Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[F:32][C:29]([F:30])([F:31])[O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:18]2[CH2:17][CH2:16][N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=3)[CH2:20][CH2:19]2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OCc4ccccc4)cn3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
5′-Benzyloxy-4-(4-trifluoromethoxyphenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (0.93 g) and 10% palladium on carbon (93 mg) were added to ethanol (9.3 ml), and the mixture was stirred at room temperature under a hydrogen atmosphere (atmospheric pressure) for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→6:4). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow powder (0.55 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:14])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1Cl

Procedure:
4-chloro-3-methoxybenzyl alcohol (5 g, 1 equiv) in 15 mL of DCM was treated with thionyl chloride (5 mL, 3 equiv) at reflux for 2 hours. Evaporation of volatiles gave 4-chloro-3-methoxybenzyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14].[CH:15](OC)(OC)OC>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15]
Reactant: COC(OC)OC
Reactant: Nc1cnccc1-c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 14.9 g (72.8 mmol) 4-(2-chloro-phenyl)-pyridin-3-ylamine in 80 ml trimethyl orthoformate and 5 drops trifluoroacetic acid was heated for 2.5 h at 130° C. The reaction mixture was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 130 ml tetrahydrofuran and 220 ml (220 mmol) of 1 M borane-tetrahydrofuran complex were added dropwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated, cooled to 0° C. and 130 ml 5 N hydrochloric acid solution in ethanol were added carefully. The solution was refluxed for 1 h, cooled to room temperature again and crushed ice was added. The aqueous phase was washed with three 100 ml portions diethyl ether and the organic layers were extracted with 100 ml 1 N hydrochloric acid solution. The combined aqueous layers were adjusted to pH 8-9 by addition of concentrated sodium hydroxide solution and were extracted with three 500 ml portions ethyl acetate. The combined organic extracts were dried (magnesium sulfate), evaporated and the solid residue was recrystallized from hexane/ethyl acetate to give 12.3 g (77%) of the title compound as white crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[N:31]1[CH:36]=[CH:35][C:34]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)=[CH:33][CH:32]=1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Reactant: OB(O)c1ccncc1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccncc4)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 4-pyridylboronic acid by the method described for Example 36 Step 3. MS (ES+) 521 ([MH]+).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[H-].[Na+].[Br-].[Li+].Br[CH2:15][C:16]1[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>CN(C=O)C.CS(C)=O.CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]#[N:23])[C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: N#Cc1ccccc1CBr
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of 6-chlorouracil (20 g, 122 mmol) in a mixture of DMF-DMSO (6:1, 600 mL) under nitrogen at 0° C., was added sodium hydride (60%, 5.5 g, 137 mmol) in portions. After 0.5 h, lithium bromide (8 g, 96 mmol) was added into the mixture and stirred for 15 min at 0° C. A solution of α-Bromo-o-tolunitrile (25.1 g, 128 mmol) in DMF (30 mL) was added dropwise, and stirred at this temperature for 1 h, and then RT overnight. The mixture was evaporated and co-evaporated with water in vacuo to remove most of the DMF, and then poured into ice water (1 L). The precipitate was collected by filtration. The crude product was suspended in hot AcOEt-CHCl3 and sonicated for 5 min, allowed to stand at 0° C. for 1 h, and then filtered to give a white solid of the title compound (19 g) in 54% yield. 1H-NMR (400 MHz, DMSO): δ 11.82 (s, 1H), 7.87 (d, 1H, J=7.6 Hz), 7.71 (t, 1H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.37 (d, 1H, J=8 Hz), 6.06 (s, 1H), 5.31 (s, 2H). MS (ES) [m+H] calc'd for C12H9ClN3O2, 262.0; found 262.0.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])=[CH:17][CH:16]=1>C(O)C>[CH2:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([F:26])([F:22])([F:23])([F:24])[F:25])=[CH:17][CH:16]=3)[N:7]2[N:8]=1)[CH3:12]
Reactant: CCc1nc2nc(C)cc(Cl)n2n1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CCO
Product: CCc1nc2nc(C)cc(Nc3ccc(S(F)(F)(F)(F)F)cc3)n2n1
Temperature: 50 °C

Procedure:
A suspension of Intermediate 5 (80 mg, 0.407 mmol) and 4-aminophenylsulfur pentafluoride (MANCHESTER, 89 mg, 0.407 mmol) in ethanol (5 mL) was heated at 50° C. for 1 h, starting material dissolving during the process. The reaction mixture was concentrated under vacuum, redissolved in DCM (20 mL) and washed with aq. Na2CO3 (2×15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16](=[O:24])[C:17]([Cl:23])=[C:18]([Cl:22])[C:19](O)=[O:20])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[CH3:36])[CH3:26]>C(OC(=O)C)(=O)C>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2([C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]([CH2:25][CH3:26])[C:28]=4[CH3:36])[O:24][C:19](=[O:20])[C:18]([Cl:22])=[C:17]2[Cl:23])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCn1c(C)cc2ccccc21
Reactant: O=C(O)C(Cl)=C(Cl)C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(-c4ccccc4)[nH]c4ccccc34)OC(=O)C(Cl)=C2Cl)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 7.0 g (0.02 mole) of 4-(2-phenyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid (prepared in part A above), 3.5 g (0.02 mole of 1-ethyl-2-methylindole and 200 ml of acetic anhydride was stirred at ambient temperature in an atmosphere of air for approximately seventeen hours. The pale blue solid that formed was collected by filtration and dried in vacuo at 60° C. to obtain 5-(2-phenyl-3-indolyl)-5-(1-ethyl-2-methyl-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=Y=Y1 =H; R1 =C6H5 ; R2 =CH3CH2 ; R3 =CH3) as a tan-colored solid which started to sinter at 213° C. and was completely melted at 225° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([F:32])[CH:26]=1.Cl>CC(O)CCC>[ClH:2].[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:27]([F:32])[CH:26]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)cnnc2cc1OCCCN1CCCC1
Yield: 73.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (130 mg, 0.32 mmol), (prepared as described for the starting material in Example 13), and 4-chloro-2-fluoroaniline (70 mg, 0.48 mmol), in 2-pentanol (4 ml) and 5M isopropanolic hydrogen chloride (1 ml) was heated at 120° C. for 2.5 hours. The solid was filtered off, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (110 mg, 66%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([CH2:14][C:15]2[N:25]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]3[N:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:12][CH:11]=1.C(Cl)Cl>CN(C=O)C.CO>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][N:25]1[C:18]2[N:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH2:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)Cn1c(Cc2ccc(CBr)cc2)cc2cnc(C#N)nc21
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)Cn1c(Cc2ccc(Cn3cncn3)cc2)cc2cnc(C#N)nc21
Yield: 57 %

Procedure:
1,2,4-Triazole (0.6 mmol) is dissolved in DMF (1 ml) and sodium hydride (0.6 mmol) is added. The mixture is stirred and 6-(4-bromomethyl-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.5 mmol) in DMF (1 ml) is added at 0° C. The mixture is stirred at room temperature for 0.5 h, and quenched with H2O. The mixture is extracted with AcOEt. The organic layer is washed with water and brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 57% yield. Rf=0.50 (CH2Cl2:MeOH=9:1). 1H NMR (400 MHz, CDCl3) δ 1.04(s, 9H), 4.06(s, 2H), 4.22(s, 2H), 5.36(s, 2H), 6.22(s, 1H), 7.18(d, 2H), 7.23-7.39(m, 2H), 7.98(s, 1H), 8.09(s, 1H), 8.83(s, 1H).
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.Cl[CH:16]([CH3:19])[C:17]#[N:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([CH3:19])[C:17]#[N:18])[CH:10]=2)[O:3]1
Reactant: CC(Cl)C#N
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, Cat. No. 525057)(0.22 g, 1.1 mmol), 2-chloropropanenitrile (Aldrich, Cat. No. 192406) (0.12 g, 1.4 mmol), and cesium carbonate (0.82 g, 2.5 mmol) in acetonitrile (4.0 mL) was stirred at 80° C. for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product. LCMS (M+H)+=248.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[CH:5]=[CH:4][N:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(c2ccccc2)CCN(c2ccnc(Cl)n2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)CCN(c2ccnc(-c3ccc(F)cc3)n2)C(=O)O1
Yield: 25 %

Procedure:
To a solution of 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.165 mmol) and 4-fluorophenylboronic acid (32 mg, 0.33 mmol), K2CO3 (0.5 mL, 2 M) in 1,4-dioxane (1.5 ml) at 0° C. under N2 was slowly added Pd(Ph3)2Cl2 (10 mg, 20%). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2-(4-fluorophenyl)pyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (15 mg, yield 25%). 1H NMR (CDCl3, 400 MHZ): δ=1.75 (s, 3H), 2.4 (m, 1H), 2.54 (m, 1H), 3.6 (m, 1H), 4.4 (m, 1H), 7.1 (m, 2H), 7.25-7.4 (m, 5H), 8.08 (m, 1H), 8.34 (m, 2H), 8.62 (m, 1H). LC-MS Method 3, tR=1.519 min, m/z=364.1. 1H NMR (CDCl3) 1.80 (s, 3H), 2.40 (m, 1H), 2.60-2.70 (d, 1H), 3.60 (m, 1H), 4.40 (t, 1H), 7.10 (t, 2H), 7.20-7.45 (m, 5H), 8.17 (d, 1H), 8.35 (t, 2H), 8.65 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]2[N:9]=[CH:8][N:7](C(OC(C)(C)C)=O)[C:6]=2[CH:17]=1.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)n1cnc2c(NCCC(F)(F)F)cc(Br)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)CCNc1cc(Br)cc2[nH]cnc12
Reaction time: 2 h

Procedure:
To a stirred solution of intermediate tert-butyl 6-bromo-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazole-1-carboxylate (7.63 g, 18.69 mmol) in DCM (200 mL) at -rt was added water (20 mL) and TFA (200 mL). After stirring for 2 h, the solution was concentrated, ethyl acetate was added and the organic phase was washed with sodium carbonate solution and water. Evaporation of the yielded 5.17 g 6-bromo-N-(3,3,3-trifluoropropyl)-1H-benzimidazol-4-amine (89.8%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:29])[C@@H:15]1[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>N1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:29])[C@@H:15]1[CH2:19][C@@H:18]([O:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][N:16]1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
540 Grams (2.84 moles) of technical p-toluenesulfonyl chloride were charged to a 5 liter flask. 1.5 Liters of anhydrous pyridine was added and the flask swirled to dissolve. Gradually, 600 g (2.40 moles) of (trans)-1-benzoyl-4-hydroxy-L-proline methyl ester were added and dissolved by swirling. The clear solution was maintained at room temperature and the conversion followed by TLC. After the starting material completely disappeared, the reaction mixture was transferred to a 12 liter beaker with an efficient agitator. 0.8 Liters of ice water and some tosylate seeds were added. Thick crystal slurry formed in about 10 minutes. Strong agitation was maintained and another 7 liters of an ice-water mixture were added over a period of one hour. The crystals were collected on a filter, the cake pressed down and washed with cold water until the effluent was free of chloride ions and suction applied to the cake until no more liquid emerged. The filtrate was discarded and the product dried to constant weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[N:36]=[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:38][C:39]=1[CH3:40])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15](OCC)=[O:16])=[CH:11][N:10]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:9]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[N:36]=[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:38][C:39]=1[CH3:40])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:11][N:10]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)[N:9]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccc(C(F)(F)F)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2/C=C/CO)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoate (0.507 g) in tetrahydrofuran (50 mL) was added diisobutylaluminum hydride (0.95 M hexane solution, 7.0 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (2.14 g) was added to the reaction mixture, and the mixture was further stirred for 2 hrs. After removing the precipitate by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propen-1-ol as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless powder (0.300 g, yield 63%). melting point: 118-119° C.
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:15]1([CH2:21][N:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH:24]2[CH2:26][O:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CO.C1(C)C=CC=CC=1>[C:28]1([CH2:27][N:22]([CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:23][CH:24]([OH:25])[CH2:26][N:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:3]2=[O:2])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Reactant: Oc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1ncccn1CC(O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 55 °C
Yield: 45 %

Procedure:
A solution of 2-hydroxypyrimidine hydrochloride (1:1) (0.075 mol) in methanol (150 ml) was stirred for 30 minutes and then added to a solution of sodium carbonate (0.075 mol) in methanol (20 ml). The mixture was stirred and refluxed for 15 minutes, and cooled to 55° C. A solution of N,N-bis(phenylmethyl)oxiranmethanamine (0.075 mol) in toluene (160 ml) was added dropwise and the reaction mixture was stirred at 50° C. overnight. Water (75 ml) was added and the mixture was stirred at 55° C. for 15 minutes. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH3OH/CH2Cl2 97/3). The pure fractions were collected and the solvent was evaporated, yielding 11.8 g (45%) of (±)-1-[3-[bis(phenylmethyl)amino]-2-hydroxypropyl]-2(1H)pyrimidinone (interm. 2).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1)([O-:5])=[O:4].[CH3:16][O:17][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[CH3:16][O:17][C:18](=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:11]1[C:10]2[CH:15]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=2[O:13][C:12]1=[O:14]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)oc2ccc([N+](=O)[O-])cc21

Procedure:
The product is produced as described in example 1 from 6 g. of NaH (80% suspension in mineral oil), 36 g. of 5-nitrobenzoxazolin-2-one (produced in usual manner by reacting 2-amino-4-nitrophenol-hydrochloride with phosgene), 400 cc. of DMF, 47.4 g. of 8-bromo caprylic acid methyl ester and 6 g. of NaJ.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH3:39][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4cccc5ccccc45)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3cccc4ccccc34)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-methyl-2-(4-{2-[5-methyl-2-(3-naphthalen-1-ylphenyl)oxazol-4-yl]ethoxy}phenoxy) propionic acid ethyl ester (0.711 mmol) in ethanol (8.9 mL) was treated with NaOH(aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield a white, crystalline solid: Rf=0.22 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.90-7.82 (m, 3H), 7.90-7.39 (m, 6H), 6.86-6.75 (m, 4H), 4.16 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.35 (s, 3H), 1.47 (s, 6H); MS (EI) 508.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:33]1([C:39]#[CH:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O.CCCCCC.[Cu](I)I>[C:33]1([C:39]#[C:40][C:12]2[C:9]3[CH2:10][CH2:11][N:5]([C:3](=[O:4])[C:2]([F:25])([F:24])[F:1])[CH2:6][CH2:7][C:8]=3[CH:15]=[CH:14][CH:13]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(N1CCc2cccc(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(N1CCc2cccc(C#Cc3ccccc3)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
Combine 3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.75 mmol), dichlorobis(triphenylphosphine)-palladium(II) dichloromethane adduct (54 mg, 0.08 mmol), copper iodide (42 mg, 0.23 mmol) and tetrabutyl ammonium iodide (830 mg, 2.25 mmol) in DMF (3.3 mL) containing triethylamine (0.67 mL) and stir the mixture for 5 min at room temperature. Add phenylacetylene (0.17 mL, 1.5 mmol) and heat the mixture to 70° C. under nitrogen atmosphere for 16 h. Cool the reaction to room temperature and dilute with EtOAc/hexane (1:1, 250 mL). Filter the slurry through Celite®. Wash the filtrate with water (2×300 mL), dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 9:1) to afford 6-phenylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (251 mg, 98%) as a yellow oil.