Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[S:34]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:35])=[O:36]
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1S(=O)(=O)n1ccc2c3c(ccc21)OCCN(C(=O)OC(C)(C)C)C3C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-methoxy-4-methylbenzenesulfonyl chloride (25 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2-methoxy-4-methylphenyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (21 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (7 mg). MS m/z 387 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]#[CH:23])[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].C1(C=O)CCCCC1>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.[Cu]I.C(N(CC)CC)C>[CH2:11]([C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]#[C:23][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH2:20][CH2:21]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C#CC1CCC(CCCCC)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=CC1CCCCC1
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H](C#Cc2ccc(C#N)c(F)c2)CC1
Reaction time: 12 h

Procedure:
0.2 mmol of bis-(triphenylphosphine)-palladium(II) chloride and 0.1 mmol of copper(I) iodide are added to a mixture of 0.01 mol of 2-fluoro-4-bromobenzonitrile, 0.01 mol of 4-pentylcyclohexylacetylene (which can be prepared, for example, from the corresponding cyclohexanecarbaldehyde by the method of Corey, Fuchs in Tetrahedron Letters (1972) 3769) and 40 ml of triethylamine at room temperature and the mixture is stirred for 12 hours. The reaction can be monitored with the aid of thin layer chromatography. When the reaction has ended, the suspension is filtered and the filtrate is evaporated. Purification by chromatography and/or crystallization gives 1-(trans-4-pentylcyclohexyl)-2-(3-fluoro-4-cyano- phenyl)-acetylene of M.=38° and C.=40.3°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[H-].[Na+].C[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=2)[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: COc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: Oc1ccc(CO[C@H](c2ccc(Br)cc2)C(F)(F)F)cc1

Procedure:
(R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (3.5 g, synthesis described in J. Org. Chem. 2009, 74, 1605-1610) was dissolved in THF (50 ml) under an argon atmosphere, NaH (719 mg) was added at 0° C. followed by tetrabutylammonium iodide (507 mg) then 4-methoxy-benzylbromide (3.04 g) and the mixture was stirred for 3.5 h at 20° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:18][O:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc(C(=O)OC)c([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1sc(C(=O)OC)c([N+](=O)[O-])c1OC
Yield: 43.6 %

Procedure:
To a solution of methyl 4-hydroxy-5-(methoxycarbonyl)-3-nitrothiophene-2-carboxylate (650 mg, 2.5 mmol) in acetone (20 mL) was added potassium carbonate (0.68 g, 5 mmol) at it Dimethyl sulfate (0.36 mL, 3.73 mmol) was added to the above reaction mixture slowly with stirring and a catalytic amount of KI was added. The mixture was refluxed for 4 h and the cooled reaction mixture was filtered and the solids were washed with acetone. Acetone was removed under reduced pressure and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as a pale yellow color solid (0.3 g, 45%), mp 80-82° C. 1H NMR (400 MHz, CDCl3): δ 4.08 (3H, s), 3.94 (3H, s), 3.92 (3H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[N:20]([CH3:31])[C:19](=[O:32])[C:18]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[Cl:30][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:33]3[CH:34]=[C:35]([CH3:40])[CH:36]=[C:37]([CH3:39])[CH:38]=3)[C:19](=[O:32])[N:20]2[CH3:31])=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3n(C)c2=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc([N+](=O)[O-])c(Cl)cc3n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (ca. 100 mg crude from EXAMPLE17, StepB in a mixture of 1 mL trifluoroacetic acid and 0.01 mL anisole) was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo, resolvated in methylene chloride and washed with saturated sodium bicarbonate. The concentrated organics were purified by flash chromatography on silica gel (chloroform:1% ammonium hydroxide in methanol:, 9:1) to give the title compound (22 mg). MASS: 470 (M+H)
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][NH:12][C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18]([NH2:20])=[O:19])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.CO>[C:21]([NH:29][C:30]([CH:11]([NH:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH2:20])=[O:19])[C:7]1[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][C:8]=1[Cl:10])=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCc1nc(Cl)c(CNc2nc[nH]c2C(N)=O)[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(Nc2nc[nH]c2C(N)=O)C(=S)NC(=O)c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.7 %

Procedure:
4-{[(2-Butyl-4-chloro-1H-imidazol-5-yl)methyl]amino}-1H-imidazole-5-carboxamide (0.30 g, 1.01 mmol, obtained from Example 7(a)) was dissolved in CH2Cl2 (5 mL) and methanol (2 mL). Benzoylisothiocyanate (0.18 g, 1.11 mmol) was added and the mixture was stirred at r.t. for 4 h. The mixture was then concentrated in vacuo and dissolved in ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 20% methanol), obtaining 0.175 g (38%) of the title compound. MS (ESI) m/z 460 (M+1).
Reaction SMILES: [N:1]1([CH:6]([CH3:10])[CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)([O-])=O>>[N:1]1([CH:6]([CH3:10])[CH2:7][CH2:8][O:9][C:17]2[CH:18]=[CH:19][C:14]([NH2:11])=[CH:15][CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCO)N1CCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(CCOc1ccc(N)cc1)N1CCCC1

Procedure:
The target compound was obtained by the method according to Example 18, using 3-pyrrolidin-1-yl-butan-1-ol (racemic mixture) manufactured by the method described in the literature (J. Org. Chem., 1949, Vol. 14, p. 862) and 4-nitrofluorobenzene as starting materials.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]([CH3:24])[C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[N:16]=1.[OH:25][C:26](=O)[CH2:27][N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:10][N:11]([CH3:24])[C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:26](=[O:25])[CH2:27][N:28]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:19][CH:18]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reactant: CN(C)c1nc(-c2ccc(N)cc2)cs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(-c2ccc(NC(=O)CN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
DIPEA (4.21 mL, 24.2 mmol) was added to a solution of N,N-dimethyl-4-(4-aminophenyl)-2-thiazolamine (1.77 g, 8.07 mmol, described in the previous section), tert-butyl N-(2-hydroxy-2-oxoethyl)-N-(phenylmethyl)carbamate {2.35 g, 8.87 mmol, described in example 2, section a)} and BOP (3.92 g, 8.87 mmol) in DMF (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h then diluted with EtOAc (300 mL). The solution was washed successively with H2O (2×60 mL), saturated aqueous NaHCO3 (60 mL) and brine (60 mL), dried (MgSO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, Hex:EtOAc:EtOH, 5:2:1) gave the title compound (3.13 g, 83% yield) as a beige solid: 1H NMR (400 MHz, DMSO-d6) δ9.98, 9.92 (2s, 1 H), 7.80 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.26-7.38 (m, 5H), 7.06 (s, 1H), 4.48 (s, 2H), 3.97, 3.86 (2s, 2H), 3.08 (s, 6H), 1.37 (s, 9H); MS (FAB) m/z 467 (MH)+; Anal. Calcd for C25H30N4O3S: C, 64.35; H, 6.48; N, 12.01. Found: C, 64.54; H, 6.56; N, 12.12.
Reaction SMILES: BrC[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH3:18][C:19]1[CH:24]=[C:23]([NH2:25])[C:22]([CH3:26])=[CH:21][C:20]=1[NH2:27]>O1CCCC1>[NH2:25][C:23]1[C:22]([CH3:26])=[CH:21][C:20]([NH:27][C:8]2[C:7]([C:9]([CH3:10])([CH3:11])[CH3:12])=[C:6]([OH:13])[C:5]([C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:4][CH:3]=2)=[C:19]([CH3:18])[CH:24]=1
Reactant: Cc1cc(N)c(C)cc1N
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Product: Cc1cc(Nc2ccc(C(C)(C)C)c(O)c2C(C)(C)C)c(C)cc1N

Procedure:
4-Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran. In a separate conical flask 2,5-dimethyl-benzene-1,4-diamine (2.17 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottom flask containing solution of 4-Bromomethyl-2,6-di-tert-butyl-phenol was kept in oil-bath at 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. 2,5-dimethyl-para-phenylene diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. Product was separated by solvent evaporation. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 4-[(4-Amino-2,5-dimethyl-phenylamino)-2,6di-tert-butyl-phenol is 1.86 g (65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:34])[C:20]([C:29]([O:31]CC)=[O:30])=[CH:21][N:22]3[CH2:25][CH2:26][C:27]#[N:28])=[CH:17][C:16]=2[F:35])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:34])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH2:25][CH2:26][C:27]#[N:28])=[CH:17][C:16]=2[F:35])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC(NC(=O)OC(C)(C)C)CC3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCC#N)CC1
Reaction time: 3 h

Procedure:
A suspension of EXAMPLE 66A (0.71 g) in THF (100 mL) and methanol (50 mL) at reflux was treated with 1M LiOH (100 mL), stirred for 3 hours, concentrated to half volume, acidified with 10% citric acid, and filtered.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:28])[CH:21]=[C:22]([O:26]C)[C:23]=1[O:24][CH3:25]>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([C:21]1[C:20]([CH3:28])=[CH:19][C:18]([O:17][CH3:16])=[C:23]([O:24][CH3:25])[C:22]=1[OH:26])=[O:9]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(O)c1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Aluminum chloride (14.67 g, 0.1 mol), 2,6-dichlorobenzoyl chloride (20.95 g, 0.1 mol) and a solution of 3,4,5-trimethoxytoluene (18.22 g, 0.1 mol) in dichloromethane (50 ml), are slowly and consecutively added to dichloromethane stirred at 0° C., stirred for 1 h at ice bath temperatures and for 16 h at room temperature, and poured into ice. The organic layer is separated, washed with dilute hydrochloric acid and water, dried, and, after addition of silica gel (100 g), concentrated in vacuo. A flash chromatography column is packed with silica gel (400 g) and the charged silica gel is layered on top of that. Elution with petrol ether/ethyl acetate (90/10, 1 l; 80/20, 1 l; 50/50, 1 l ) yields 2,6-dichloro-3',4'-dimethoxy-2'-hydroxy-6'-methylbenzophenone, 10.35 g, (30% y), mp. 161° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.Cl.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:29])[CH:28]=1.CN(C)[CH:32]=[O:33]>O1CCCC1.O>[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:29])[C:28]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(Cl)cncc1Cl
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
Form a solution of lithium diisopropylamide by the adding n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to diisopropylamine (8.40 mL, 0.06 mol) in tetrahydrofuran (200 mL) at −10 to−20° C. under a nitrogen atmosphere. Stir for 30 min., and cool to −60° C. Add 3,5-dichloropyridine hydrochloride (7.40 g, 0.05 mol) in small portions and stir for 1.5 hours at this temperature. Add N,N-dimethylformamide (7.75 mL, 0.10 mol) dropwise via syringe and stir for 1 hour near −60° C. Add water (200 mL) when the mixture is warmed near 0° C. and extract with ethyl acetate. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel with methanol/dichloromethane to give the desired aldehyde (2.94 g, 33%) as a light solid. MS(EI): Exact Mass Calc'd for: C6H3NOCl2 176.9562 m/z. Found: 176.9582 m/z.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]1=[O:18]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:15]1[C:16](=[O:17])[N:12]([CH3:11])[C:13](=[O:18])[CH2:14]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1C(=O)C=CC1=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(c2c[nH]c3ccc(Br)cc23)C1=O
Yield: 74.7 %

Procedure:
To a solution of 5-bromoindole (5 g, 25.50 mmol) in glacial acetic acid (60 mL) was added N-methylmaleimide (6.1 g, 56.11 mmol) and the resulting mixture was heated to reflux for 4 days. The excess acetic acid was distilled and the crude product dissolved in diethyl ether (500 mL) and washed with saturated sodium bicarbonate (2×100 mL) and brine (3×100 mL). The solvent was evaporated and the residue chromatographed on silica gel using hexane/ethyl acetate (1:1) as the eluent to provide 3-(5-bromo-1H-indol-3-yl)-N-methylsuccinimide (5.85 g, 75%) which was used directly for the next reaction. Yellow solid, m.p. 194°-195° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:12][CH:11]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.159 mL, 0.159 mmol) was added to a solution of [4′-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 54-(1); 27.2 mg, 0.053 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (20.2 mg, 76%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][N:21]=[C:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:20][NH:21][C:22](=[O:23])[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1
Reactant: CN=C=O
Reactant: Oc1cccc(C2CCCN2Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-[1-phenylmethyl-2-pyrrolidinyl]phenol (1.0 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.24 ml) followed by milled potassium carbonate (0.7 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 1 hr, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane/0-10% ethyl acetate). The appropriate fractions were collected and concentrated to give 0.8 g (70%) of product.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[CH2:1]([C:5]1[N:6]([CH2:42][C:39]2[CH:40]=[CH:41][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:27](=[O:29])(=[O:28])[NH:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:37][CH:38]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 85 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2-[5-(carbomethoxy)-2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl- 4-yl]methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5.0% MeOH in CH2Cl2) gave an 85% yield of the title compound as a white solid, mp 65°-67° C., homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 555 [M-(t-Bu)]+.
Reaction SMILES: Br[CH2:2][C:3](OC(=O)CBr)=[O:4].[NH2:10][C:11]1[CH:12]=[C:13]([CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][C:17]([C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:22])=[C:16]2[OH:32].C(N(CC)CC)C.CO>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:23][C:21]([C:17]2[C:16](=[O:32])[C:15]3[C:20]4[N:19]([CH:18]=2)[CH2:2][C:3](=[O:4])[NH:10][C:11]=4[CH:12]=[C:13]([CH2:33][N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH:14]=3)=[O:22])=[CH:26][CH:27]=1
Reactant: O=C(CBr)OC(=O)CBr
Reactant: Nc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(CN4CCOCC4)cc(c32)N1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
Bromoacetic anhydride (290 mg) is added to a stirred solution of 8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (Preparation 3, 426 mg) in anhydrous DMF (5.0 mL). After 30 min, triethylamine (100 mg) and additional bromoacetic anhydride (100 mg) are added. After 1 h, triethylamine (300 mg) is added and the solution is heated briefly at 80° C. Methanol (8 mL) is added and the resulting precipitate is filtered off, washed with water and dried to afford 262 mg of the title compound as a DMF solvate. Physical characteristics: 1H NMR (DMSO-d6) δ2.37, 2.73, 2.89, 3.53, 3.57, 4.56, 5.11, 7.23, 7.35, 7.40, 7.72, 7.95, 8.72, 10.35, 11.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][C:11]1[N:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C=O)C>[Br:17][C:14]1[CH:15]=[N:16][C:11]([N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:19]([CH3:18])(=[O:21])=[O:20])=[N:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1cnc(NCc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(Cc1ccccc1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.1 g, 60% disp. in oil) was added to a stirred solution of benzyl-(5-bromo-pyrimidin-2-yl)-amine (0.55 g) in DMF (8 ml) at 0° C. After 30 min methanesulphonyl chloride (0.286 g) was added and the mixture stirred at RT for 2 h then partitioned between ethyl acetate and water. The organics were separated washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with dichloromethane. Yield 0.41 g