Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:16]([OH:18])=[O:17])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[N:6]=1.O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)C>CO.CCCCCC>[CH3:1][C:2]1[S:3][C:4]([C:16]([OH:18])=[O:17])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:20])=[O:14])[N:6]=1
Reactant: Cc1nc(CCCCCCC(=O)O)c(C(=O)O)s1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: COC(=O)CCCCCCc1nc(C)sc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
5.15 g of 2-methyl-4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, R1 = CH3) and 5.4 g of p-toluenesulphonic acid monohydrate were dissolved in 200 ml of methanol. The reaction mixture was stirred for 2 hours at room temperature, then poured onto 500 ml of water. After saturating the aqueous solution with ammonium sulphate it was extracted with 3 × 200 ml of ethyl acetate, the ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated in vacuo. Recrystallization of the obtained crude product from a mixture of diethyl ether and n-hexane afforded 4.3 g of 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid (X, R1 = CH3). M.p.: 106°-107° C. IR spectrum (KBr): ν OH (carboxylic acid) 3200-2200, ν C=O 1735, 1695, ν C-O 1235 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:14]1([CH3:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:14]1([CH3:21])[CH2:19][CH2:18][CH:17]([NH2:29])[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CCC(NC(=O)OCc1ccccc1)C1(C)CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(NC(=O)OCc1ccccc1)C1(C)CCC(N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
2.10 g (6.92 mmol) of the ketone (78) were dissolved in 21 mL of absolute methanol, then 5.34 g (69.2 mmol) of ammonium acetate and 435 mg (6.92 mmol) of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated, the residue dissolved in 50 mL of 1N aqueous sodium hydroxide and extracted twice with 100 mL of dichloromethane. The combined organic layer was dried over magnesium sulphate, filtered, and evaporated to give 1.70 g of the title compound 79 in a purity sufficient to be used directly in the next step. Rt=0.75 min (Method P). Detected mass: 305.2 (M+H+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([CH3:19])[O:7][C@@H:6]1[CH2:20][P:21]([O:32][CH2:33][O:34][C:35](=[O:40])[C:36](C)(C)C)([O:23][CH2:24][O:25][C:26](=[O:31])[C:27](C)(C)C)=[O:22])(=[O:3])[CH3:2].C(OCBr)(=O)C.C(OCI)(=O)C(C)(C)C>>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([CH3:19])[O:7][C@@H:6]1[CH2:20][P:21]([O:32][CH2:33][O:34][C:35](=[O:40])[CH3:36])([O:23][CH2:24][O:25][C:26](=[O:31])[CH3:27])=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](CP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)[C@H]1OC(C)=O
Agent: CC(=O)OCBr
Agent: CC(C)(C)C(=O)OCI
Product: CC(=O)OCOP(=O)(C[C@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)OCOC(C)=O

Procedure:
This compound was synthesized by the same procedure used for the synthesis of (2S,3S,4R,5R,6S)-2-((bis((pivaloyloxy)methoxy)phosphoryl)methyl)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate, but using bromomethyl acetate (commercially available from Sigma Aldrich) instead of iodomethyl pivalate: ESI (M+H) 513.0; calc for C19H29O14P 512.4; 1H NMR (400 MHz, CD3OD) δ ppm 5.71-5.61 (m, 4 H) 5.29 (dd, J=3.33, 0.78 Hz, 1 H) 5.12 (dd, J=3.33, 10.17 Hz, 1 H) 5.05 (dd, J=9.59, 9.98 Hz, 1 H) 4.00-3.83 (m, 2 H) 2.35-2.17 (m, 2 H) 2.18 (s, 3 H) 2.16 (s, 3 H) 2.15 (s, 3 H) 2.09 (s, 3 H) 1.96 (2, 3 H) 1.18 (d, J=6.46 Hz, 3 H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([CH:11]=[CH:12][CH:13]=1)N.N([O-])=[O:16].[Na+]>O>[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=N[O-]
Reactant: Cc1c(N)cccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1c(O)cccc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution of concentrated sulphuric acid (7.3 mL) in water (97 mL) was added to 3-chloro-2-methylaniline (0.84 mL, 7.06 mmol) and the mixture heated at 90° C. until solution was achieved. The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (510 mg, 12.75 mmol) in water (5 mL) was added dropwise. The reaction mixture was allowed to warm to ambient temperature over 2 h. Excess sodium nitrite was destroyed by the addition of urea. The resultant mixture was added to a solution of concentrated sulphuric acid (5.0 mL) in water (55 mL), heated to 90° C. and stirred at this temperature for a further 1 h. The resultant product mixture was filtered through dicalite and extracted with dichloromethane (2×200 mL). The organic phase was washed with NaHCO3 (aq.), dried (MgSO4) and evaporated under reduced pressure to afford the desired product (830 mg, 83%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Si:26]([O:33][CH2:34][CH2:35]I)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(OCC)(=O)C.ClCCl>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:35][CH2:34][O:33][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Alternately, combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.72 g, 5.43 mmol) and sodium hydride (0.36 g, 60% in oil, 8.15 mmol) in dimethylformamide (40 mL). After 4 hours, add 2-(t-butyldimethylsilyloxy)ethyl iodide (1.56 g, 5.43 mmol). After 72 hours, heat to 80° C. After 3 hours, cool to ambient temperature and add ice to quench. Partition the reaction mixture between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL). Separate the layers and extract the organic layer with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 40% ethyl acetate/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:26].[CH2:28](I)[CH3:29]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:28][CH3:29]
Reactant: CCI
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: CCOc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 327 and ethyl iodide, white powdery 3-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 330.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH:23]([CH2:25][C:26]([O:28]CC)=[O:27])[C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=4[CH2:20][C:19]=3[CH:35]=2)[CH:5]=1.CCO.C(O)(C(F)(F)F)=O>C1COCC1.O>[NH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=4[CH2:20][C:19]=3[CH:35]=2)[CH:5]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3cc(N)ccn3)cc2Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)c1
Reaction time: 19.5 h
Yield: 65.2 %

Procedure:
1.0 N LiOH (0.74 mL, 0.74 mmole) was added all at once to a solution of ethyl (±)-10,11-dihydro-3-[3-(4-amino-2-pyridylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (216.3 mg, 0.49 mmole) in THF (2.5 mL) and H2O (1.8 mL) at RT. The two-phase mixture was warmed for 1 hr in an oil bath set at 40° C., then absolute EtOH (ca. 1 mL) was added to combine the phases. The reaction was kept at 40° C. for 19.5 hr, then was concentrated, and the residue was dissolved in 1:1 CH3CN/H2O (5 mL). The solution was acidified with TFA (0.11 mL, 1.47 mmole) and concentrated. ODS chromatography (40% CH3CN/H2O containing 0.1% TFA) followed by concentration to remove CH3CN left an oily, aqueous solution, which was made homogeneous by addition of a little CH3CN. The pH was adjusted to 7 with 1.0 N NaOH, and an oily semisolid precipitated. The mixture was concentrated to remove the CH3CN, and the resulting solid was collected. This was dissolved in aqueous NaOH, and the pH was adjusted to 7. The solid was collected, washed with plenty of H2O, and dried in high vacuum at 45° C. to afford the title compound (133.3 mg, 61%) as an off-white solid: HPLC (Hamilton PRP-®, 35% CH3CN/H2O containing 0.1% TFA) k'=3.0; 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=6.3 Hz, 1 H), 7.04-7.22 (m, 4 H), 6.95 (d, J=8.2 Hz, 1 H), 6.88-7.02 (m, 1 H), 6.82 (d, J=2.4 Hz, 1 H), 6.67 (dd, J=8.2, 2.4 Hz, 1 H), 6.27 (br s, 2 H), 5.95 (dd, 1 H), 5.65 (narrow d, 1 H), 4.18 (d, J =14.7 Hz, 1 H), 4.00 (t, J=6.1 Hz, 2 H), 3.88 (d, J=14.7 Hz, 1 H), 3.59-3.70 (m, 1 H), 3.13-3.30 (m, 3 H), 2.82 (dd, J=15.2, 10.0 Hz, 1 H), 2.46 (dd, J=15.8, 8.8 Hz, 1 H, partially obscured by residual solvent signal), 2.58 (dd, J=15.8, 5.2 Hz, 1 H), 1.86-2.01 (m, 2 H); MS (ES) m/e 418 (M+H)+. Anal. Calcd for C25H27N3O3 . 1.67 H2O: C, 67.09; H, 6.83; N, 9.39. Found: C, 66.99; H, 6.59; N, 9.34.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[O:4]1[CH2:5][CH2:6][N:7]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[C:2]2[CH:31]=[CH:30][CH:29]=[CH:28][C:3]1=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCOc3ccccc3Br)nc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOc4ccccc43)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(2-(2-bromophenoxy)ethylamino)-2-phenylquinoxaline-6-carboxylate (363.9 mg, 0.76 mmol, 1.00 equiv), Pd2(dba)3 (70.2 mg, 0.08 mmol, 0.10 equiv), BINAP (189.8 mg, 0.31 mmol, 0.40 equiv), Cs2CO3 (746.1 mg, 2.29 mmol, 3.00 equiv), 1,4-dioxane (5 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 166.8 mg (44%) of methyl 3-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11](C(CCC)=CCC)=[C:10]2[C:5]([C:6]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[CH:7][CH:8]=[CH:9]2)=[N:4]1.CN1C(C(O)(CCC)CCC)=C2C(C(C3C(C)=CC(C)=CC=3C)=CC=C2)=N1>>[CH3:2][N:3]1[CH:11]=[C:10]2[C:5]([C:6]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[CH:7][CH:8]=[CH:9]2)=[N:4]1
Reactant: CCC=C(CCC)c1c2cccc(-c3c(C)cc(C)cc3C)c2nn1C
Agent: CCCC(O)(CCC)c1c2cccc(-c3c(C)cc(C)cc3C)c2nn1C
Agent: Cl
Product: Cc1cc(C)c(-c2cccc3cn(C)nc23)c(C)c1

Procedure:
2-Methyl-3-(1-propyl-but-1-enyl)-7-(2,4,6-trimethyl-phenyl)-2H-indazole Hydrochloride (Ib or 6b Scheme 1)—Prepared from 4-[2-Methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazol-3-yl]-heptan-4-ol (5b) using the procedure in step 8 of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][N:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1.NC1C2C(C(C3C=CN=C(NS(C4C=CC=CC=4F)(=O)=O)C=3)=O)=CN(C(C)C)C=2N=CN=1>>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([NH:30][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:27]=[CH:26][N:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(C)n1cc(C(=O)c2cc(N)ccn2)c2c(N)ncnc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: CC(C)n1cc(C(=O)c2ccnc(NS(=O)(=O)c3ccccc3F)c2)c2c(N)ncnc21
Product: CC(C)n1cc(C(=O)c2cc(NS(=O)(=O)c3ccccc3F)ccn2)c2c(N)ncnc21

Procedure:
The title compound was prepared from 2-fluoro-benzenesulfonyl chloride (0.53 mL, 0.41 mmol) and (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-amino-pyridin-2-yl)-methanone (0.10 g, 0.34 mmol) by procedures analogous to those described for the preparation of N-[4-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-2-yl]-2-fluoro-benzenesulfonamide. MS: 455.3 (MH+); HPLC Rf: 2.4 min. (HPLC method 2).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:31][C:32]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][C:35](B(O)O)=[C:34]([O:44][CH3:45])[CH:33]=1.[OH-].[K+]>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[C:35]3[CH:36]=[C:37]([CH:38]([CH3:40])[CH3:39])[C:32]([F:31])=[CH:33][C:34]=3[O:44][CH3:45])[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(F)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (1.0 g, 2.0 mmol) in 1,4-dioxane (6 mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (509 mg, 2.4 mmol), [1,1′-bis(diphenylphosphino) ferrocene] dichloropalladium (II) (82 mg, 5 mol %) and aq. potassium hydroxide (1.3 mL, 3M, 2 eq.). The reaction mixture was purged with nitrogen and then sealed in a microwave vessel. The reaction vessel was subject to microwave irradiation at 150° C. for 40 min. Crude mixture was worked up with water. Volatiles were evaporated. The resulting mixture was extracted with EtOAc. The combined extracts were dried over Na2SO4. The resulting purple residue was purified by SiO2 (Biotage 40+M cartridge, eluted by EtOAc/hexane, gradient; 5% to 25%). The titled compound was obtained as clear solid. LC-MS:588.23 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 6:4 mixture of rotamers δ 7.85 (s, 1H), 7.69 (s, 2H), 7.16-7.21 (m, 1.5H), 7.04-7.13 (m, 1.5H), 6.96 (dd, J=14.3, 8.80 Hz, 1H), 6.65 (d, J=10.0 Hz, 1H), 5.59 (d, J=8.0 Hz, 0.6H), 5.43 (d, J=8.0 Hz, 0.4H), 4.85 (d, J=15.8 Hz, 0.6H), 4.82 (d, J=15.8 Hz, 0.4H), 4.02 (d, J=15.8 Hz, 0.6H), 3.85 (m, 0.6H), 3.76-3.81 (m, 0.8H), 3.75 (s, 1.8H), 3.73 (s, 1.2H), 3.19 (m, 1H), 1.14-1.26 (m, 6H), 0.56 (d, J=6.6 Hz, 1.2H), 0.38 (d, J=6.6 Hz, 1.8H).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[NH:11][CH:10]=[CH:9][C:8]2=[O:17].CC(O)=O>[OH-].[Na+]>[I:1][C:9]1[C:8](=[O:17])[C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH3:3])[CH:6]=2)[NH:11][CH:10]=1
Reactant: II
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc2[nH]cc(I)c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of iodine (14.84 g, 58.48 mmol) in KI (20% aq, 100 mL) was added to a solution of 6,7-dimethoxyquinolin-4(1H)-one (10.00 g, 48.73 mmol) in 2 N NaOH (aq, 100 mL), and the solution stirred at RT for 17 h. The mixture was acidified with AcOH and the resulting dark purple mixture was filtered and washed with water. The dark purple filter cake was recrystallized from water to afford an off-white suspension. This material was filtered and dried to afford 3-iodo-6,7-dimethoxyquinolin-4(1H)-one as an off-white solid. MS (ESI, pos. ion) m/z: 332.1 (M+H). Mass Calc'd for C11H10INO3: 331.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[N:6][C:7]([C:14]2[NH:15][C:16](=[O:23])[C:17]([CH:20]([CH3:22])[CH3:21])([CH3:19])[N:18]=2)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[N:6][C:7]([C:14]2[NH:15][C:16](=[O:23])[C:17]([CH:20]([CH3:21])[CH3:22])([CH3:19])[N:18]=2)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:1])[CH3:3]
Reactant: COC(=O)c1cc(C(C)O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)=O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 8.2 g of methyl 5-(1-hydroxyethyl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate, 14.5 g of pyridinum dichromate and 1.99 g of pyridinium trifluoroacetate in 30 mL of methylene chloride is stirred at room temperature under nitrogen for 3 days. The reaction mixture is flash-chromatographed through florisil using methylene chloride as eluent, and the combined eluates are washed with water, dried, and concentrated in vacuo to a dark oil. Chromatography of this oil on silica gel using ether-hexane as eluant affords the desired product as a solid. Recrystallization of this solid from methylene chloride-hexane affords a white solid, mp 105°-108° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][NH:13][CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3cc(CNC4CCNC4)ncn3)ccc21

Procedure:
(±)-3-({6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (20 mg, 3.30 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is then extracted with EtOAc (3×) and the combined organic layers are washed with water, brine, dried with Na2SO4, filtered, and condensed. The residue is purified by FCC (0-10% 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 496.8 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.65 (s, 1 H), 8.36 (d, J=8.84 Hz, 1 H), 8.06 (s, 1H), 7.95 (d, J=3.54 Hz, 1 H), 7.88 (s, 1 H), 7.57 (t, J=7.83 Hz, 1 H), 7.44 (d, J=7.83 Hz, 1 H), 7.42 (d, J=2.27 Hz, 1 H), 7.03-7.13 (m, 2 H), 6.75 (d, J=3.79 Hz, 1 H), 3.80-3.85 (m, 2 H), 2.81-3.02 (m, 3 H), 2.52-2.75 (m, 2 H), 2.19-2.35 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11](=O)[CH2:12][CH2:13][CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CCCC=O
Product: CCCC(c1c[nH]c2ccc(F)cc12)c1c[nH]c2ccc(F)cc12
Yield: 45 %

Procedure:
This was prepared in the same way as described in example 2/2 starting from 5-fluoroindole and butyraldehyde. The reaction, however, was heated under reflux for 24 hours. The end product was isolated and purified by chromatography on an SiO2 column using a hexane:ethyl ether gradient ranging from 7:3 to 4:6 as the eluent. Yield 45%.
Reaction SMILES: CO.[OH-].[K+].C[O:6][C:7]([C:9]1[C:10]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:11]=2[S:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:8].Cl>O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:10]2[C:9]([C:7]([OH:8])=[O:6])=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11]=2[CH:22]=1
Reactant: COC(=O)c1c(-c2ccc(OC)cc2)sc2cc(OC)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)O)cc1
Yield: 97.2 %

Procedure:
To methanol (25 ml) and water (10 ml) is added 2.5 N potassium hydroxide in methanol (7 ml, 18.5 mmol) and 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid methyl ester (2.00 g, 6.09 mmol). The contents are heated to reflux for 16 hours, then cooled and poured into a solution of 1 N hydrochloric acid (50 ml). The resulting slurry is further diluted with water (75 ml), then filtered, and the filter cake rinsed with water, and dried in vacuo to afford 1.86 g (97%) of title compound. IR (KBr) 3100-2400 (br), 2935, 1673, 1608, 1527, 1433, 1250, 1178, 1030, 828 cm-1 ; 1H NMR (CDCl3 /DMSO-d6): δ8.27 (d, 1 H, J=9.0 Hz), 7.49 (d, 2 H, J=8.5 Hz), 7.26 (d, 1 H, J=1.7 Hz), 7.06 (dd, 1 H, J=9.0, 1.7 Hz), 6.93 (d, 2 H, J=8.5 Hz), 3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (CDCl3 /DMSO-d6): d 166.0, 160.1, 157.6, 148.5, 139.8, 133.2, 131.0, 126.6, 125.7, 123.0, 115.1, 113.8, 104.3, 55.7, 55.5. Anal. Calcd. for C17H14O4S: C, 64.95; H, 4.49; S, 10.20. Found: C, 64.72; H, 4.49; S, 10.40.
Reaction SMILES: F[As-](F)(F)(F)(F)F.[CH3:8][N:9]([CH3:25])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]#[N:17])=[CH:12][C:11]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O(C1C=CC=CC=1N)C1C=CC=CC=1.S(OC)(OC)(=O)=O.CN(C)C1C=CC=CC=1OC1C=CC=CC=1.[Cl-].[Cl:64][C:65]1[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][C:66]=1[N+]#N>>[Cl:64][C:65]1[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][C:66]=1[N:17]=[N:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([CH3:25])[CH3:8])=[C:11]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=1
Reactant: N#[N+]c1cc(Cl)ccc1Cl
Reactant: CN(C)c1ccc([N+]#N)cc1Oc1ccccc1
Agent: CN(C)c1ccccc1Oc1ccccc1
Agent: F[As-](F)(F)(F)(F)F
Agent: Nc1ccccc1Oc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CN(C)c1ccc(N=Nc2cc(Cl)ccc2Cl)cc1Oc1ccccc1

Procedure:
4-Dimethylamino-3-phenoxybenzenediazonium hexafluoroarsenate was also prepared by the following route: o-phenoxyaniline was methylated with dimethyl sulfate to N,N-dimethyl-o-phenoxyaniline, m. 34°-5°, which was coupled with 2,5-dichlorobenzenediazonium chloride to give 4-(2,5-dichlorophenylazo)-N,N-dimethyl-2-phenoxyaniline, m. 93°-4°. This was then reduced catalytically to N1,N1 -dimethyl-2-phenoxy-p-phenylenediamine, m. 76°-6°, which was diazotized as above.