of 1 (3-(4-methoxyphenoxy)propionitrile (1)) was charged to a 22 L round bottom flask equipped with an overhead stirrer under N2. To the stirred solids, 4 L of concentrated HCl was slowly added, followed by 2 L of H2O. The reaction mixture was heated to 100° C. for 3.5 h, at which point the reaction was complete by HPLC analysis. The reaction was cooled to 10° C. by the addition of ice to the reaction mixture, and was filtered. The dried solids gave 920 g of crude 2. The crude material was dissolved in 5 L of 6 wt. % sodium carbonate (such that pH=9), and 2 L of DCM (dichloromethane) was added to the reaction vessel. After stirring thoroughly, the organic layer was separated and discarded via a separatory funnel, and the aqueous layer charged back into the 22 L flask. The pH of the aqueous layer was carefully adjusted to 4.0, by slow addition of 6 M HCl. The precipitated solids were filtered, and dried in a vacuum oven to give 900 g of 2 as a white solid (Yield: 86.04%). 1H NMR (450 MHz, CDCl3); δ=2.78 (t, 2H; CH2COOH); 3.70 (s, 3H; OCH3); 4.18 (t, 2H; OCH2); 6.78 (m, 4H; Ar—H); 13C NMR (112.5 MHz, CDCl3): δ=34.703 (CH2COOH); 55.925 (OCH3); 64.088 (OCH2); 114.855 (CH3OCCH); 115.984 (CH2OCCH); 152.723 (CH3OC); 154.302 (CH2OC); 177.386 (COOH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.O.C(=O)(O)[O-].[Na+].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O1CCOCC1>[C:31]([N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1)[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:33])[CH3:32]
Reactant: O=C1NC(=O)C(Cc2ccc(OCCNc3ncccn3)cc2)S1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
A stirred solution of 5-[4-(2-(2-pyrimidinylamino)ethoxy)benzyl]-2,4-thiazolidinedione (800mg) in acetic anhydride (15 ml) and 1,4-dioxan (5 ml) was boiled under reflux for 3 hours. After cooling, the mixture was added to water (300 ml), neutralized (sodium bicarbonate) and extracted with dichloromethane (3×200 ml). The organic extracts were washed with brine (100 ml), dried (MgSO4), filtered and evaporated to dryness. Chromatography on silica-gel in dichloromethane of the residual oil afforded the title compound (m.p. 137° C.).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N([CH2:27][CH3:28])CC)C.C(Cl)Cl.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:32]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:21][CH2:2][CH2:3][CH2:4][CH2:27][CH3:28]
Reactant: OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCN(CC)CC
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (2.0 g, 6.84 mmol), triethylamine (1,0 g, 10 mmol) in DCM (70 ml) decanoyl chloride (1.7 g, 8.9 mmol) was added dropwise at room temperature. The mixture was stirred for 1 hour., then was concentrated to a crude solid. The solid was extracted into ethyl acetate, and the insoluble salts were filtered. The solvents were removed. The crude product was purified by flash chromatography (Sorbsil C-30, 30 g, eluted with a mixture of MeOH in DCM). The oil thus obtained (2.5 g, 81%) was converted to a fumarate salt with fumaric acid (650 mg, 1.0 eq) in ethanol. Crystals were collected: 1.48 g, m.p.=109°-110° C.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH3:30])[C:24]=1[N+:31]([O-:33])=[O:32]>CN(C=O)C>[CH3:30][NH:29][C:25]1[C:24]([N+:31]([O-:33])=[O:32])=[C:23]([O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:14][CH:13]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CNc1nccc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 59.5 %

Procedure:
N-Boc-4-hydroxyaniline (334 mg, 1.6 mmol) was dissolved in dry DMF (5 mL) and the solution was degassed by argon bubbling for 10 minutes. Potassium tert-butoxide (179 mg, 1.6 mmol) was added, and the stirring and argon bubbling continued for 50 minutes. 4-Chloro-N-methyl-3-nitropyridin-2-amine (260 mg, 1.4 mmol) was added to the reaction mixture. The reaction mixture was heated and stirred at 80° C. for 9 hours, under argon. The solvent was evaporated and the residue was extracted between DCM and aqueous NaOH 1M. The extraction was repeated twice, the organic layer was dried over MgSO4, and evaporated. The residue was purified by column chromatography (eluent gradient DCM to DCM:AcOEt 15:1) to afford the title compound (300 mg, 60%). 1H-NMR (δ, ppm, DMSO-d6): 1.48 (s, 9H, t-Bu), 2.91 (d, 3H, Me, J=4.60 Hz), 5.94 (d, 1H, HPy,5, J=5.70 Hz), 7.09 (d, 2H, Harom,Ph,3+5, J=9.00 Hz), 7.45 (m, 1H, NHPy), 7.53 (d, 2H, Harom,Ph,2+6), 8.07 (d, 1H, HPy,6), 9.46 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=O)OC(C)(C)C)[CH2:12]3)=[N:7][C:6]=12.IC.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12]3)=[N:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
(S)-tert-butyl (1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate (3.6 g, 9.4 mmol) taken up in 15 mL DMF and cooled to 0° C. in an ice bath. Iodomethane (1.026 mL, 16.5 mmol) added and stirred 5 minutes. Then sodium hydride 60% in oil (754 mg, 18.8 mmol) was slowly added. Reaction stirred 5 minutes at 0° C. then removed from ice bath and stirred 30 minutes at room temperature. Reaction was quenched with ice then extracted with ethyl acetate 2×. Ethyl acetate fractions combined dried over magnesium sulfate filtered reduce in vacuo. This was then taken up in 26 mL DCM and 4 mL TFA added. Stirred 1 hour until complete by LC/MS. Reaction washed with 1N NaOH, DCM layer removed dried over magnesium sulfate filtered, reduced in vacuo to get 2.72 g crude product carried on as is to part C. LRMS (ESI) m/z 296/298 [(M+H)]+, calc'd for C11H14BrN5: 296.17.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 63.2 %

Procedure:
Following general procedure II, (R)-tert-butyl[1-(5-{[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (150 mg, 0.29 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (120 mg, 0.43 mmol) to afford the product (119 mg, 64%) as an orange solid: ESI MS m/z 649 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=C)=[CH:7][CH:6]=1.[OH:13]C1C=CC(C=O)=CC=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:13])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OCCO)cc1
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(OCCO)cc1

Procedure:
Ueno et al. (U.S. Pat. No. 6,340,759) also describe a two-step procedure for preparing p-(2-hydroxyethoxy)styrene starting with p-hydroxybenzaldehyde. In the first step, p-(2-hydroxyethoxy)benzaldehyde is formed by reacting p-hydroxybenzaldehyde, sodium hydride, and (2-bromoethoxy)-tert-butyldimethylsilane. In the second step, p-(2-hydroxyethoxy)styrene is formed by reacting the isolated p-(2-hydroxyethoxy)benzaldehyde with (ethyl)triphenylphosphonium bromide in the presence of sodium hydride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[C:22]([CH2:27][NH2:28])=[N:23][CH:24]=[CH:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:22]2[C:21]([CH3:20])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: Cc1cccnc1CN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(3-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+]([O-])(O)=O.[N+]([O-])([O-])=O.[Ag+:23]>C(OCCCC)(=O)C>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Ag+:23]
Reactant: CCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: CCCCOC(C)=O
Product: CCCCCCCCCCCC(=O)[O-]

Procedure:
11 g of lauric acid was dissolved in 100 ml of butyl acetate and the resulting solution was kept at 10° C. To the solution were added with stirring by means of a stirrer 100 ml of a dilute aqueous solution of nitric acid (25° C, pH = 2.0) and 50 ml of an aqueous solution of silver ammonium complex salt containing 8.5 g of silver nitrate (cooled to 0° C) for 1 minute, thus reacting the lauric acid and the silver ion and obtaining spindle-shaped silver laurate crystals having a length of about 1 micron and width of about 0.05 micron. After washing this silver salt with water and further with methanol, 3.0 g of polyvinyl butyral and 20 ml of isopropyl alcohol were added to 2.7 g of the silver laurate and dispersed in a ball mill to prepare a silver salt polymer dispersion.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH:36]=O)[CH:33]=[C:32]([O:38][CH2:39][CH3:40])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16].[C:41]1([NH2:48])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47].O>C(#N)C>[NH:47]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:48]=[C:36]1[C:34]1[CH:35]=[C:30]([CH:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:22][CH:21]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:31]=[C:32]([O:38][CH2:39][CH3:40])[CH:33]=1
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C=O)cc(OCC)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in acetonitrile (1.5 ml) was added dropwise very slowly (2 h.) to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-formyl-phenyl)-acetate (460 mg, 1.305 mmol) obtained in Example 244.1 and 1,2-phenylenediamine in acetonitrile (2 ml). The reaction mixture was stirred for 4 h. at room temperature. Water/saturated Na2CO3 solution (1:1) was added and the mixture was extracted with CH2Cl2. The organic phase was washed with H2O, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 3:2). There were obtained 173 mg (30%) of ethyl (RS)-[3-(1H-benzoimidazol-2-yl)-5-ethoxy-phenyl]-(4-cyano-phenylamino)-acetate as a colorless solid; MS: 441 ([M+H]+).
Reaction SMILES: [Br-].[CH2:2]([Li])CCC.[PH4+].[CH2:8]([C:12]1[NH:13][C:14]2[C:19]([C:20](=[O:22])[N:21]=1)=[CH:18][C:17]([CH:23]=O)=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH3:11]>O1CCCC1>[CH2:8]([C:12]1[NH:13][C:14]2[C:19]([C:20](=[O:22])[N:21]=1)=[CH:18][C:17]([CH:23]=[CH2:2])=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH3:11]
Reactant: [Li]CCCC
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Agent: [Br-]
Agent: [PH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
To a suspension of 15.14 g of mothyltriphenylphosphonium bromide in tetrahydrofuran, cooled to -78° C., is slowly added 21.73 ml of 1.95 M n-butyllithium in hexanes. The reaction mixture is allowed to warm to room temperature and stirred until all of the phosphonium salt dissolves. This takes approximately 30 minutes. The reaction mixture is cooled to -78° C. and 1.95 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde added in one portion as a solid. The reaction mixture is allowed to warm to room temperature and stirred for 18 hours. The reaction mixture is quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The organic layer is separated, washed with briner dried with MgSO4 and concentrated in vacuo to a residue which is purified by chromatography on silica gel using 1:3 ethyl acetate-hexanes to give 2.48 g of the desired product as a solid. CI MASS SPEC 229 (M+H)
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1.[CH3:12]N(C=O)C.C[Sn](C)(C)C>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.CO.C(Cl)(Cl)Cl>[CH3:12][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: Nc1cc(Br)c2[nH]cnc2c1
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(N)cc2nc[nH]c12
Temperature: 140 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To the solution of 4-bromo-6-aminobenzimidazole (0.85 g, 6.0 mmol) in sealed tube with 10 ml of DMF was added tetramethyltin (1.7 ml, 12 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.20 g). The resulting reaction mixture was stirred for 12 h at 140° C. and concentrated in vacuo, yielding oily residue which was subjected to column chromatography (5% MeOH/CHCl3)to produce 0.28 g (45%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:9]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[F:25][C:26]([F:47])([F:46])[C:27]1[CH:28]=[C:29]([C@@H:37](OC(=N)C(Cl)(Cl)Cl)[CH3:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:46])([F:47])[C:27]1[CH:28]=[C:29]([C@H:37]([O:14][C@H:13]2[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH3:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O)CC[C@@H]1C(=O)OCC
Product: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC

Procedure:
The title compound was prepared from the first eluting isomer diethyl (1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step G) and (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (Example 6, step E) according to the procedure of Example 6, step F. 1H-NMR (CDCl3): δ: 7.65 (1H, s), 7.15 (2H, s), 7.08–6.92 (4H, m), 4.25 (1H, q, J=6.0 Hz), 4.20–4.10 (2H, m), 3.85–3.66 (2H, m), 3.42 (1H, m), 3.21 (1H, t), 2.90–2.79 (2H, m), 2.35 (1H, m), 2.25 (1H, m), 2.22 (3H, s), 1.69–1.56 (2H, m), 1.30 (3H, d, J=6.0 Hz), 1.23 (3H, t, J=7.2 Hz), 0.77 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH3:18])[CH3:17])[O:12][C:11]1=[O:19].C(=O)([O-])[O-].[Na+].[Na+].[CH2:26](Br)[C:27]#[CH:28]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:28][C:27]#[CH:26])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH3:17])[CH3:18])[O:12][C:11]1=[O:19]
Reactant: C#CCBr
Reactant: CC(C)=C1OC(=O)N(c2cc(O)c(Cl)cc2F)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CCOc1cc(N2C(=O)OC(=C(C)C)C2=O)c(F)cc1Cl
Yield: 65 %

Procedure:
To an acetonitrile solution (30 ml) of 3-(2'-fluoro-4'-chloro-5'-hydroxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (0.72 g, 2.5 mmol) was added sodium carbonate (0.16 g), and the mixture was heated at reflux for 1 hour. After the addition of propargyl bromide (0.36 g, 3.0 mmol), the reaction mixture was further refluxed for 1 hour. After the solution was quenched with 0.1N hydrochloric acid, the product was extracted with chloroform. The extracts combined were dried and evaporated as small a volume as possible. The resulting pale yellow oil was purified by silica gel column chromatography to give pure 3-(2'-fluoro-4'-chloro-5'-propargyloxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione. (0.53 g, 65% yield)