Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), was coupled with 1-methyl-piperazine (31 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) to give the titled compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])[O:9][CH2:8][CH2:7][O:6]1.[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(C(C)=O)C(C)C>[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5]2([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[O:9][CH2:8][CH2:7][O:6]2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1cc(F)ccc1C1(CCCBr)OCCO1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1cc(F)ccc1C1(CCCN2CCC(O)(c3cccc(C(F)(F)F)c3)CC2)OCCO1

Procedure:
A mixture of 3.7 g of 4-bromo-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane, 2.5 g of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 1.4 g of anhydrous potassium carbonate, a catalytic amount of potassium iodide and 20 ml of methyl isobutyl ketone was heated at 80°-90° C for 2 hours. After cooling, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The extracts were washed with water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane as a residual oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=2[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: COc1cc2nc(CCl)n(C)c2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5n4C)CC3)n(C)c2c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-5,6,7-trimethoxy-benzimidazole (39 mg) and homopiperazine (7 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C[N:12](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:12])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)cc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)cc1C(N)=O
Yield: 46 %

Procedure:
4-Bromo-1-methyl-1H-pyrrole-2-carboxylic acid (122 mg, 0.60 mmol), HATU (274 mg, 0.72 mmol) and DIEA (194 mg, 1.50 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature with ammonia gas bubbled through continuously overnight. The reaction mixture was diluted with 100 mL of DCM, and then washed with water (50 mL). The aqueous layer was extracted with DCM (20 mL×2). All organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 6/1) to give 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (56 mg, yield 46%). 1H NMR (300 MHz, CDCl3): δ 6.74 (d, J=1.8 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H), 3.92 (s, 3H). LC-MS calcd for C6H7BrN2O (m/e) 201.97, obsd 203 and 205 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][NH:4][C@H:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([NH2:8])=[O:7].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:4]([CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([NH2:8])=[O:7])[CH2:3][C:2]([CH3:16])([CH3:15])[CH3:1])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)CN[C@@H](C(N)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CN(C(C(N)=O)c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 3 %

Procedure:
(R)-2-(2,2-Dimethyl-propylamino)-2-phenyl-acetamide (700 mg, 3.2 mmol) was dissolved in dichloromethane (15 mL) and chilled in an ice bath. The solution was treated with triethylamine (553 uL, 4.0 mmol) followed by 4-chlorobenzenesulfonyl chloride (671 mg, 3.2 mmol). After heating at 50° C. for 18 h, the mixture was cooled, diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to an oil. Purification on a silica gel flash column (40% EtOAc in hexanes, eluent) afforded the title compound in 3% yield. 13CNMR (100 MHz, CDCl3) 28.6, 33.2, 62.7, 70.0, 128.8, 129.0, 121.1, 129.2, 130.7, 133.6, 138.7, 139.0, 172.7. MS 395.1 m/z (M+1).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NC[C@@H](NC(=O)c1ccsc1Nc1ccnc2[nH]ccc12)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC[C@@H](NC(=O)c1ccsc1Nc1ccnc2[nH]ccc12)c1ccccc1
Yield: 92.7 %

Procedure:
To a solution of 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid ((S)-2-azido-1-phenyl-ethyl)-amide (40 mg, 0.1 mmol), 5% Pd/C (cat) in methanol (5 mL) was subjected to an atmosphere of hydrogen (balloon). After completion the solution was filtered and concentrated in vacuo. The residue was purified by ISCO Companion (silica, 10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid ((S)-2-amino-1-phenyl-ethyl)-amide (35 mg) (ESI) 378 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.61 (1H, br. s.) 11.45 (1H, s) 9.32 (1H, d, J=8.20 Hz) 8.28 (3H, br. s.) 8.08 (1H, d, J=6.88 Hz) 7.75 (1H, d, J=5.81 Hz) 7.47 (2H, d, J=5.86 Hz) 7.33 (2H, dd, J=7.57, 1.81 Hz) 7.12-7.24 (3H, m) 6.81 (1H, dd, J=2.49, 1.22 Hz) 6.68 (1H, d, J=6.88 Hz) 5.28 (1H, dd, J=10.54, 4.73 Hz) 3.40 (1H, td, J=11.53, 5.44 Hz) 3.12 (1H, dd, J=7.39, 4.61 Hz)
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:13][C:14]([NH:16][C@H:17]([C@H:21]([OH:25])[CH:22]([CH3:24])[CH3:23])[C:18](O)=[O:19])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)(OC(N[C@H]([C@@H](O)C(C)C)C(O)=O)=O)CCCCC1C=CC=CC=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:1][C:2]([O:13][C:14](=[O:15])[NH:16][C@H:17]1[C:18](=[O:19])[O:25][C@@H:21]1[CH:22]([CH3:24])[CH3:23])([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)[C@@H](O)[C@@H](NC(=O)OC(C)(C)CCCCc1ccccc1)C(=O)O
Agent: CC(C)[C@H](O)[C@@H](NC(=O)OC(C)(C)CCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1OC(=O)[C@@H]1NC(=O)OC(C)(C)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-2-[(1,1-dimethyl-5-phenyl-pentoxy)-carbonylamino]-3-hydroxy-4-methyl-pentanoic acid and (2R*,3S*)-2-[(1,1-dimethyl-5-phenyl-pentoxy)-carbonylamino]-3-hydroxy-4-methyl-pentanoic acid (0.11 g, 0.30 mmol) in dry CH2Cl2 (15 mL), at 0° C., Et3N (0.126 mL, 0.9 mmol) and subsequently TBTU (0.116 g, 0.36 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 100:0 to 80:20) to afford the pure title compound (0.019 g, 18%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 365 [M−NH4]+; (ESI) m/z: 346 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (d, J=6.66 Hz, 3H), 0.95 (d, J=6.54 Hz, 3H), 1.27-1.35 (m, 2H), 1.36 (s, 6H), 1.55 (p, J=7.56 Hz, 2H), 1.66-1.85 (m, 2H), 1.96 (dt, J=6.52, 8.91 Hz, 1H), 2.57 (t, J=7.71 Hz, 2H), 4.17 (dd, J=4.40, 9.09 Hz, 1H), 4.69 (dd, J=4.40, 8.33 Hz, 1H), 7.11-7.33 (m, 5H), 7.81 (d, J=8.32 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH:9]([CH:15]=[N:16][O:17][CH2:18][CH3:19])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([CH2:21][S:22][CH3:23])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH:9]([CH:15]=[N:16][O:17][CH2:18][CH3:19])[C:10]([CH:12]2[CH2:13][CH2:14]2)=[O:11])=[C:4]([CH2:21][S:22]([CH3:23])=[O:32])[CH:3]=1
Reactant: CCON=CC(C(=O)c1ccc(Br)cc1CSC)C(=O)C1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCON=CC(C(=O)c1ccc(Br)cc1CS(C)=O)C(=O)C1CC1
Yield: 78.9 %

Procedure:
To a stirred solution of 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropyl-2-(ethoxyiminomethyl)propan-1,3-dione (0.95 g) in dichloromethane cooled to -25° C. was slowly added m-chloroperbenzoic acid (50 to 60%, 0.55 g). The mixture was filtered in the cold and the filtrate diluted with ether and washed with 1M sodium metabisulphite, 25% sodium acetate and brine, dried (anhydrous sodium sulphate) and evaporated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate and hexane, giving as a yellow gum 1-[4-bromo-2-(methylsulphinylmethyl)phenyl]-3-cyclopropyl-2-(ethoxyiminomethyl)propan-1,3-dione (compound 8, 0.78 g), NMR (CDCl3) δ 1.0-1.4(7H, m), 2.55(3H, s), 2.8(1H, m), 4.0-4.2(4H, m), 7.2(1H, d), 7.5(1H, dd), 7.65(1H, d), 7.7(1H, bs).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=C([CH:19]=[CH:20][CH:21]=2)C(O)=O)[CH2:9][CH2:8]1>C(Cl)Cl.CN(C)C=O>[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:1]([CH:19]=[CH:20][CH:21]=2)[C:2]([Cl:4])=[O:3])[CH2:9][CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (0.14 ml) was added to a solution of 3-morpholinobenzoic acid (0.28 g) in methylene chloride (10 ml) which contained N,N-dimethylformamide (2 drops). The reaction mixture was stirred for 18 hours at ambient temperature. The mixture was evaporated and azeotroped with toluene to yield 3-morpholinobenzoyl chloride (0.3 g); M/z M+H+ 222.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:41](=[O:42])[C:40]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:39]2[C:38]1=[O:47])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(#N)C>C(N(CC)CC)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:38](=[O:47])[C:39]2=[CH:46][CH:45]=[CH:44][CH:43]=[C:40]2[C:41]1=[O:42])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 12.5 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (1.65 g), ethyl 2-bromo-10-phthalimidodecanoate (2.4 g), acetonitrile (100 ml) and triethylamine (0.75 g) is heated at 80° C. for 4 days. After evaporation of the solvent, ethyl acetate (200 ml) and water (100 ml) are added to the residue. The ethyl acetate layer is dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction gives tert-butyl 3(S)-[1(R)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.45 g) as a colorless oil.
Reaction SMILES: CO[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[C:10]([NH2:14])(=[O:13])[CH:11]=[CH2:12].C1(C)C(S(O)(=O)=O)=CC=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.N#N>>[N:4]1([CH2:3][NH:14][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: C=CC(N)=O
Reactant: COCN1CCCC1=O
Agent: Cc1ccccc1S(=O)(=O)O
Agent: N#N
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)NCN1CCCC1=O
Yield: 40 %

Procedure:
The mixture of 1-methoxy methyl-2-pyrrolidone (65.6 g), acrylamide (75.5 g), toluene sulfonic acid (0.20 g) and phenothiazine (0.20 g) was stirred under the condition of N2 for 1 hour at 150° C. while removing methanol by distillation. The residue was cooled, then recrystallized in acetone to give the title compound in the yield of 40%.
Reaction SMILES: [Cl-].Cl[C:3]1C(C)=C(C(C)=CC=1C)C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH2:33][CH2:34][CH3:35].C1OC1CC>>[CH2:32]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[CH:45]=[CH2:3])[CH2:33][CH2:34][CH3:35]
Reactant: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1Cl
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: CCC1CO1
Agent: [Cl-]
Product: C=CC(C)=CC=CC(C)=CC(=O)OCCCC

Procedure:
16 g of 3-chloro-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride and 10 g of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester are heated to boiling with stirring after the addition of 40 g of 1,2-butylene oxide. The 1,2-butylene oxide is slowly distilled off. The reaction mixture is stirred for 30 minutes at 80°-82° C., then cooled and thoroughly extracted with hexane. The hexane extract is shaken out 5 times with 50 ml of methanol/water 70:30 parts by volume each time, then dried over sodium sulphate and evaporated under reduced pressure to produce 9-(3-chloro-2,4,6-trimethyl-phenyl), 3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester as a residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].N1C=CC=CC=1>C(#N)C>[Cl:12][CH2:13][CH2:14][C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:16]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(CCCl)Nc1ccc(C(=O)O)c(O)c1
Reaction time: 0.33 h

Procedure:
7.5 g of 4-Aminosalicyclic acid was dissolved in 300 ml of acetonitrile at about 60° C. 12 ml of 3-chloropropionyl chloride was added dropwise and followed by addition of 5 ml of pyridine, the resulting mixture was refluxed for three hours. The mixture, which became clear after approximately 20 minutes of refluxing, was cooled and evaporated to dryness under reduced pressure. A gummy oil was dissolved in isopropanol-water and refrigerated for several days. A small amount of solid thus produced was filtered off. The filtrate was evaporated to dryness and approximately 16.8 g of crude 4-(3-chloropropionamido) salicyclic acid was produced. A lens treated with this compound was found to be clear with excellent UV blockage up to about 320 nm. ##STR9##
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19].O>CCCCCC>[CH3:10][CH:11]([CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: OCc1ccc(O)cc1
Solvent: O
Solvent: CCCCCC
Product: CC(C)CCCCCCC(=O)OCc1ccc(O)cc1
Temperature: 50 °C
Yield: 67.2 %

Procedure:
4-Hydroxybenzyl alcohol (651 mg, 5.24 mmol), 8-methylnonanoic acid (948 mg, 5.50 mmol) and Novozyme 435 (50 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 4-hydroxybenzyl 8-methylnonanoate (0.98 g, yield 67.3%) as a thin-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.C(Cl)Cl.O>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Agent: O=C1CCC(=O)N1
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A four-necked glass flask equipped with a stirrer and reflux condenser was charged with 180 g of methylene chloride, 63.2 g of 4'-methylbiphenyl-2-carbonitrile, 58.8 g of N-bromosuccinimide and 90 mg of 2,2'-azobis (2,4-dimethylvaleronitrile) and the reaction was conducted under reflux with stirring at an internal temperature of 45°-47° C. for 3 hours. Refluxing was further continued for 1 hour and after cooling to an internal temperature of 35°-38° C., the reaction mixture was treated with 200 g of water twice to transfer the byproduct succinimide into the water layer. The methylene chloride layer was allowed to cool gradually to 0° C., whereupon white crystals separated. The crystals were recovered by filtration, washed with cold methylene chloride and dried to give 71.6 g of 4'-bromomethylbiphenyl-2-carbonitrile. Yield 80.5%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(C(C)C)CC)(C)C.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>O1CCCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Fluoro-4-trifluoromethyl-2-nitrobenzene (5.1 g) was dissolved in tetrahydrofuran (100 mL) and diisopropylethylamine (5.5 ml) and 4-amino-1-tert-butoxycarbonylpiperidine (5.37 g) were added. The mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and the extract solution was dried and concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-trifluoromethyl-2-nitrophenyl)aminopiperidine.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:27](=[O:28])[C:26]([C:29]([NH2:31])=[O:30])=[C:25]([OH:32])[C@:24]2([OH:33])[C@H:5]1[CH2:6][C@H:7]1[C:21]([C:22]2=[O:23])=[C:20]([OH:34])[C:10]2[C:11]([OH:19])=[C:12]([NH2:18])[CH:13]=[C:14]([N:15]([CH3:17])[CH3:16])[C:9]=2[CH2:8]1)[CH3:3].ClCC(OC)(OC)OC.Cl[CH2:45][C:46]1O[C:48]2[CH:54]=CC=C[C:49]=2[N:50]=1.C(N)CC.C(NCC1OC2C=CC=CC=2N=1)CC.N>CN(C=O)C>[CH3:17][N:15]([CH3:16])[C:14]1[C:9]2[CH2:8][C@@H:7]3[C:21](=[C:22]([OH:23])[C@@:24]4([OH:33])[C@@H:5]([CH2:6]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]([OH:28])=[C:26]([C:29]([NH2:31])=[O:30])[C:25]4=[O:32])[C:20](=[O:34])[C:10]=2[C:11]2[O:19][C:45]([CH2:46][NH:50][CH2:49][CH2:48][CH3:54])=[N:18][C:12]=2[CH:13]=1
Reactant: ClCc1nc2ccccc2o1
Reactant: CN(C)c1cc(N)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Agent: CCCNCc1nc2ccccc2o1
Agent: COC(CCl)(OC)OC
Agent: N
Solvent: CN(C)C=O
Solvent: CCCN
Product: CCCNCc1nc2cc(N(C)C)c3c(c2o1)C(=O)C1=C(O)[C@]2(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]2C[C@@H]1C3
Temperature: 25 °C

Procedure:
9-aminominocycline sulfate salt (1.0 g, 1.50 mmol) is dissolved in DMF (50 mL) and treated with a solution of 2-chloro-1,1,1-trimethoxyethane (0.463 g, 3.00 mmol, 2 equivalents). The reaction is stirred at room temperature until mass spectrometry shows conversion to the chloromethylbenzoxazole derivative. The solution is then treated with n-propylamine (10 mL, excess) and stirred until mass spectrometry shows conversion to the n-propylaminomethyl benzoxazole. The mixture is concentrated under reduced pressure to remove excess n-propylamine, and then poured slowly into ether (1 L) and HCl/ether is added to precipate the salt. The solid is rinsed with fresh ether and dried under vacuum. The crude solid is dissolved in water (100 mL) giving a solution at pH 2. The pH is raised successively by 0.5 units with aqueous ammonia, and extracted with dichloromethane. The fractions extracted at pH 4–4.5 are combined, dried (Na2SO4), filtered and concentrated nearly to dryness. A small volume of methanol is added and the solution is treated with 1M HCl in ether. The precipitated solid is collected by filtration, washed with fresh ether and dried under vacuum to yield 0.067 g of the product as its HCl salt.