Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[O:21][CH2:20]1)(=O)=O>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: Oc1cccc2ncccc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OC[C@H]2CO2)c2cccnc2c1
Temperature: 5 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
Sodium hydride (60 weight %; 1.79 g; 44.8 mmol) is washed with hexanes (3×10 mL) under an argon blanket. DMF (17 mL) is then added at ambient temperature and the stirred slurry is cooled to 5° C. A solution of 5-hydroxyquinoline (5.00 g; 34.4 mmol) in DMF (65 mL) is added dropwise over 30 minutes. The resulting mixture is allowed to warm to ambient temperature over 1 hour affording a clear, reddish-brown solution. A solution of (R)-(−)-glycidyl tosylate (10.22 g; 44.8 mmol) in DMF (50 mL) is added dropwise over 20 minutes. The resulting mixture is stirred at ambient temperature for 4 hours, quenched by the addition of saturated aqueous ammonium chloride (25 mL), poured onto water (750 mL), and extracted with ether (3×375 mL). The combined ether layers are washed with saturated aqueous sodium bicarbonate (2×375 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (33%→50% ethyl acetate in hexanes) affording the desired product (4.95 g) as a tan solid. ESMS: MH+ 202.2 (base).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:10][CH2:9][NH:8]2)[CH:2]=1.C=O.[CH:13](O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:13][N:8]1[CH2:9][CH2:10][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=CO
Reactant: c1cncc(C2CCN2)c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCC1c1cccnc1
Temperature: 0 °C

Procedure:
To a solution of 920 mg (6.88 mmoles) of the 2-(3-pyridyl)azetidine produced in Example 2 in 9 ml of water was added a solution of 660 mg (8.83 mmoles) of formaldehyde (40% w/w) in 9 ml of water and 755 mg (14.5 mmoles) of 88% formic acid in 9 ml of water. After heating on a steam bath for 2 hours, cooling to 0° C. and adding 1.21 g (14.4 mmoles) of sodium bicarbonate, the colored solution was concentrated under reduced pressure to 7 ml. It was then dried by azeotroping in benzene and ethyl alcohol to give a dry benzene solution containing insolubles. These insolubles were then filtered off to yield a solution of N-methyl-2-(3-pyridyl)azetidine.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:11])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.OO.NC(N)=[O:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([CH:6]2[CH:7]([CH2:8][CH2:9][CH3:10])[O:16]2)=[O:11])[CH2:3][CH2:2]1
Reactant: CCC/C=C/C(=O)NC1CC1
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCC1OC1C(=O)NC1CC1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a three-neck 250 mL round bottom flask equipped with mechanical stirrer and containing compound 37 (10.0 g, 65.3 mmol) and urea hydrogen peroxide (UHP) (25.0 g, 4.0 eq.) in CH2Cl2 (100 mL, 10 vol) at 0° C., was added trifluoroacetic anhydride (41.1 g, 27.2 mL, 3.0 eq.). The reaction mixture was heated to 35±5° C. and stirred for 2 hours. After cooling the reaction mixture down to room temperature, another aliquot of trifluoroacetic anhydride (13.7 g, 9.0 mL, 1.0 eq.) was added. The reaction mixture was heated again to 35±5° C. and stirred for another 3 hours. The reaction mixture was then again cooled to 0° C. and quenched by adding saturated NaHCO3 (5 vol.) slowly and stirring for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL, 5 vol). The combined organic layer was dried and evaporated to afford the crude product, N-cyclopropyl-3-propyloxirane-2-carboxamide (38), as a pale yellow oil. The crude product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.[Mg].BrC1C=CC(C)=CC=1.C(N1CCCCC1=[O:46])C1C=CC=CC=1.[Cl-].[NH4+]>BrC1C=CC(C)=CC=1.C(OCC)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([OH:21])([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH2:12][C:13]1=[O:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: Cc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccc(C2(O)CCN(Cc3ccccc3)C(=O)C2)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1-Benzyl-4-hydroxy-4-(4-methylphenyl)piperidine may be prepared in the following manner: several drops of p-bromotoluene and a crystal of iodine are added to magnesium turnings (1.7 g) in diethyl ether (25 cc), under a current of argon. The mixture is heated to boiling, then a solution of p-bromotoluene (12.1 g) in diethyl ether (70 cc) is poured in in such a manner as to maintain the reflux. The reaction medium is stirred for 30 minutes at the boiling point of the solvent, then cooled to a temperature of about 20° C. A solution of 1benzylpiperidone (6.7 g) in diethyl ether (60 cc) is added, and stirring is maintained for 15 hours at the same temperature. A saturated solution of ammonium chloride (150 cc) is added to the mixture; the aqueous phase is decanted and the organic phase is extracted with diethyl ether (2 x 150 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and methanol (95-5 vol) as eluant. 1-Benzyl-4-hydroxy-4(4-methylphenyl)piperidone (5 g) is obtained in the form of an oil, which is used in the crude state in the subsequent syntheses.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13]>>[C:9]1([CH3:8])[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][NH:13][CH:3]=[CH:4][C:5](=[O:7])[CH3:6])[CH:10]=1
Reactant: COC=CC(C)=O
Reactant: Cc1cccc(CN)c1
Product: CC(=O)C=CNCc1cccc(C)c1

Procedure:
The title compound 62 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.1 g, 1 mmol) and 3-methylbenzylamine (0.125 g, 1 mmol) as reactants. Yellow oil. (Yield 0.19 g, 100%).
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].N1CCC[C:10]1=O.C=O.ClCN1CCCC1=O.C[O-].[Na+]>CO>[CH3:10][O:1][CH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: O=C1CCCN1
Reactant: O=C1CCCN1CO
Agent: C=O
Agent: C[O-]
Agent: O=C1CCCN1CCl
Solvent: CO
Product: COCN1CCCC1=O
Yield: 64 %

Procedure:
N-hydroxymethyl pyrrolidinone is a compound known in the art as an intermediate in the preparation of dyestuffs. As taught in U.S. Pat. No. 3,073,843, this material is prepared by the reaction of pyrrolidinone and formaldehyde or a precursor of formaldehyde. This patent does not suggest the formation of derivatives of this compound however. In addition, Chemical Abstracts, Volume 55, page 27267H (1961) discloses the reaction of N-chloromethyl-2-pyrrolidinone with a mixture of sodium methylate and methanol to yield 64% of N-methoxymethyl-2-pyrrolidinone. Also, Chemical Abstracts, Volume 54, page 1286f (1960) teaches that N-chloromethyl-2-pyrrolidinone can be prepared in 87% yield by treatment of the methylol derivative with SOCl2 in benzene solvent at 8°C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[C:47]2[N:60]=[C:59]([NH2:61])[S:58][C:48]=2[C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:50][CH:51]=1>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([NH:61][C:59]1[S:58][C:48]2[C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[N:50][CH:51]=[C:46]([O:45][CH3:44])[C:47]=2[N:60]=1)=[O:9]
Reactant: COc1cc(C(=O)O)ccn1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-methoxy-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br[CH2:12][CH2:13][CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCNCC1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN1CCN(CCCC#N)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 25 mL flask was placed 1-butyl-piperazine (712 mg, 5.0 mmol), 4-bromobutyronitrile (779 mg, 5.3 mmol) and potassium carbonate (687 mg, 5.0 mmol) suspended in acetonitrile (5 mL). The reaction mixture was stirred at rt for 12 h., followed by addition of H2O (20 mL) and extraction with ethyl acetate (3×25 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO4) and evaporated to dryness to produce 0.89 g of crude 16 which was used without further purification in the synthesis of compound 17.
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:18]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:35])[CH:27]=4)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.FC(F)O[C:40]1C=C(S(Cl)(=O)=O)C=C[CH:45]=1>>[CH2:40]([O:31][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][CH2:14][N:13]([S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:36])[CH:5]=4)(=[O:12])=[O:11])[C:18]=3[CH:19]=2)=[O:24])=[CH:27][C:28]=1[F:35])[CH3:45]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(OC(F)F)c1)CCO2
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(OC(F)F)c2)CCO3)cc1F

Procedure:
4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=521.2 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-difluoromethoxy-benzenesulfonyl chloride and yielded 4-{[4-(3-difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]ox-azine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[S:36])[CH:30]=[CH:31][C:32]=1[CH3:33].Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[S:36])[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=S)cc1Cl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(NC(=S)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 3-chloro-4-methylphenyl isothiocyanate (0.26 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The mixture was stirred at ambient temperature for 3 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-(3-chloro-4-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-thiourea as a white solid (0.52 g, 84% yield); mp 240-242° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.11 (97.48%); 1H NMR (DMSO-d6) δ 1.95-2.06 (m, 1H, CHH), 2.29 (s, 3H, CH3), 2.35-2.47 (m, 1H, CHH), 2.55-2.67 (m, 1H, CHH), 2.84-3.00 (m, 1H, CHH), 4.32 (d, 1H, CHH), 4.46 (d, 1H, CHH), 4.86 (d, J=5.1 Hz, 2H, CH, and CHH), 5.11 (dd, 1H, CH), 7.25 (dd, 1H, Ar), 7.28 (d, 1H, Ar), 7.47 (d, 1H, Ar), 7.54 (s, 1H, Ar), 7.61 (s, 1H, Ar), 7.70 (d, 1H, Ar), 8.37 (t, 1H, NH), 9.73 (s, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.96, 22.49, 31.20, 47.13, 51.58, 122.14, 122.88, 123.48, 127.13, 130.39, 130.97, 131.12, 132.67, 138.29, 142.27, 143.32, 167.92, 170.99, 172.86, 181.00; LCMS: MH=457/459; Anal. Calcd for C22H21ClN4O3S: C, 57.83; H, 4.63; N, 12.26. Found: C, 57.57; H, 4.51; N, 12.21.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[C@@H:11]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:16]=[CH:17][CH:18]=1)[OH:12]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[C@@H:11]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])[CH:16]=[CH:17][CH:18]=1)[OH:12]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)OC)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Trifluoroacetic acid (0.04 mL) was added to a solution of (R)-[4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-3-yl]-hydroxy-acetic acid methyl ester (Example 156-(2); 3.6 mg, 0.0056 mmol) in dichloromethane (0.20 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 to 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (2.6 mg, 87%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[C:26]([CH3:40])[CH:25]=3)=[O:23])[CH2:12][C:11]=2[CH:10]=[N:9]1>ClCCl.C(N(CC)CC)C>[CH3:40][C:26]1[CH:25]=[C:24]([C:22]([N:13]2[CH2:12][C:11]3[CH:10]=[N:9][N:8]([CH3:7])[C:17]=3[NH:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]2=3)=[O:23])[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:1](=[O:3])[CH3:2])[CH2:36][CH2:35]1
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCCOc2ccc(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride (Compound number 408) (2.67 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=503.2
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:9]([CH3:23])[CH:8]=1)=[O:6]>CO>[CH3:23][C:9]1[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:12]=[CH:11][C:10]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Add sodium hydroxide (5.0N, 0.03 mL, 0.15 mmol) to 2-methyl-4′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (2.52 g, 8.6 mmol) in methanol (15 mL) and stir for two hours. Acidify with 1.0 N HCl and extract desired compound with ethyl acetate three times. Wash organic phase with saturated sodium chloride solution, dry over Na2SO4, filter and concentrate under reduced pressure to provide 2.31 g (96%) of title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:7])[CH2:4][CH2:5][SH:6].[CH2:8]([C:15]([N:33]([CH3:35])[CH3:34])([CH2:31][CH3:32])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[CH2:8]([C:15]([N:33]([CH3:35])[CH3:34])([CH2:31][CH3:32])[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([S:6][CH2:5][CH2:4][CH2:3][SH:7])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(-c2ccc(Br)cc2)cc1)N(C)C
Reactant: SCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(-c2ccc(SCCCS)cc2)cc1)N(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
9.2 mmol of sodium hydride are suspended in 40 ml of dry dimethylformamide and 2.3 ml (23 mmol) of 1,3-propanedithiol are added dropwise. Then 2.0 g (4.6 mmol) of 2-benzyl-1-(4'-bromo-biphenyl-4-yl)-2-dimethylamino-butan-1-one (prepared by the method described in U.S. Pat. No. 5,534,629) in 60 ml of dimethylformamide are added dropwise. After stirring the solution at 100° C. for 2 h, the solution is poured into water. The crude product is extracted with methylene chloride, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent. The structure of the product is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 0.72 (t, 3H), 1.37 (t, 1H), 1.84-2.01 (m, 3H), 2.09 (dq, 1H), 2.40 (s, 6H), 2.68 (dt, 2H), 3.10 (t, 2H), 3.23 (s, 2H), 7.15-7.29 (m, 5H), 7.41 (d, 2H), 7.55-7.62 (m, 4H), 8.41 (d, 2H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16]Br)=[O:5].[CH3:25][NH:26][CH3:27]>C1COCC1>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:26]([CH3:27])[CH3:25])=[O:5])[CH3:1]
Reactant: CNC
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Cl)cc(CN(C)C)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 0.200 g (0.48 mmol) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (previously described) in THF (3 ml) at RT, 0.17 ml of dimethyl amine (5.6 M in EtOH) was added. The reaction mixture was stirred at RT for one hour and concentrated under vacuo. The crude was dissolved in CH2Cl2 (1 m) and at RT 0.2 ml of TFA was added and stirring was continued over night. Preparative HPLC (30% CH3CN/H2O) afforded 67 mg (50%) of 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid ethyl ester as colorless oil. ES-MS m/e (%): 281.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH:20]([CH3:22])[CH3:21])[CH:14]=2)=[C:7]([Br:23])[CH:6]=1.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC.[CH2:50]=[O:51]>Cl[Sn](Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:14]=[C:15]([CH:20]([CH3:22])[CH3:21])[C:16]([OH:19])=[C:17]([CH:50]=[O:51])[CH:18]=2)=[C:7]([Br:23])[CH:6]=1
Reactant: C=O
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c(Br)c1
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
Methyl[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenyl]acetate (2.0 g, 4.4 mmol), SnCl4 (25 μl, 0.2 mmol), trioctyl amine (0.77 mL, 1.76 mmol) and toluene (15 mL) were mixed in a reaction vial. After 20 minutes stirring at room temperature, paraformaldehyde (0.264 g, 8.8 mmol) was added to the reaction solution. The reaction vial was sealed and the temperature increased to 105° C. After 20 hours stirring, the reaction was quenched with ice-water and acidified with hydrochloric acid (1 N). Extraction with ethyl acetate, washing with brine, drying over Na2SO4 and concentration gave the crude product. The residue was purified on column (silica, gradient elution: n-heptane/ethyl acetate from 1:0 to 4:1) to give 1.08 g (51%) of methyl[3,5-dibromo-4-(3-formyl-4-hydroxy-5-isopropylphenoxy)phenyl]acetate.
Reaction SMILES: [Cl-:1].[Cl-].C([Hf:11]([SiH2]C1C=CC=CC=1)([CH:21]1[C:29]2[C:24](=CC=CC=2)[CH:23]=[CH:22]1)[CH:12]1[C:20]2[C:15](=CC=CC=2)[CH:14]=[CH:13]1)CCCCCCC>[Cl-].[Cl-].C(C1([Zr+2]C2(CCCC)C=CC=C2)C=CC=C1)CCC.[Cl-].[Cl-].C[SiH]([Zr+2](C1C2C(=CC=CC=2)C=C1)C1C2C(=CC=CC=2)C=C1)C.[Cl-].[Cl-].C[SiH]([Zr+2](C1C2C(=CC=CC=2)C=C1C)C1C2C(=CC=CC=2)C=C1C)C.C1([Ti](Cl)(OCC)OCC)C2C(=CC=CC=2)C=C1.[Cl-].[Cl-].CC1C([Zr+2]C2(C)C(C)=C(C)C(C)=C2C)(C)C(C)=C(C)C=1C.[Cl-].[Cl-].C1([Zr+2]C2C3C(=CC=CC=3)C=C2)C2C(=CC=CC=2)C=C1.[Cl-].[Cl-].C[Zr]([SiH2]CCCCCCCC)(C1C2C=CC=CC=2C2C1=CC=CC=2)C1C2C=CC=CC=2C2C1=CC=CC=2>[Cl-:1].[Cl-:1].[CH:21]1([Hf+2:11][CH:12]2[CH:20]=[CH:15][CH:14]=[CH:13]2)[CH:22]=[CH:23][CH:24]=[CH:29]1
Reactant: CCCCCCCC[Hf]([SiH2]c1ccccc1)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Agent: C1=CC([Zr+2]C2C=Cc3ccccc32)c2ccccc21
Agent: CC1=C(C)C(C)([Zr+2]C2(C)C(C)=C(C)C(C)=C2C)C(C)=C1C
Agent: CC1=Cc2ccccc2C1[Zr+2](C1C(C)=Cc2ccccc21)[SiH](C)C
Product: C1=CC([Hf+2]C2C=CC=C2)C=C1

Procedure:
1,2-ethanediylbis(η5-1-indenyl)di-n-butoxyhafnium; 1,2-ethanediylbis(η5-1-indenyl)dimethylzirconium; 3,3-pentanediylbis((η5-4,5,6,7-tetrahydro-1-indenyl)hafnium dichloride; methylphenylsilylbis(η5-4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride; bis(n-butylcyclopentadienyl)bis(di-t-butylamido)hafnium; bis(n-butylcyclopentadienyl)zirconium dichloride; dimethylsilylbis(1-indenyl)zirconium dichloride; octylphenylsilylbis(1-indenyl)hafnium dichloride; dimethylsilylbis(η5-4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride; dimethylsilylbis(2-methyl-1-indenyl)zirconium dichloride; 1,2-ethanediylbis(9-fluorenyl)zirconium dichloride; indenyl diethoxy titanium(IV) chloride; (isopropylamidodimethylsilyl)cyclopentadienyltitanium dichloride; bis(pentamethylcyclopentadienyl)zirconium dichloride; bis(indenyl)zirconium dichloride; bis(indenyl)zirconium dichloride; methyloctylsilyl bis(9-fluorenyl)zirconium dichloride; bis-[1-(N,N-diisopropylamino)boratebenzene]hydridozirconium trifluoromethylsulfonate; or any combination thereof.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][O:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.NN>>[NH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:31][O:32][CH2:33][CH3:34]
Reactant: CCOCc1nc2c(N)nc3c(c2n1CCCCON1C(=O)c2ccccc2C1=O)CCCC3
Agent: NN
Product: CCOCc1nc2c(N)nc3c(c2n1CCCCON)CCCC3

Procedure:
The method described in Part C of Example 140 can be used to treat 2-{4-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione with anhydrous hydrazine to provide 1-[4-(aminooxy)butyl]-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine.