Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:31])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1.Cl[S:33]([NH2:36])(=[O:35])=[O:34].C(=O)(O)[O-].[Na+]>CN(C=O)C>[S:33]([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13]([C:22](=[O:31])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)(=[O:35])(=[O:34])[NH2:36]
Reactant: NS(=O)(=O)Cl
Reactant: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(N)(=O)=O)ccc4[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
About 29.6 mg of sodium hydride was added to a solution comprising about 250 mg of compound 4a in about 20 ml of anhydrous DMF at 0° C. under nitrogen. The solution was stirred for 30 minutes and about 1.22 g of chlorosulfonamide was slowly added in one portion. The solution was then stirred at room temperature for 24 hours. The mixture was poured into a cold saturated sodium bicarbonate solution and the resulting solution was extracted with methylene chloride (3×50 ml). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure to give a light yellow oil (5a) (183 mg 61.2%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][OH:13])[C:5]=2[N:6]=1>[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([CH:12]=[O:13])[CH:8]=[C:9]([CH3:11])[CH:10]=2)[N:6]=1
Reactant: Cc1cc(CO)c2nc(N)sc2c1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1cc(C=O)c2nc(N)sc2c1

Procedure:
67.6 g (0.348 mol) of 5b are treated with 241 g (2.77 mol) of manganese(IV) oxide in analogy to Example 1b.
Reaction SMILES: NC1C(F)=C([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])N=C(C(OC(C)C)=O)C=1.[C:25]([NH:28][C:29]1[C:34]([F:35])=[C:33](Cl)[N:32]=[C:31]([C:37]([O:39][CH3:40])=[O:38])[C:30]=1[Cl:41])(=[O:27])[CH3:26]>>[C:25]([NH:28][C:29]1[C:34]([F:35])=[C:33]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:32]=[C:31]([C:37]([O:39][CH3:40])=[O:38])[C:30]=1[Cl:41])(=[O:27])[CH3:26]
Reactant: COC(=O)c1nc(Cl)c(F)c(NC(C)=O)c1Cl
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(NC(C)=O)c1Cl

Procedure:
Methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate was prepared in analogous fashion to isopropyl 4-(amino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate in Example 10 except that methyl 4-acetamido-3,6-dichloro-5-fluoropicolinate was used in place of isopropyl 4-amino-6-bromo-5-fluoropicolinate: mp=175-177° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J=8.4, 1.6 Hz, 1H), 7.38 (dd, J=8.4, 7 Hz, 1H), 3.95 (d, J=0.8 Hz, 3H), 3.94 (s, 3H), 2.17 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 168.0, 163.9, 154.4, 153.7, 151.9, 151.0, 144.9 (d, JF-C=4.4 Hz), 143.9 (d, JF-C=13.3 Hz), 139.5 (d, JF-C=16.7 Hz), 133.7 (d, JF-C=14.4 Hz), 129.3 (d, JF-C=3.2 Hz), 126.7, 125.9 (dd, JF-C=14.6, 3.6 Hz), 121.9 (d, JF-C=13.2, 4.3 Hz), 61.7 (d, JF-C=4.4 Hz), 53.1, 22.5; 19F{1H} NMR (376.5 MHz, DMSO-d6) δ −119.0 (d, JF-F=28.6 Hz), −129.0 (d, JF-F=28.6 Hz); IR: 3182, 3008, 2952, 1736, 1674, 1512, 1464, 1422, 1401, 1372, 1263, 1238, 1213, 1173, 1049, 1026, 977, 904, 687; MS Calcd. for C16H12Cl2F2N2O4: 404.0. Found: 404 (M+), 369.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:21])([F:20])[CH2:17][CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC(Cl)=CC=1)=O)=NC(OCC1C=CC(Cl)=CC=1)=O>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([O:11][CH2:18][CH2:17][C:16]([F:21])([F:20])[F:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: OCCC(F)(F)F
Agent: O=C(N=NC(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)c1cc(OCCC(F)(F)F)cc(C(C)(C)C)c1
Reaction time: 120 h

Procedure:
To a solution of 1-(3-tert-butyl-5-hydroxyphenyl)ethanone (O3.106; 300 mg, 1.56 mmol), 3,3,3-trifluoropropanol (178 mg, 1.56 mmol) and triphenylphosphine (409 mg, 1.56 mmol) in dichloromethane (5 ml) at RT was added a solution of di(4-chlorobenzyl) azodicarboxylate (573 mg, 1.56 mmol) in dichloromethane (1 ml). The mixture was stirred for 5 days and then filtered. The solvent was removed and the residue was purified by flash chromatography (n-heptane:ethyl acetate). Yield: 170 mg, 38%.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][OH:6])[CH2:3][OH:4].C1(N=C=NC2CCCCC2)CCCCC1.[C:22](O)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:22]([O:4][CH2:3][C:2](=[CH2:1])[CH2:5][OH:6])(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: C=C(CO)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(CO)COC(=O)CCCCCCCCCCCCCCC
Reaction time: 24 h

Procedure:
2-Methylenepropane-1,3-diol (3.0 g) was dissolved in methylene chloride (40 ml). Dicyclohexylcarbodiimide (8.7 g), 4-dimethylaminopyridine (0.4 g) and hexadecanoic acid (8.7 g) were added. The mixture was stirred for 24 hours, filtered, and the filtrate was purified through a column of silica gel 60 (70-230 mesh, 30 g) eluting with ether/chloroform/pentane 1:1:1. The eluate was washed with saturated sodium hydrogen carbonate solution (3×70 ml), dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. Further purification was achieved by chromatography on a Waters PrepLC®/System 500A using a PrepPAK®-500/SILICA cartridge with ether/chloroform/pentane 1:1:3 as eluent.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]=3[C:12](I)=[CH:11]2)[O:7][C@@H:6]1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])#[CH:47]>CN(C=O)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]=3[C:12]([C:47]#[C:46][Si:48]([CH3:51])([CH3:50])[CH3:49])=[CH:11]2)[O:7][C@@H:6]1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](n2cc(I)c3c(CCc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1C[C@H](n2cc(C#C[Si](C)(C)C)c3c(CCc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a suspension of (2R,3S,5R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(5-iodo-4-phenethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydrofuran-3-yl acetate 9 obtained from example 132, step d) (0.36 g, 0.578 mmol), CuI (0.022 g, 0.0116 mmol), Pd(PPh3)2Cl2 (0.040 g, 0.0570 mmol) and DIPEA (0.20 mL, 1.15 mmol) in DMF was added ethynyltrimethylsilane (0.230 g, 2.34 mmol). The mixture was stirred at r.t. for 12 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with H2O, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) to give the title compound (0.305 g, 58%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C@@H:8]1([N:17]2[CH:24]=[C:23]([I:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@@H:9]1[OH:10]>N1C=CC=CC=1>[I:25][C:23]1[C:21](=[O:22])[NH:20][C:18](=[O:19])[N:17]([C@@H:8]2[O:14][C@H:13]([CH2:15][O:16][C:5](=[O:7])[CH3:6])[C@@H:11]([O:12][C:11](=[O:12])[CH3:13])[C@@H:9]2[O:10][C:9](=[O:10])[CH3:8])[CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)cc1I
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 187.5 %

Procedure:
Acetic anhydride (1.04 ml, 11 mmol) was added to a solution of 1 g of 1-(β-D-arabinofuranosyl)-5-iodouracil from Example 4(c)(2.7 mmol) in 10 ml of dry pyridine. After stirring for 3 hours at room temperature, the solvent was evaporated and the residue was co-evaporated with CH2Cl2 several times. The residue was triturated with ethanol, the solid filtered and dried to give 1.256 g (93%) of the title compound, melting at 175°-9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([NH2:1])[CH:11]=[CH:10]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc2cc(N)ccc2c1
Temperature: 60 °C
Yield: 88.1 %

Procedure:
3 grams (g) (18.85 millimoles (mmol)) of 6-aminonaphthalene-2-ol is dissolved in 100 milliliters (mL) of acetone, and 4 g (20.7 mmol) of 1-bromooctane and 13.0 g (94.2 mmol) of potassium carbonate (K2CO3) are added thereto. The reaction mixture is stirred under reflux at 60° C. for 24 hours, and cooled down to room temperature (25° C.). The obtained reaction mixture is concentrated, and purified by silica gel column chromatography (n-hexane:EtOAc=3:1 volume ratio), to give 4.5 g (16.6 mmol) of 6-octyloxynaphthalene-2-amine. The yield is 88%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][C@H:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C@@H:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@@H]1COCCO1
Agent: Cl
Product: O=C(C[C@@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 80%), MS (ISP) m/z=459.5 [(M+H)+], mp 193.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (R)-[1,4]dioxan-2-yl-acetic acid.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12](Cl)=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[CH3:34][O:35]C1C=C2C(=CC=1)C=NC(OS(C(F)(F)F)(=O)=O)=C2>>[ClH:4].[ClH:1].[ClH:4].[CH3:34][O:35][C:14]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)=[CH:7]2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: COc1ccc2cnc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: Cl
Product: COc1ccc2cnc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)cc2c1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 6-methoxyisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.16-2.29 (m, 4H), 3.05-3.17 (m, 2H), 3.38 (d, J=12.6 Hz, 2H), 4.00 (s, 3H), 4.48-4.59 (m, 1H), 7.46-7.54 (m, 2H), 8.13 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.48-8.51 (m, 2H), 8.59 (s, 1H), 8.80 (d, J=2.3 Hz, 1H), 9.19 (br. s., 1H), 9.28 (br. s., 1H), 9.45 (s, 1H). MS (ES+): m/z=318.16 [MH+]. HPLC: tR=1.70 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18]N1C(=O)CCC1=O>C(#N)C.[Fe](Cl)(Cl)Cl>[Cl:18][C:13]1[C:12]([OH:17])=[CH:11][CH:10]=[C:9]2[C:14]=1[CH2:15][CH2:16][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:8]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: Oc1ccc2c(c1Cl)CCC(c1ccccc1)O2
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a suspension of 200 mg of 2-phenyl-chroman-6-ol (0.88 mmol) and 142 mg of iron(III) chloride (0.88 mmol) in 15 ml of acetonitrile at room temperature 118 mg of N-chlorosuccinimide (0.88 mmol) were added in one portion and stirring was continued for 16 h. The volatile components were removed under reduced pressure. The resulting residue was purified by reversed phase HPLC. 127 mg of the title compound were obtained as a pale yellow solid (55%).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[F:13].S(=O)(=O)(O)O>O>[F:13][C:5]1[C:6]([F:12])=[C:7]([F:11])[C:8]([F:10])=[CH:9][C:4]=1[C:3]([OH:14])=[O:2]
Reactant: COC(=O)c1cc(F)c(F)c(F)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(F)c1F
Yield: 91.8 %

Procedure:
Into a 300 ml three necked flask, 20 g (0.096 mol) of the 2,3,4,5-tetrafluorobenzoic acid-methyl ester prepared in Example 15 and 40 g of 70 wt % sulfuric acid were charged, and the mixture was reacted for 10 hours at 140° C. with stirring. Then, 100 ml of water was added to the reaction solution, and the mixture was left to cool. Then, the mixture was extracted with hot toluene. Then, the solvent was distilled off to obtain 17.1 g of 2,3,4,5-tetrafluorobenzoic acid. The yield was 92%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:42])[C:15]([O:17][CH2:18][CH2:19][C:20]2([CH3:41])[O:25][C:24]3[C:26]([CH3:40])=[C:27]([CH3:39])[C:28]([O:31]CC4C=CC=CC=4)=[C:29]([CH3:30])[C:23]=3[CH2:22][CH2:21]2)=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCC>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:42])[C:15]([O:17][CH2:18][CH2:19][C:20]2([CH3:41])[O:25][C:24]3[C:26]([CH3:40])=[C:27]([CH3:39])[C:28]([OH:31])=[C:29]([CH3:30])[C:23]=3[CH2:22][CH2:21]2)=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCOC(=O)C(C)c1ccc(-c3ccccc3)c(F)c1)O2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCOC(=O)C(C)c1ccc(-c3ccccc3)c(F)c1)O2
Reaction time: 18 h
Yield: 36 %

Procedure:
A solution of 2-(6-benzyloxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2yl)ethyl 2-(3-fluoro4-phenyl-phenyl)propionate in ethyl acetate was treated with 10% palladium on charcoal (Aldrich, 0.5 g). The resulting mixture was hydrogenated on a Parr Apparatus [initial pressure 60 pounds/inch2 (psi)]. After 18 hours, the reaction mixture was filtered, and the resulting solution concentrated in vacuo. The residue was subjected to flash chromatography (silica gel, 2:8, v:v, ethyl acetate:hexane). Concentration of the appropriate fractions afforded a clear oil. Hexane was added to the oil and a white solid formed upon standing. The white solid was collected by filtration to afford 0.91 g (36% yield) of 2-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2yl)ethyl 2-(3-fluoro4-phenyl-phenyl)propionate as a mixture of stereoisomers.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH2:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:27][C@H:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:28]([N:30]([CH2:47][CH3:48])[CH2:31]/[CH:32]=[CH:33]\[Sn](CCCC)(CCCC)CCCC)[CH3:29].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:28]([N:30]([CH2:47][CH3:48])[CH2:31]/[CH:32]=[CH:33]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH2:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:27][C@H:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1C[C@H]21
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Temperature: 100 °C
Yield: 101.9 %

Procedure:
A mixture of methyl cis-(1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylmethyl)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 5, 0.66 g), N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 2, 1.17 g), tri-tert-butylphosphonium tetrafluoroborate (0.145 g), Iris-(dibenzylideneacetone)-dipalladium (0.066 g) in dioxane (16 mL) and DMSO (1.6 mL) was degassed and purged with nitrogen, then heated at 100° C. for 1.5 hours. After cooling, the mixture was poured into brine and extracted with ethyl acetate. The organic layer was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give methyl cis-(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylmethyl]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.72 g) as a glass.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13]OC(=O)C)[CH:11]=2)[CH:6]=[N:5]1)(=O)C.[BrH:18]>>[BrH:18].[Br:18][CH2:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[N:5][NH:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)OCc1ccc2cnn(C(C)=O)c2c1
Agent: Br
Product: BrCc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
A suspension of 1-acetyl-6-(acetoxymethyl)indazole (9.5 g, 41 mmol) (98) in aqueous hydrobromic acid (48% aqueous solution, 20 mL, 177 mmol) was stirred at room temperature for 46 hours. The solid was collected on a Buchner funnel and dried under vacuum for 12 hours. The filtrate was stirred at room temperature for additional 24 hours and more solid was collected. After drying under vacuum, title compound was obtained as a yellow solid (10.0 g, 84%) which was used as such without further purification. MS (electrospray) 211 (M+1 for 79Br), 213 (M+1 for 81Br); 1H N MR (CDCl3) δ4.85 (s, 2H), 7.65 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=8.4 Hz), 8.05 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][CH2:30][S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32].C(N(CC)CC)C>>[CH3:35][N:34]([CH3:36])[S:31]([CH2:30][CH2:29][NH:28][C:21]([C:14]1[C:15](=[O:20])[N:16]([CH3:19])[C:17]2[C:12]([C:13]=1[OH:26])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:23])(=[O:33])=[O:32]
Reactant: CN(C)S(=O)(=O)CCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 48.9 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92, 2-amino-N,N-dimethylethanesulfonamide hydrochloride (200 mg, 1.09 mmol), and triethylamine (0.5 mL, 3.27 mmol), was prepared N-{2-[(dimethylamino)sulfonyl]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (19 mg, 49% yield) as a brown solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.55 (br s, 1 H), 8.55 (s, 1 H), 7.38 (s, 1 H), 7.16-7.12 (m, 2 H), 7.03-6.98 (m, 2 H), 4.12 (s, 2 H), 3.89 (m, 2 H), 3.57 (s, 3 H), 3.24 (m, 2 H), 2.89 (s, 6 H); HRMS m/z calcd for C21H24FN4O5S: 463.1446 Found: 463.1451.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[N:10]([C:12]1[CH:17]=[C:16]([CH2:18][C@H:19]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:20](=[O:32])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=[CH:14][C:13]=1[OH:43])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:51]([O:53][C:54](=[O:58])[CH:55](Br)[F:56])[CH3:52]>CN(C=O)C>[CH2:51]([O:53][C:54](=[O:58])[CH:55]([O:43][C:13]1[CH:14]=[CH:15][C:16]([CH2:18][C@H:19]([NH:33][S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:20](=[O:32])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:17][C:12]=1[N:10]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:44])[CH3:11])[F:56])[CH3:52]
Reactant: CCOC(=O)C(F)Br
Reactant: CN(C(=O)OCc1ccccc1)c1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)Oc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{5-[(2S)-2-Benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-hydroxy-phenyl}-methyl-carbamic acid benzyl ester of Step B (100 mg, 0.16 mmol) is dissolved in DMF (2 mL). Potassium carbonate (23 mg, 0.16 mmol) and bromo-fluoro-acetic acid ethyl ester (20 μl, 0.16 mmol) are added. The mixture is stirred at RT overnight. 40 μl (0.32 mmol) more of bromo-fluoro-acetic acid ethyl ester is added and stirred overnight. The mixture is purified through a silica plug to provide [4-[(2S)-2-benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-(benzyloxycarbonyl-methyl-amino)-phenoxy]-fluoro-acetic acid ethyl ester which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11]1>CO>[O:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH2:19][CH:10]1[CH2:9][CH2:8][NH:7][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: NCCC1CCc2ccccc2O1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNCCC1CCc2ccccc2O1
Reaction time: 16 h
Yield: 55.3 %

Procedure:
3.01 g (35 mmol) of acrylic acid methyl ester are added at 0°-5°, while stirring, to a solution of 6.2 g (35 mmol) of 2-(2-aminoethyl)chroman in 200 ml of methanol. Stirring is continued for a further 16 hours at 0°-5° and the mixture is then concentrated by evaporation in vacuo. 8.76 g (95.2%) of crude product are obtained and are chromatographed on 250 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 5.10 g (55.4%) of N-[2-(chroman-2-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine are thus obtained in the form of a yellow oil. The N-[2-(chroman-2-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and melts at 152°-153°.