Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH2:20][S:21]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=[O:23])=[O:22])[C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([OH:14])=O)=[O:9])=[O:4].Cl.[CH3:35][NH:36][CH3:37].C(P(=O)(OCC)OCC)#N.Cl>CN(C)C=O.C(N(CC)CC)C>[CH3:35][N:36]([CH3:37])[C:12]([CH2:11][N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([CH:7]([CH2:20][S:21]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=[O:22])=[O:23])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:9])=[O:14]
Reactant: CCCCCN(CC(=O)O)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Reactant: CNC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCN(CC(=O)N(C)C)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of N-[2-(2-methoxycarbonylethyl)-3-(2-naphthylsulfonyl)propionyl]-N-pentylglycine (100 mg), dimethylamine hydrochloride (21 mg), and triethylamine (70 μl) in N,N-dimethylformamide (1 ml) was added diethyl cyanophosphonate (42 μl) at 0° C. After stirring at room temperature for 16 hours, a dilute hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and evaporated at reduced pressure. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (15:1) to give 95 mg of methyl 4-[N-(N,N-dimethylcarbamoylmethyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoate as oil. ##STR19##
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:27])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:8]=1[CH3:26]>C1COCC1.CO>[CH3:26][C:8]1[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]=1[CH2:6][C:5]([OH:27])=[O:4]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc([N+](=O)[O-])cc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1M Aqueous NaOH (1.18 ml) is added to a stirring suspension of [2-methyl-1-(4-nitro-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.2 g, 0.54 mmol) in 4:1 THF/MeOH (5 ml). The reaction mixture is allowed to stir at room temperature for 4 hours and then the solvent is removed in vacuo. The crude residue is dissolved in 1:1 THF/water and acidified to pH 3-4 using 6M HCl. After stirring for 30 minutes the resulting suspension is filtered and dried in vacuo at 110° C. to yield the titled product as a yellow solid. (MH+ 326)
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1>CO.[Pd]>[CH3:11][C:8]1[N:9]=[CH:10][C:5]([O:4][C:3]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:2]=2[CH3:1])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1

Procedure:
A solution of 5-(2-methyl-4-nitrophenoxy)-2-methylpyridine (compound 12.1) (5 g) in methanol (50 mL) with palladium on carbon (10%, 300 mg) was hydrogenated on a Parr shaker for 24 hours at 60 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure to give a white crystalline solid, which was used without further purification. LCMS ESI(+) m/z: 215 (M+1).
Reaction SMILES: [Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:56])[C@:16]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])([OH:47])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([O:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])=[C:26]([CH3:46])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3].[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].ClCCl>>[F:60][C:59]([F:62])([F:61])[C:57]([OH:63])=[O:58].[Br-:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:56])[C@:16]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])([OH:47])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:25]=[C:26]([CH3:46])[C:27]([O:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])=[C:28]([CH3:30])[CH:29]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)#[N:3]
Reactant: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Br-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)[C@@H]1CCCN1

Procedure:
To a solution of 3 g of 3,5-dimethyl-4-hydroxybenzyl bromide in CH3CN(30 mL) was added 1.2 g of (1R,2R)-4-[2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]thiazol-4-yl]benzonitrile and stirring was continued for 2 h at room temperature. The precipitate was filtered and washed with ether to give 1.37 g(81% y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxy)benzyl-1H-[1,2,4]triazol-4-ium bromide(Ro09-3846) as a white solid. To a mixture of 30 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-diflouro-phenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxybenzyl)-1H-[1,2,4]triazol-4-ium bromide, 10.9 g of Boc-(L)-proline and 2.8 g of N,N-dimethylaminopyridine in 1.2 L of dichloromethane was added 17.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture was stirred for 1.5 h at room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2 /MeOH=14/1) to give 30.9 g(79% y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide as a white solid. 30.9 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide was stirred in 600 mL of 10% TFA -dichloromethane for 5 h at room temperature and the solvent was removed in vacuo. The residue was diluted with ether and the precipitate was washed with ether to give 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH:10]1[CH2:14][CH2:13][CH2:12][CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH2:5][OH:6])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCc1cccc(I)c1
Reactant: C1=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CCN(CC)CC
Product: OCc1cccc(C2CCCC2)c1
Yield: 232.3 %

Procedure:
According to example 61, 10.0 g of 3-iodobenzyl alcohol (Aldrich) was treated with 30 mL of cyclopentene using 0.96 g of Pd(OAc)2, 2.60 g of tri-ortho-tolylphosphine, and 6.6 mL of Et3N. The resulting olefin mixture was hydrogenated for 2.5 h using 0.62 g of 5% Pt(C) in MeOH to afford 5.77 g (76%) of 3-cyclopentylbenzyl alcohol as a light yellow liquid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].[CH2:18]([N:25]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH2:18]([N:25]1[CH2:29][CH2:28][CH:27]([CH2:30][O:31][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
Diisopropylethylamine and tert-butyldimethyl-chlorosilane were added in that order to a chloroform solution of (1-benzylpyrrolidin-3-yl)methanol and stirred at room temperature for 5Hours. Thereafter, its work-up and purification were carried out in the standard method to obtain 1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl]pyrrolidine. EP: 306.
Reaction SMILES: [CH3:1][O:2][O:3][P:4](OCCOC(N1C2C(=CC=CC=2)/C(=C/C2NC(C)=CC=2C)/C1=O)=O)([O:6][O:7][CH3:8])=[O:5].[OH:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)/[C:42](=[CH:49]/[C:50]2[NH:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])/[C:41]1=[O:57])=[O:39]>>[CH3:1][O:2][O:3][P:4]([O:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)/[C:42](=[CH:49]/[C:50]2[NH:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])/[C:41]1=[O:57])=[O:39])([O:6][O:7][CH3:8])=[O:5]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCCO)c3ccccc32)[nH]1
Reactant: COOP(=O)(OCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Product: COOP(=O)(OCCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC

Procedure:
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)-propyl ester was prepared using the same protocol for synthesizing 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(dimethoxy-phosphonooxy)-ethyl ester by replacing 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-ethyl ester with 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-hydroxy-propyl ester with a yield of (31%). 1H NMR (400 MHz, CDCl3) δ 12.63 (s, br, 1H, NH-1′), 7.82-7.84 (m, 1H, H-4), 7.48-7.52 (m, 1H, H-7), 7.41 (s, 1H, H-vinyl), 7.17-7.24 (m, 2H, H-5, 6), 6.04 (s, br, 1H, H-4′), 4.61 (t, J=6.25 Hz, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1), 4.31 (q, J=6.38, 10.94 Hz, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1), 3.80 (s, 3H, NCOOCH2CH2CH2OPO(OCH3)2-1), 3.77 (s, 3H, NCOOCH2CH2CH2OPO(OCH3)2-1), 2.40 (s, 3H, CH3), 2.35 (s, 3H, CH3), and 2.23-2.29 (m, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1). 13P NMR (162 MHz, CDCl3) δ 2.40.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:22]([OH:24])=O)[CH:15]=[CH:14]1.[C:25]([C:29]1[CH:30]=[CH:31][C:32]([CH2:36][NH:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[C:33]([OH:35])[CH:34]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([CH2:36][N:37]([CH2:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[C:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[NH:13][CH:14]=[CH:15]3)=[O:24])=[C:33]([OH:35])[CH:34]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)c(O)c1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)c(O)c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
1.69 g (8.8 mmol) of EDC.HCl were added to 1.46 g (8.8 mmol) of 1H-indol-7-carboxylic acid and 2.41 g (8.8 mmol) of 5-tert-butyl-2-{[2-(4-fluoro-phenyl)-ethylamino]-methyl}-phenol dissolved in 80 ml DCM. The reaction mixture was stirred at rt over night, diluted with DCM and washed once with water and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (250 g silica gel; heptane/EtOAc 7:3) to yield 2.9 g (82%) 1H-indole-7-carboxylic acid (4-tert-butyl-2-hydroxy-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amide as a colorless foam. MS (ISP) 445.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)(Cl)Cl.ClCCl>[Cl:24][CH2:25][C:26]([N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)=[O:27]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A solution of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20 mmol), triethylamine (2.1 g, 21 mmol) in chloroform (50 ml) was added to a solution of chloroacetyl chloride (2.5 g, 22 mmol) in chloroform (100 ml) dropwise at room temperature. The mixture was stirred for 2 hours. The solution was diluted with dichloromethane (DCM, 100 ml) and then washed with H2O and brine. The solvent was removed and the oily product was purified by flash chromatography (SiO2, 50 g; eluted with DCM and 1% CH3OH in DCM). The pure product was obtained as an oil, 4.2 g. Crystallization from ethanol yielded 2.2 g of white crystals, m.p. 101°-102° C.
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].[CH2:35]([O:39][C:40]([N:42]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:43][C:44](OC(OCC(C)C)=O)=[O:45])=[O:41])[CH2:36][CH2:37][CH3:38]>>[NH2:31][C:29]([C:26]1[C:25](=[O:32])[C@:24]2([OH:33])[C@@H:5]([CH2:6][C@H:7]3[C:21](=[C:22]2[OH:23])[C:20](=[O:34])[C:10]2[C:11]([OH:19])=[C:12]([NH:18][C:44](=[O:45])[CH2:43][N:42]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:40](=[O:41])[O:39][CH2:35][CH2:36][CH2:37][CH3:38])[CH:13]=[C:14]([N:15]([CH3:16])[CH3:17])[C:9]=2[CH2:8]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]=1[OH:28])=[O:30]
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
Reactant: CCCCOC(=O)N(CC(=O)OC(=O)OCC(C)C)C(C)(C)C
Product: CCCCOC(=O)N(CC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2)C(C)(C)C

Procedure:
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(butoxycarbonyl)-N-(tert-butyl)glycinate Reference Example 118 to give the product of the example.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[C:7]2[C:11]([CH:12]=[CH:13][CH:14]=1)=[N:10][N:9]([CH3:15])[C:8]=2[S:16]([NH2:19])(=[O:18])=[O:17].C(=O)([O-])O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:1]([O:5][C:6]1[C:7]2[C:11]([CH:12]=[CH:13][CH:14]=1)=[N:10][N:9]([CH3:15])[C:8]=2[S:16]([NH2:19])(=[O:18])=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: Cn1nc2cccc(O)c2c1S(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2nn(C)c(S(N)(=O)=O)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
1.3 g of allyl bromide was added to a mixture comprising 5 g (22 mmol) of 4-hydroxy-2-methyl-2H-indazole-3-sulfonamide and 50 ml of a DMF solution of 1.9 g (22 mmol) of sodium hydrogencarbonate, and the mixture was stirred at room temperature for 12 hours. The mixture was poured into ice water, acidified with citric acid and extracted with ethyl acetate. The organic layer was washed, then concentrated and purified by column chromatography (hexane/ethyl acetate=2/1) to obtain 1.9 g (yield: 32.5%) of the desired product. Melting point: 143°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([O:32]C)=[O:31])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])=[CH:34][CH:35]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
In 150 ml of methanol, was dissolved 30 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate. After addition of 145 ml of 1 N sodium hydroxide, the mixture was stirred at 50° C for 2 hours. The reaction mixture was neutralized with hydrochloric acid, concentrated and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 23.9 g of N-(4-methoxybenzoyl)-phenylalanyltyrosine with a mp. 198°-200° C in a yield of 82%. Analysis, calculated for CZ26H26O6N2C 67.52, H 5.67, N 6.06, found C 67.17, H 5.69, N 5.95.
Reaction SMILES: [Na].[CH3:2][OH:3].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.[OH-].[Na+]>CS(C)=O>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:3][CH3:2])[CH:10]=1
Reactant: CO
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cncc(Br)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Sodium (2.33 g, 101.3 mmol) was added to methanol (50 ml) and was allowed to react, the mixture was evaporated. 3.5-Dibromopyridine (20.0 g, 84.4 mmol) and dimethyl sulfoxide (100 ml) were added. The mixture was stirred at 90° C. for 2 h. Sodium hydroxide (400 ml, 1 M) was added and the mixture was extracted twice with diethyl ether (200 ml). Chromatography on silica gel with dichloromethane and 3% ethanol as solvent gave the title compound. Yield 10.6 g, 67%. Mp 30-32° C.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[O:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28]3)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([O:6][CH2:7][C:8]2[C:12]([CH2:13][O:14][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30]([C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28]5)=[CH:23][CH:24]=3)=[C:11]([CH:15]([CH3:17])[CH3:16])[O:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC(C)c1onc(COC2CCCC2)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(COC5CCCC5)noc4C(C)C)cc3)ccc2n1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
A solution of [3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (50 mg, 0.21 mmol) in dichloromethane (2.1 mL) was added to a mixture of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (57 mg, 0.21 mmol) and triphenyl phosphine (82 mg, 0.31 mmol) in a microwave reaction tube. Diisopropyl azodicarboxylate (60 μL, 0.31 mmol) was added before the tube was sealed and heated for 20 minutes at 100° C. The mixture was concentrated and the residue was purified by chromatography (silica gel, hexane to 2:3 ethyl acetate:hexanes). Fractions containing the product were combined and concentrated. The residue was purified by chromatography (silica gel, 10:9:1 hexanes:dichloromethane:ethyl acetate) to provide methyl 6-[4-({[3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (11 mg, 11% as 0.10 ethyl acetate). 1H NMR (400 MHz, CDCl3): δ 8.37-8.32 (m, 2H), 8.22 (d, J=9 Hz, 1H), 8.05-8.00 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 4.99 (s, 2H), 4.58 (s, 2H), 4.09 (s, 3H), 3.99-3.97 (m, 1H), 3.27 (septet, J=7 Hz, 1H), 1.70-1.59 (m, 6H), 1.49-1.46 (m, 2H), 1.33 (d, J=7 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.C[C@H](NC)[C@@H](O)C1C=CC=CC=1.[Cl-].[Na+].O.Cl>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: CN[C@@H](C)[C@@H](O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of racemic 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (100 g; 0.37M) in ethyl acetate (1.5 L) and methanol (75 mL) was added solid (1S,2S)-(+)-pseudoephedrine (61.1 g; 0.37M). With efficient agitation the mixture was warmed to reflux, held for 30 minutes and slowly cooled to 25° C. After a minimum of 2 h the slurry was filtered and washed with ethyl acetate to yield enriched diastereomeric salt (88.6 g; 0.20M; 55%; diastereomeric ratio 80:20, as determined by HPLC). The enriched salt was slurried in 3% methanolic ethyl acetate (2.74L), warmed to reflux, held 30 minutes,cooled to 25° C. slowly, held 2 h and then filtered and washed with ethyl acetate to provide further enriched salt (70 g; 0.16M; 79%; diastereomeric ratio 95:5, as determined by HPLC). Treatment of the further enriched salt with 5% methanolic ethyl acetate using the same procedure yielded highly enriched salt (60.0 g; 0.14M; 85%; diastereomeric ratio 99:1, as determined by HPLC). This salt (60 g; 0.14M) was added to water (1L) and the consequent suspension acidified to pH 2-3 with concentrated hydrochloric acid (15 mL) and then extracted with diethyl ether (3×500 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to an oil. Hexane was added and evaporated to afford enantiomerically enriched acid (36 g; 0.13M; 98% recovery; enantiomeric ratio 99:1, as determined by HPLC) as a white solid. Crystallisation from a mixture of hexane (360 mL) and cyclohexane (720 mL) afforded enantiomerically pure (9S,10S)-2-chloro-9,10-dihydro-9,10-methano-9-anthracene-carboxylic acid as a white solid (30 g, 0.11 mol, 81%) mp 172°-173° C. αD =+101° (c=2.0,CHCl3).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:5]2[C:10]([C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCc1[nH]c2ccccc2c1Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CC)c(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.9 %

Procedure:
2-Ethyl-3-(4-nitrobenzyl)-1H-indole (3.0 g, 10.7 mmol) was weighed, and dissolved in 30 mL DMF. Cesium carbonate (6.98 g, 21.4 mmol) was added, and stirred at room temperature for 15 min. Ethyl bromoacetate (1.97 g, 11.8 mmol) was added, reacted at room temperature for 10 h, and filtered. The filtrate was added into water, and extracted with ethyl acetate. The extract was washed with water and a saturated solution of sodium chloride, rotate evaporated to dryness, purified by preparative liquid phase to obtain a yellow solid 350 mg, at a yield of 8.97%.