Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Si:5]([O:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH2:20][CH2:21][OH:22])[S:18][CH:19]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(N(CC)CC)C>C1COCC1>[C:1]([O:22][CH2:21][CH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][CH2:13][O:12][Si:5]([C:8]([CH3:9])([CH3:11])[CH3:10])([CH3:7])[CH3:6])[CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CCO)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCc1cc(CCO[Si](C)(C)C(C)(C)C)cs1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A solution of acetyl chloride (0.36 mL) in dry THF (3 mL) was added dropwise over 10 minutes to a stirred solution at 20° C. of 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethanol [Aromatic Intermediate 20] (1.10 g) and triethylamine (1.18 mL) in dry THF (30 mL). The mixture was stirred at 20° C. for 20 minutes and then partitioned between ethyl acetate and brine. The organic layer was dried, filtered and the solvent evaporated under reduced pressure to give the subtitled compound. Yield 1.20 g.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:8][C:6]=2[N:7]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:30][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([NH:2][CH3:1])=[N:7][C:6]=3[CH:8]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccccc1N
Reactant: CNc1nc2cc(NCc3ccc(C(=O)O)cc3)ccc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1nc2cc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)ccc2s1
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of acid 456c (729 mg; 2.54 mmol), 1,2-phenylenediamine (376 mg; 3.47 mmol; 1.36 eq) and BOP (1.43 g; 3.23 mmol; 1.27 eq) was dissolved in acetonitrile (15 mL), treated with triethylamine (3 mL) and stirred overnight. The reaction mixture was quenched with methanol, concentrated and purified by chromatographic column on silica gel (40% EtOAc in DCM) and the obtained material crystallized from DCM to give 358 mg (0.88 mmol; 35% yield) of pure compound 456. 1H-NMR (300 MHz; DMSO-d6) δ (ppm): 9.57 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.66 (d, J=4.8 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.76 4.87 (bs, 2H), 6.58 (t, J=7.5 Hz, 1H), 6.54 (d, J=1.8 Hz, 1H), 6.13 (dd, J=1.8, 8.3 Hz, 1H), 6.27 (t, J=5.7 Hz, 1H), 4.87 (bs, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H). LRMS: calc: 403.5008. found: 404.2(M+NH) and 202.6 (M+2H)/2.
Reaction SMILES: [CH3:1][C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[NH:6][C:7]([C:9]3[NH:10][N:11]=[C:12]4[C:17]=3[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=3)[CH2:13]4)=[N:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.[Pd].C([O-])([O-])=O.[Ca+2]>[CH3:1][C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[NH:6][C:7]([C:9]3[NH:10][N:11]=[C:12]4[C:17]=3[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:13]4)=[N:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc([N+](=O)[O-])cn3)C4)[nH]c2cc1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc(N)cn3)C4)[nH]c2cc1C
Yield: 59.6 %

Procedure:
55 mg of Pd/CaCO3 10% are added to a solution of 545 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-(5-nitropyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine in 60 ml of ethanol. After stirring for 15 hours at 35° C. under 3 bar of hydrogen, the reaction medium is brought back to ambient temperature, filtered through celite and then concentrated under reduced pressure. 300 mg of 6-[3-(5,6-dimethyl-1H-benzimidazol-2-yl)-2,4,5,7-tetrahydropyrazolo [3,4-c]pyridin-6-yl]-pyridin-3-ylamine are thus obtained in the form of a brown powder, the characteristics of which are as follows:
Reaction SMILES: Cl.Br[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.Cl.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(C(=O)O)cn2)cn1

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part I, but with 6-bromonicotinic acid hydrochloride and 6-methoxypyridin-3-ylboronic acid hydrochloride as starting materials, and 10 molar equivalents of 0.4M aqueous sodium carbonate. 1H NMR (DMSO) δ 13.40 (br s, 1H), 9.10 (d, 1H), 8.95 (d, 1H), 8.43 (dd, 1H), 8.28 (dd, 1H), 8.09 (d, 1H), 6.95 (d, 1H), 3.91 (s, 3H). ESI MS (M+1)+: 231.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:18]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=2[F:16])=[C:2]([CH:3]=1)[O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(OCc2c(F)cccc2F)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C(C)=O)ccc1OCc1c(F)cccc1F

Procedure:
A mixture of 3′-hydroxy-4′-(2,6-difluorobenzyloxy)-acetophenone (15.0 g, 53.96 mmol), ethyl bromoacetate (7.2 mL, 64.75 mmo), and K2CO3 (14.9 g, 107.92 mmol) in acetone (350 mL) is refluxed 18 hours. After cooling, the mixture is filtered, and the filtrate is concentrated in vacuo. Recrystallizaton from EtOAc yields ethyl [5-acetyl-2-(2,6-difluorobenzyloxy)-phenoxy]-acetate.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=3)[C:44]3[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=3)[N:21]=2)[CH2:16]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]=[C:27]3[C:23]([N:24]=[CH:25][N:26]3[C@@H:29]3[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]3[OH:40])=[C:22]([NH:41][CH2:42][CH:43]([C:44]3[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=3)[C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=3)[N:21]=2)[CH2:16]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of {(R)-1-[6-[2,2-Bis-(4-hydroxy-phenyl)-ethylamino]-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester trifluoroacetate (0.4 g, 0.57 mmol) in DCM (5 ml) and TFA (2.5 ml) is stirred at room temperature for 2 hours. The solvent is removed in vacuo to afford the title compound.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:12][C:13](Br)=[C:14]([CH3:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:1]1([S:7]([NH:10][C:11]2[S:12][C:13]([C:25]3[CH:26]=[CH:27][O:23][CH:24]=3)=[C:14]([CH3:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccoc1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(Br)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(-c2ccoc2)c1C
Temperature: 150 °C
Yield: 36.2 %

Procedure:
A mixture of ethyl 2-benzenesulphonylamino-5-bromo-4-methylthiophene-3-carboxylate (Intermediate 34, 0.134 g), 3-furan boronic acid (0.056 g) and potassium carbonate (0.114 g) in dioxane (1.3 ml) and water (0.33 ml) was degassed and placed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.019 g) was added and the mixture was heated in the microwave at 150° C. for 15 minutes. The solvent was removed and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-benzenesulphonylamino-5-(furan-3-yl)-4-methyl-thiophene-3-carboxylate (0.047 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I-:17].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:11][C:12](=[O:15])[CH2:13][I:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(NC(=O)CCl)C(=O)OCC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(NC(=O)CI)C(=O)OCC

Procedure:
A solution of 5.02 g (0.02 mole) of (2-chloroacetamido)-malonic acid diethyl ester [see Ajay Kumar Bose, J.Indian Chem. Soc. 31, 108-110 (1954)] and 4.50 g (0.03 mole) of sodium iodide in 100 ml of acetone is refluxed for 30 minutes. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed once with diluted aqueous sodium bisulphite solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from methylene chloride/hexane. After filtration with suction and drying in vacuo, there is obtained (2-iodoacetamido)-malonic acid diethyl ester, m.p. 95°-97°.
Reaction SMILES: [CH2:1]([C:5]1C=CC=C[C:6]=1[OH:11])[CH2:2]CC.[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Cl)(Cl)(Cl)=O>C(Cl)CCl>[CH3:12][NH:13][C:14](=[O:15])[O:11][CH2:6][CH2:5][CH2:1][CH3:2]
Reactant: CCOC(=O)NC
Reactant: CCCCc1ccccc1O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)NC

Procedure:
To a solution of 2-sec butylphenol (1.5 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) in ethylene dichloride (6 ml) was added phosphoryl chloride (0.77 g, 0.05 mole) and the reaction mixture was refluxed under stirring for twenty hours. It was poured onto ice-cold water. The organic layer separated and aqueous layer was extracted with dichloroethane. The combined organic layer was washed with water, dried (Na2SO4) and distilled to give liquid residue, which was further purified by distillation to give 2-sec butyl N-methylcarbamate of the formula (III) [96% by GLC, DV-101 (3%), 150° C., nitrogen, 30 ml/min.] as a liquid, b.p. 110° C. (vap.)/4 mm; IR: 3320 (N--H), 1730 (--COO--), 1535,1490 and 750 (aromatic); PMR (CDCl3, 90 MHz): 0.81 (3H,t, primary methyl of side chain, 1.58 (2H, m, methylene protons of side chain), 2.88 (4H, doublet overlapping a multiplet, NH--CH3 and benzylic proton), 4.97 (1H, br s, N--H) and 6.95 to 7.25 (4H, m, aromatic).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:14]([C:15]=1[O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6]
Reactant: COC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1c(OCc2ccccc2)c2ccccc2n1-c1ccccc1
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A mixture of 1.2 g (0.025 mole) of 50% sodium hydride/mineral oil suspension in 20 ml of hexamethylphosphoramide under a nitrogen atmosphere was cooled in ice and treated over 15 minutes with a solution of 5.3 g (0.020 mole) of 3-hydroxy-1-phenyl-1H-indole-2-carboxlic acid methyl ester [P. Friedlander and K. Kurz, Chem. Ber., 55, 1597 (1922)] in 25 ml of hexamethylphosphoramide. The mixture was stirred in ice an additional one hour, 2.6 ml (2.9 g, 0.023 mole) of benzyl chloride was added in one portion, the ice bath was removed and stirring was continued for a total of 18 hours. The reaction mixture was added to 200 g of ice/water, stirred for one hour, and the precipitated product was filtered and washed with water. Recrystallization from aqueous methanol yielded 3.8 g (54% yield) of the ester product. An additional recrystallization as above yielded analytically pure ester, mp 117°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:21])=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1[CH2:15]Cl)=[O:4].C(Cl)Cl.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:21])=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1[CH2:15][N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[O:4]
Reactant: COC(=O)c1c(Cl)nc2cc3c(cc2c1CCl)OCCO3
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(Cl)nc2cc3c(cc2c1CN1CCN(C)CC1)OCCO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with a mechanical stirrer and 250-mL addition funnel. Under nitrogen, the flask is charged with 7-chloro-9-chloromethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (340 g, 1.04 mol), prepared as in example 13c, and methylene chloride (2 L). To the stirred solution is added N-methylpiperazine (237 mL, 2.14 mol) over 10 min. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 h. The reaction mixture is poured into water (3 L) and the organic layer is separated. The aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant thick brown slurry is successively treated with methylene chloride (300 mL) and hexane (1.5 L). The mixture is swirled at 0° C. for 30 min. The precipitate is collected on a Buchner funnel, washed with hexane (1 L) and dried in vacuo. at 30° C. yielding [7-chloro-9-(4-methyl-piperazin-1-yl-methyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow powder: mp 143° C. 1H NMR (CDCl3, 200 MHz) δ2.28 (s, 3H), 2.38-2.49 (m, 8H), 3.81 (s, 2H), 3.96 (s, 3H), 4.59 (s, 2H), 4.40 (s, 4H), 7.45 (s, 1H), 7.65 (s, 1H). Elemental analysis: Calculated for C19 H22ClN3O4 : C 58.24, H 5.66, N 10.72. Found: C 58.08, H 5.72, N 10.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1C
Yield: 45.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.032 g (45%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:15]([C:31]([F:34])([F:33])[F:32])=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27]C(=O)[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].C(O)C.O>>[NH2:25][C@@:24]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)[C:15]=2[C:31]([F:33])([F:34])[F:32])[CH:20]=1)([CH3:30])[CH2:28][OH:27]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](c4ccccc4)CC3)ccc2c1
Yield: 50.1 %

Procedure:
The mixture of (R)-4-(6-(cis-4-phenyl-cyclohexyloxy)-5-trifluoromethylnaphthalen-2-yl)-4-methyloxazolidin-2-one (46.7 mg, 0.0000995 mol) and lithium hydroxide (26 mg, 0.0011 mol) in ethanol (2 mL, 0.04 mol) and water (0.4 mL, 0.02 mol) was heated to reflux overnight. LCMS showed reaction complete. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous layer was extensively extracted with CH2Cl2. The combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product as a white solid (22.1 mg, 50% yield). LCMS 427.26 ([M-NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 1.52 (s, 3 H), 1.67 (brd, J=11.8 Hz, 2 H), 1.82 (dd, J=13.4, 13.1 Hz, 2 H), 2.02 (ddd, J=13.1, 12.8, 3.0 Hz, 2 H), 2.20 (d, J=14.8 Hz, 2 H), 2.65 (ddd, J=12.2, 12.2, 3.8 Hz, 1H), 3.68 (d, J=10.9 Hz, 1H), 3.73 (d, J=10.9 Hz, 1H), 5.01 (brs, 1H), 7.14-7.30 (m, 5H), 7.50 (d, J=9.3 Hz, 1H), 7.71 (dd, J=9.3, 2.2 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 8.08 (d, J=9.3 Hz, 1H), 8.16 (d, J=9.3 Hz, 1 H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[Br:12]N1C(=O)CCC1=O.C(O)(=O)C>O>[Br:12][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: CNc1ccccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Yield: 93 %

Procedure:
5.0 g (33 mmol) of N-methyl-2-nitroaniline and 5.9 g (33 mmol) of N-bromosuccinimide were added with 60 mL of acetic acid, and the whole was refluxed under heating for 7 hours. After the completion of the reaction, the reaction solution was poured into 500 mL of water, and the precipitated solid was filtered out. The solid that had been filtered out was dissolved into ethyl acetate and dried with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was dried at room temperature under reduced pressure to obtain 7.1 g of the orange solid of 4-bromo-N-methyl-2-nitroaniline (93% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[CH:32]([C:35]1[CH:36]=[CH:37][C:38]([S:41](Cl)(=[O:43])=[O:42])=[N:39][CH:40]=1)([CH3:34])[CH3:33]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:11]1[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:41]([C:38]1[CH:37]=[CH:36][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:40][N:39]=1)(=[O:42])=[O:43]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)C)cn2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.12 g of methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in a mixture of toluene/pyridine (20 ml/30 ml) treated dropwise while cooling with ice with a solution of 1.05 g of 5-isopropylpyridine-2-sulphonyl chloride in toluene (30 ml) and subsequently stirred at room temperature for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was washed with water and dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 4-(2-chloro-5-methoxy-phenoxy)-3-(5-isopropyl-pyridine-2-sulphonylamino)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[CH2:17][C:18]([O-:20])=[O:19].[Na+].Cl>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=C([O-])CCl
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
17.94 g of sodium hydride with 61% purity and 350 ml of dried dimethyl sulfoxide were added to a well dried 1-litre 4-necked flask and suspended at room temperature. 99.00 g of methyl 3,4-dichlorophenylacetate was added dropwise thereto under cooling with ice water, the solution being continuously stirred at room temperature even after the end of the dropwise addition. Then 50.38 g of sodium chloroacetate was added under cooling with ice water and the solution was stirred at room temperature. The produced red suspension was poured into a mixture of 500 ml of 1N hydrochloric acid and 300 ml of ice water, and the solution was stirred vigorously. The reaction mixture was extracted with 800 ml of ether, and the organic layer was washed with 500 ml of water (three times) and 500 ml of a saturated saline solution (once). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled away to obtain 123.94 g of an oily substance. This oily substance was crystallized by treating it with about 400 ml of an ethyl acetate/hexane (1/20) mixture. The precipitated crystals were filtered out, washed with a small quantity of ethyl acetate/hexane (1/20) and then dried to give 93.46 g of the primary crystals of the title substance. Meanwhile, the filtrate was concentrated and crystallized from ethyl acetate/hexane, and the precipitated crystals were filtered out and dried to obtain 9.29 g of the secondary crystals (102.75 g with the primary and secondary crystals put together, 81.0% yield) of the title substance.