Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:24]([F:29])([F:28])[C:23]([F:31])([F:30])[C:22]([F:33])([F:32])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc21

Procedure:
The procedure of Preparation Example 1 (6) was repeated using 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester, potassium heptafluorobutyrate, cuprous iodide, toluene and N,N-dimethylformamide to give 2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1-benzopyran-4-carboxylic acid ethyl ester as an oil;
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]2[N:13]=[CH:14][C:15](I)=[CH:16][C:6]1=2.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]2[N:13]=[CH:14][C:15]([C:35]3[CH:34]=[CH:33][C:32]([C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:31])=[CH:37][CH:36]=3)=[CH:16][C:6]1=2
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC1(C)CN(Cc2cc(F)ccc2F)c2cc(I)cnc2N1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)ccc3F)CC(C)(C)N4)cc2)CC1
Yield: 55 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (44 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as an off-white solid (55% yield). M.p. 191-192° C., LCMS: m/z=492.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.34 (s, 6H), 2.32 (s, 3H), 2.38-2.50 (m, 4H), 3.13 (s, 2H), 3.45-3.58 (m, 2H), 3.65-3.85 (m, 2H), 4.52 (s, 2H), 4.90 (bs, 1H), 6.79 (d, J=1.3 Hz, 1H), 6.90-6.97 (m, 1H), 6.99-7.08 (m, 2H), 7.42 (dd, J=8.6 Hz, 4H), 7.74 (d, J=1.5 Hz, 1H).
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:13]4[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: NCc1ccncc1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ccncc1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-4-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 43% yield: mp >200° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55-8.53 (m, 2H), 7.23 (d, J=6.0 Hz, 2H), 6.17-6.13 (m, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.14-4.09 (m, 2H), 3.73-3.68 (m, 2H), 3.18 (d, J=7.1 Hz, 2H), 2.62 (s, 3H), 0.99-0.91 (m, 1H), 0.60-0.54 (m, 2H), 0.27-0.22 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.8, 157.5, 155.2, 153.9, 149.9, 147.5, 122.2, 116.4, 48.6, 42.6, 42.2, 42.1, 17.3, 8.9, 3.4; MS (ES+) m/z 372.2 (M+1).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.O.ON1C2C=CC=CC=2N=N1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([OH:36])=O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH:5]2[CH2:4][N:3]([CH3:2])[C:34](=[O:36])[CH2:33][C:29]1[S:28][CH:32]=[CH:31][CH:30]=1
Reactant: CNCC1CCCc2c(OC)cccc21
Reactant: O=C(O)Cc1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CCCC2CN(C)C(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
The product from Example 17 (1.04 g), 1-hydroxybenzotriazole hydrate (1.51 g) and 2-thiopheneacetic acid (720 mg) in dry THF (30 ml) at 0° C. was treated with dicyclohexylcarbodiimide (1.16 g). The reaction was warmed to room temperature and stirred for 18 hr. The mixture was filtered and concentrated. The residue was dissolved into EtOAc (60 ml) washed with 5% aq. HCl (15 ml), water (15 ml), 10% aq. KOH (15 ml), dried (MgSO4) filtered and concentrated. Chromatography on SiO2 afforded 1.58 g of product as a viscous oil.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[NH:5]2.[C:15]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16]([C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:27](C(Cl)=O)=[C:26]([Cl:33])[CH:25]=2)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1>>[CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[CH2:9][N:8]([C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:16]3[C:15]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])=[CH:25][C:26]=1[Cl:33])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[NH:5]2
Reactant: c1ccc2c(c1)NCc1cscc1N2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Product: O=C(Nc1ccc(N2Cc3cscc3Nc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 400, 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine is reacted with 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride to give the product as a solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:11]=1.[Li+].[OH-]>C1COCC1.CO.O>[F:21][C:2]([F:1])([F:20])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:11]=1
Reactant: CCOC(=O)c1cnc2ccc(COCC(F)(F)F)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc2ccc(COCC(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (97) (280 mg, 0.92 mmol) in THF/MeOH/H2O (3:2:1, 5 mL) was treated with 6N LiOH (0.92 mL, 5.52 mmol) and stirred at room temperature for 1 hour. All solvents were removed and 6N HCl was added to adjust pH 5-6. Then the mixture was purified by HPLC to give 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (98). 1H NMR (400 MHz, d6-DMSO) δ 9.34 (m, 1H), 8.40 (s, 1H), 7.88 (dd, J=0.8, 9.2 Hz, 1H), 7.65 (dd, J=1.6, 9.2 Hz, 1H), 4.83 (s, 2H), 4.18 (q, J=9.6 Hz, 2H). MS m/z 275.1 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.O>[N:20]([CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4])=[N+:21]=[N-:22]
Reactant: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCC(=O)N1CC(c2ccccc2)c2ccccc21
Yield: 68.3 %

Procedure:
A solution of 4.0 g of N-chloracetyl-3-phenylindoline and 1.1 g of sodium azide in 70 ml of 80% aqueous ethanol was refluxed for one hour. After cooling, the solution was diluted with 100 ml of water and extracted with methylene chloride. Evaporation of the solvent gave 2.8 g of the desired N-azidoacetyl-3-phenylindoline having a melting point of 72°-3° C.
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10](=[O:28])[C@@H:11]([NH:16][C:17](=[O:27])[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5][N:4]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:4]2[CH2:5][CH2:6][CH2:7][CH:8]([NH:9][C:10](=[O:28])[C@@H:11]([NH:16][C:17](=[O:27])[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2](=[O:1])[CH2:3]2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCC(NC(=O)[C@H](CC(C)C)NC(=O)COCc3ccccc3)C(O)C2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCC(NC(=O)[C@H](CC(C)C)NC(=O)COCc3ccccc3)C(=O)C2)cc1
Reaction time: 0.5 h

Procedure:
(S)-2-(2-Benzyloxy-acetylamino)-4-methyl-pentanoic acid [3-hydroxy-1-(4-methoxy-benzenesulfonyl)-azepan-4-yl]-amide (compound 207c, 0.24 g, 0.44 mmol) was dissolved in CH2Cl2 (5 ml), then Dess-Martin periodinane (0.3 g, 0.7 mmol) was added and the reaction was stirred for 30 min. The reaction was diluted with CH2Cl2 (20 ml), then was extracted with aqueous 10% Na2S2O5 (10 ml), then aqueous 10% NaHCO3 (10 ml), water (10 ml), brine (10 ml). The combined organics were concentrated in vacuo. The residue was purified by HPLC (50:50 Ethanol:hexanes, 20 mL/min, 25 min, WhelkO-1(R,R) 21×250 mm column, UV detection at 280 nm and 305 nm) to yield the first elution as a white solid (47 mg, 43%): MS 560.4 (M+H+). 1H NMR (400 Hz,CDCl3): δ 7.73 (d, 2H), 7.40-7.30 (m, 5H), 7.05 (d, 2H), 3.99 (s, 2H), 3.88 (s, 3H), 2.28-2.10 (m, 2H), 0.95 (t, 6H), and second eluting diastereomer: MS 560.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:42](=[O:44])[CH3:43])=[CH:21][C:20]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
The 3-(4-amino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (5.56 g, 11.3 mmol) was dissolved in 100 mL methylene chloride, and triethylamine (2.8 mL) is added. One equivalent of acetyl chloride was added and stirred at room temperature. Additional portions of acetyl chloride were added approximately every 30 min until the starting material was consumed. (A total of 1.5 equivalents of acetyl chloride was used over about 2 hours.) The solvent was removed and replaced with ethyl acetate. The organic solution was washed twice with 5% cold HCl, then once with water, once with saturated potassium carbonate, then once with brine. The solution was dried over anhydrous magnesium sulfate, filtered and the solvent removed. The product was chromatographed with 30% chloroform/ethyl acetate, to yield 5.16 g (85%) of 3-(4-acetylamino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic tert-butyl ester acid as a yellow foam. 1H NMR (CDCl3) 7.73 (1H, d, J=8.42 Hz), 7.6-7.5 (4H, m), 7.5-7.3 (3H, m), 6.9 (1H, d, J=8.6 Hz), 5.85 (1H, d, J=9.52), 5.3-5.1 (2H, m), 4.8-4.6 (1H, m), 3.56 (3H, s), 2.92 (3H, s), 2.7-2.38 (2H, m), 2.14 (3H, s), 1.40 (9H, s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:34])=[C:15]([CH3:33])[C:16]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28]C)=[C:21]([CH:30]([CH3:32])[CH3:31])[CH:20]=1)=[O:18].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:34])=[C:15]([CH3:33])[C:16]=1[C:17]([C:19]1[CH:20]=[C:21]([CH:30]([CH3:31])[CH3:32])[C:22]([OH:28])=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=1)=[O:18]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc4ccccc4c3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 53.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (1.04 g, 2.29 mmol) and 1M boron tribromide/CH2Cl2 (4.81 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.542 g (54%) of the title compound. 1H NMR (DMSO-d6) δ1.12 (d, 12H), 1.82 (s, 3H), 2.18 (s, 3H), 3.31 (septet, 2H), 4.02 (s, 2H), 7.22 (dd, 1H), 7.43-7.50 (m, 4H), 7.55 (s, 1H), 7.76-7.86 (m, 3H), 9.12 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=C[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]#[N:4].CC(C1C=CC=CC=1)=C.C(#N)C=C>>[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:3](#[N:4])[CH:2]=[CH2:1]
Reactant: CC(C#N)=CC=Cc1ccccc1
Agent: C=C(C)c1ccccc1
Solvent: C=CC#N
Product: C=Cc1ccccc1

Procedure:
Molding was carried out using a resin composition composed of 80% by weight of α-methylstyrene-acrylonitrile copolymer having a composition consisting of 78% by weight of α-methylstyrene and 22% by weight of acrylonitrile, which contained 42% by weight of a copolymer component having a composition containing 82% by weight of α-methylstyrene, and 20% by weight of a graft copolymer obtained by graft polymerization of 60% by weight of polybutadiene rubber with 28% by weight of styrene and 12% by weight of acrylonitrile. The HDT of the resulting sample was 118° C. (Sample No. 7)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][O:19][CH2:20][C:21]1[C:26]([C:27](O)=[O:28])=[CH:25][N:24]=[C:23]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:22]=1.COC(=O)CC(=O)COC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:27]([C:26]2[C:21]([CH2:20][O:19][CH3:18])=[N:22][C:23]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[N:24][CH:25]=2)=[O:28])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Agent: COCC(=O)CC(=O)OC
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2COC)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 4-methoxy-3-oxo-butyric acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:16][OH:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([CH2:16][OH:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
Reactant: OCC1(CNc2cccc(Br)n2)CCOCC1
Reactant: OB(O)c1cc(F)ncc1Cl
Product: OCC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1

Procedure:
Following the same procedure as in Example 1b using (4-((6-bromopyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-yl)methanol (from step 3) and 5-chloro-2-fluoropyridin-4-ylboronic acid, the desired product was obtained. LCMS (m/z): 352 (MH+), retention time=0.54 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24](O)=O)=[CH:20][CH:19]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CN1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:22][CH:23]=3)[CH3:17])[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(C=C(C)c3ccc(C(=O)O)cc3)cnc2n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NCc1ccc(C(C)=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine in 50 mL of N-methylpyrrolidinone containing 0.18 g of N-methylmorpholine was added 0.22 g of phenyl N-phenylphosphoramidochloridate in a single portion. After stirring the mixture at room temperature for 1 hour, 0.20 g of diethyl L-glutamate was added. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure and the residue was triturated with chloroform. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to preparative thin layer chromatography on silica gel using a 5% methanol in chloroform mixture as the eluent. This gave 74.6 mg (25%) of the title compound as a pale yellowish solid; NMR (CDCl3, 250 MHz) d 1.22 (t, 3H, J=7.1 Hz), 1.30 (t, 3H J=7.1 Hz), 2.11-2.57 (m, 10H), 4.14 (q, 2H, J=7.1 Hz), 4.24 (q, 2H, J=7.1 Hz), 4.75-4.83 (m, 1H), 6.86 (brs, 1H), 7.18 (brs, 1H), 7.57 (d, 2H, J=8.42 Hz), 7.84 (d, 2H, J=8.42 Hz), 8.50 (d, 1H, J=2.01 Hz), 8.96 (brs, 1H), 10.34 (brs, 1H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C@H:14]([NH:18][C:19](=O)OC(C)(C)C)[CH2:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1>[CH3:19][NH:18][C@H:14]1[C:15]2[C:10](=[CH:9][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:17][CH:16]=2)[CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CN[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Reaction time: 2 h

Procedure:
In 50 mL of dry toluene, 2.0 g (5.8 mmol) of (R)-tert-butyl 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate and 1.5 g (41 mmol) of lithium aluminum hydride were combined and gently refluxed for 24 h. Next the mix was quenched with 5 g of sodium sulfate decahydrate and allowed to stir for 2 h. The mix was then filtered over celite and the pad was washed with ethyl acetate several times. The filtrate was then concentrated and the crude was purified on silica using 0 to 5% MeOH (10% ammonium hydroxide) in ethyl acetate to give the product. MS 259 (ESI, pos. ion).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH:53]1([C:58](Cl)=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([C:58]([CH:53]5[CH2:57][CH2:56][CH2:55][CH2:54]5)=[O:59])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Cl)C1CCCC1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(C1CCCC1)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) with diethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Cyclopentane carbonyl chloride (80 μl, 0.6 mmol) was added and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E43); MS (ES+) m/e 397 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[N:7]([CH3:12])[C:8](=O)[CH2:9][O:10][C:5]=2[CH:4]=1.CSC.B>C1COCC1>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[N:7]([CH3:12])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OCC(=O)N2C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc2c(c1)OCCN2C
Yield: 9.2 %

Procedure:
7-Methoxy-4-methyl-4H-benzo[1,4]oxazin-3-one (13.07 g, 0.68 mol) was added to 100 mL dry THF, and the reaction mixture was refluxed under nitrogen. Borane-dimethyl sulfide (13.6 mL, 0.136 mol) was added dropwise over one hour, and the reaction mixture was allowed to reflux for two hours. The reaction mixture was cooled and then quenched by addition of 50 mL of 10% aqueous HCl. Precipitate was removed by filtration, and the liquid was concentrated under reduced pressure to give 11.17 g of 7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine. (M+H)=180.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.C([O-])(=O)C.[NH4+].[N+:25]([CH3:28])([O-:27])=[O:26]>>[N+:25]([CH:28]=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=2)=[CH:11][CH:12]=1)([O-:27])=[O:26]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Entire reaction was performed under argon using syringe septa technique. 4-(5-trifluoromethyl-pyridin-2-yloxy)-benzaldehyde (2.170 mmol, 1 eq) and ammonium acetate (1.736 mmol, 0.8 eq) were dissolved in nitromethane (3 ml) and reaction mixture was stirred at 95° C. overnight. The volatile was removed in vacuo and the residue was partitioned between DCM and water. Organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated giving 2-[4-(2-nitro-vinyl)-phenoxy]-5-trifluoromethyl-pyridine (1.225 mmol, yield=56%, purity=95%). [M+H]+=311.23 1H NMR (300 MHz, DMSO-d6) δ/ppm 7.27-7.36 (m, 3H), 7.91-7.98 (m, 2H), 8.24-8.30 (m, 1H), 8.55-8.62 (m, 1H)
Reaction SMILES: [CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:5][CH:6]=[C:7]([CH:9]=O)[CH:8]=1)[CH3:2].C1(P(=[CH:34][CH:35]=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:5][CH:6]=[C:7]([CH:9]=[CH:34][CH:35]=[O:36])[CH:8]=1)[CH3:2]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC[Si](CC)(CC)c1cc(C=CC=O)co1

Procedure:
Reacting 2-triethylsilyl-4-furaldehyde (Compound 5) with (triphenylphosphoranylidene)acetaldehyde gives 3-(2-triethylsilyl-4-furyl)-2-propen-1-al (Compound 45). Conjugate addition of dodecylCu(CN)ZnI (Compound 30) to this aldehyde (Compound 45) gives 4-[1-(2-oxoethyl)tridecyl]-2-triethylsilylfuran (Compound 46). Treatment of this intermediate with manganese dioxide, sodium cyanide and ammonia in tert-butanol, followed by singlet oxygen oxidation gives 4-[1-(2-carboxyamido)methyl]tridecyl-5-hydroxy-2(5H)-furanone (Compound 16).