Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:25](OC)[C:26](=C=O)[CH:27]=[CH:28][CH:29]=2)[CH:18]=[C:17]3[C:34]([O:36][CH3:37])=[O:35])[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:34]([O:36][CH3:37])=[O:35])[CH:18]=[C:17]3[C:34]([O:36][CH3:37])=[O:35])[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(C3=CC=CC(=C=O)C3OC)cc(C(=O)OC)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)cc(C(=O)OC)c2c1

Procedure:
65.5 mg (0.126 mmol) of methyl 6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonyl-phenyl-4-quinolinecarboxylate obtained in Example 5 were dissolved in a mixed solvent of 2 ml of tetrahydrofuran and 2 ml of methanol and the mixture was stirred. After adding 5.24 mg (0.139 mmol) of sodium borohydride, the reaction mixture was allowed to react at room temperature for one hour. Then, the reaction mixture was concentrated under reduced pressure and dichloromethane was added to the residue followed by washing with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 50.6 mg of methyl 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonyl-phenyl)-4-quinolinecarboxylate.
Reaction SMILES: [CH:1]1([C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)(O)[CH:5]=[CH2:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:23])=O.O>C(OCC)C.CCCCCC>[CH:1]1([C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:5][CH2:6][Cl:23])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: C=CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: ClCC=C(c1ccc(Cl)cc1)C1CC1
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
A stirred solution of 11.0 grams (0.053 mole) of 1-cyclopropyl-1-(4-chlorophenyl)-2-propen-1-ol and 4.6 grams (0.058 mole) of pyridine in 100 ml of diethyl ether was cooled to 0°C., and 6.8 grams (0.058 mole) of thionyl chloride was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was stirred for 30 minutes and then was taken up in 100 ml of hexane; 50 ml of water was then carefully added. The aqueous layer was separated and was extracted with hexane. The organic layers were combined and washed with 25 ml of water and then with 25 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 8.6 grams of 1-cyclopropyl-1-(4-chlorophenyl)-3-chloro-1-propene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][CH2:59]1>C(N(CC)CC)C>[N:58]1([CH2:57][CH2:56][NH:55][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: NCCN1CCCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 g) and dimethylformamide (500 mL) were stirred and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (221 g), 1-(2-aminoethyl)pyrrolidine (45.6 g) and triethylamine (93 mL) were added. The mixture was stirred for 2 hours at ambient temperature. The solid product was collected by vacuum filtration and washed with ethanol. The solids were slurry-washed by stirring in ethanol (500 mL) for one hour at 64° C. and cooled to room temperature. The solids were collected by vacuum filtration, washed with ethanol, and dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3 Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (101.5 g, 77% yield). 1H-NMR (dimethylsulfoxide-d6) δ 1.60 (m, 4H, 2×CH2), 2.40, 2.44 (2×s, 6H, 2×CH3), 2.50 (m, 4H, 2×CH2), 2.57, 3.35 (2×m, 4H, 2×CH2), 7.53, 7.70, 7.73, 7.76 (4×m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 13.67 (s, 1H, pyrrole NH). MS m/z 396 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.C([Li])CCC.[B:22](OC)([O:25]C)[O:23]C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([B:22]([OH:25])[OH:23])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(Oc2cc(F)cc(Br)c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(Oc2ccc(F)cc2)c1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 6, using 9.1 grams (0.032 mole) of 3-fluoro-5-(4-fluorophenoxy)phenyl bromide, 14 mL (0.035 mole) of n-butyllithium (2.5M in hexanes), and 10.4 mL (0.095 mole) of trimethyl borate in 100 mL of tetrahydrofuran, yielding 3-fluoro-5-(4-fluorophenoxy)phenylboronic acid.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[C:14]3[C:15](=[O:19])[CH2:16][CH2:17][NH:18][C:13]=3[N:12]3[N:20]=[CH:21][C:22]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[C:11]3[N:10]=1)[CH2:2]2.[NH:35]1[CH:39]=[N:38][C:37]([C:40](O)=[O:41])=[N:36]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[N:35]1[N:36]=[C:37]([C:40]([N:8]2[CH:1]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([C:9]2[C:14]4[C:15](=[O:19])[CH2:16][CH2:17][NH:18][C:13]=4[N:12]4[N:20]=[CH:21][C:22]([C:23]5[CH:24]=[N:25][C:26]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)=[CH:27][CH:28]=5)=[C:11]4[N:10]=2)[CH2:2]3)=[O:41])[NH:38][CH:39]=1
Reactant: O=C1CCNc2c1c(C1CC3CCC(C1)N3)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Reactant: O=C(O)c1nc[nH]n1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1CCNc2c1c(C1CC3CCC(C1)N3C(=O)c1nnc[nH]1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(8-azabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one (86 mg, 0.19 mmoL), 1H-1,2,4-triazole-3-carboxylic acid (25.9 mg, 0.23 mmoL), EDC (73 mg, 0.38 mmoL), HOBt (51.6 mg, 0.38 mmoL) and DIEA (199 uL, 1.15 mmoL) in DMF (4 mL) was stirred at room temperature for 2 h. Purification with prep-LC provided 5-(8-(4H-1,2,4-triazole-3-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one: LCMS tR=2.33 Min (10 min run, UV254nm). Mass calculated for, M+ 545.2, observed LC/MS m/z 546.01 (M+H).
Reaction SMILES: N1([C:6]([NH:8][C@:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]2[CH:12]=[CH2:13])=[O:7])C=CN=C1.[Cl:19][C:20]1[C:21]([O:55][CH3:56])=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([N:30]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[N:31]1)[CH:26]=[C:25]2[O:39][C@@H:40]1[CH2:44][NH:43][C@H:42]([C:45]([N:47]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[CH3:48])=[O:46])[CH2:41]1.C(OC([C@@]1(NC(N2C[C@H](O)C[C@H]2C(=O)N(CCCCC=C)C)=O)C[C@@H]1C=C)=O)C>>[Cl:19][C:20]1[C:21]([O:55][CH3:56])=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([N:30]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[N:31]1)[CH:26]=[C:25]2[O:39][C@@H:40]1[CH2:44][N:43]([C:6]([NH:8][C@:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]2[CH:12]=[CH2:13])=[O:7])[C@H:42]([C:45](=[O:46])[N:47]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[CH3:48])[CH2:41]1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1ccnc1)C(=O)OCC
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Yield: 75 %

Procedure:
Compound 116 was synthesized from compounds 33 and 115 as a white solid in 75% yield, following the procedure as described for compound 50.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][C:8]3([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]3)[C:6]=2[CH:7]=1.[CH2:21](O)[CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:21]([O:19][C:18]([CH:16]1[CH2:15][C:8]2([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]2)[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:17]1)=[O:20])[CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCCOCCOCCO
Reactant: O=C1NC(=O)C2(CC(C(=O)O)Oc3ccc(F)cc32)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCCOCCOCCOCCOC(=O)C1CC2(NC(=O)NC2=O)c2cc(F)ccc2O1

Procedure:
A mixture consisting of 6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylic acid (2.8 g, 0.01 mol) (obtained through the process as described in Example 1), 3,6,9,12-tetraoxatridecanol (2.1 g, 0.01 mol) and p-toluenesulfonic acid (1.9 g, 0.01 mol) in 80 ml of toluene was heated at reflux temperature for 7.0 hours under a Dean-Stark trap. The reaction mixture was evaporated in vacuo to give a semi-solid residue which was partitioned between 50 ml of chloroform and 50 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give a pale yellow oil which was chromatographed on silica gel, eluting with ethyl acetate to give 3.9 g (82.5%) of the desired refined compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:14])[C:5]([CH3:13])([CH3:12])[C:6]2=[O:11].[BH4-].[Na+]>C(O)C.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:14])[C:5]([CH3:12])([CH3:13])[CH:6]2[OH:11]
Reactant: CC1(C)C(=O)c2cccc(Cl)c2C1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)C(=O)c2c(Cl)cccc2C1O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of chloro-2,2-dimethyl-indan-1,3-dione (1.82 g, 8.7 mmol) in ethanol (100 mL) at −40° C. is added NaBH4 (100 mg, 2.6 mmol). The reaction is warmed to −20° C. and stirred for 1 hour. The reaction is diluted with saturated aqueous NH4Cl and concentrated in vacuo to remove the volatile organics. The mixture is then diluted with ethyl acetate and the layers are separated. The aqueous layer is extracted an additional time with ethyl acetate and the organic layers are combined, dried over Na2SO4, filtered and concentrated to afford 7-chloro-3-hydroxy-2,2-dimethyl-indan-1-one without the need for further purification; MS: (ESI) m/z 211.15 (M+H)+
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:21])([F:20])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1.[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:26][C:25](=[O:33])[CH:24]=1.Cl>CS(C)=O.O>[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:26][C:25](=[O:33])[C:24]=1[C:18](=[O:19])[NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]([F:20])([F:21])[F:8])=[CH:16][CH:15]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.4 %

Procedure:
First 5.1 g (0.05 mol) of triethylamine and then, slowly, 10.2 g (0.05 mol) of 4-trifluoromethoxyphenyl isocyanate are added dropwise to 8.1 g (0.05 mol) of 4-hydroxycoumarin in 100 ml of dimethylsulphoxide at room temperature. The temperature thereby rises to 31° C. The reaction mixture is subsequently stirred at room temperature for 5 hours. It is added to a mixture of 250 ml of cold water and 15 ml of concentrated hydrochloric acid, whereupon a white precipitate separates out. The mixture is stirred for 30 minutes, with cooling, and the precipitate is filtered off with suction, rinsed with acid water and dried at 50° C. in vacuo. Recrystallization from 100 ml of dioxane gives 8.3 g (45.6% of theory) of 4-hydroxy-3-(4-trifluoromethyloxyphenyl-carbamoyl)-coumarin of melting point 194°-195° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N+:11]([O-])=O)[C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2].[H][H]>CO.O1CCCC1.[Pd]>[NH2:11][C:5]1[C:6](=[O:10])[NH:7][C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: [H][H]
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(N)c(=O)[nH]c1C

Procedure:
A yellow solution of the 5-ethyl-6-methyl-3-nitro-2(1H)-pyridinone (10 g, 55 mmol) in a mixture of methanol and tetrahydrofuran (100 mL, 1:1 v/v) was reduced catalytically in the presence of 7% palladium on charcoal (0.7g) under and atmosphere of hydrogen (50 psi) at room temperature over a period of 3.5 hours. The resultant mixture was filtered through a small pad of Celite. The filtrate was concentrated under reduced pressure (15 torr) to provide the corresponding aminopyridone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.C([O-])(=[O:44])C.[NH4+]>C1COCC1.CO.O>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:44])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NCc1ccc(CNc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Reactant: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc(N)cc3s2)cc1
Yield: 76.9 %

Procedure:
To a suspension of compound 141 (200 mg, 0.385 mmol) in a mixture of THF/MeOH/H2O (10 mL/10 mL/10 mL) were successively added tin(II) chloride dihydrate (1.35 g, 8.46 mmol) and ammonium acetate (1.09 g, 14.12 mmol). The mixture was refluxed for 2 days, the tin salts were filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and H2O (brine was added to break the emulsion). Organic phase was successively washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to afford the title compound 143 (145 mg, 77% yield). 1H NMR: (DMSO-d6) δ (ppm): 12.89 (bs, 1H), 10.79 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.90-7.68 (m, 3H), 7.62 (d, J=8.4 Hz, 2H), 7.48 (bs, 1H), 7.21 (dd, J=4.9, 3.7 Hz, 1H), 4.65 (s, 2H). m/z: 490.5 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([NH2:22])=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](OC)(OC)OC.Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[N:22]=[CH:23]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: Fc1ccc2c(c1)ncn2C1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 170 mg of 1-N-(1-benzyl-piperidin-4-yl)-4-fluoro-benzene-1,2-diamine (from Step A), 7 mL of trimethyl orthoformate, and 0.2 mL of concentrated HCl, using a procedure analogous to that described in Example 95, Step B to provide 123 mg of the title compound as a viscous brown oil
Reaction SMILES: Br[C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:8](=[O:16])[N:7]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]=2[CH:5]=[C:4](Br)[C:3]=1[C:23]([O:25][CH3:26])=[O:24].C(O)=O.C(N(CC)CC)C.Cl>CN(C)C=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.O.C(OCC)(=O)C>[CH2:17]([N:7]1[C:6]2[CH:5]=[CH:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[CH:2][C:10]=2[N:9]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:8]1=[O:16])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: COC(=O)c1c(Br)cc2c(c1Br)n(CCC(C)C)c(=O)n2CCC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: O=CO
Product: COC(=O)c1ccc2c(c1)n(CCC(C)C)c(=O)n2CCC(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
In 7 ml of N,N-dimethylformamide are suspended 0.70 g of methyl 4,6-dibromo-1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate, 0.16 g of tetrakis(triphenylphosphine)palladium(0), 0.44 ml of formic acid and 2.4 ml of triethylamine. The suspension is stirred at 100° C. for 3 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 4 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.37 g of methyl 1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate as a colorless oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][CH2:9]Cl.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:27][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc(F)cc1OCCCl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(F)cc1OCCNCCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 12 h
Yield: 72.1 %

Procedure:
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylchloride (0.3 g, 1.5 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.56 g, 2.9 mmol) in dimethylsulfoxide (20 ml) was allowed to stir for 12 h at 90° C. The reaction mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 0.39 g (77%) of product as a white solid: mp 119-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([Cl:29])[CH:23]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:21][C:22]3[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([Cl:29])[CH:23]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: Clc1cc(CBr)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3cc(Cl)nc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-3-(3-methoxy-phenyl)-6-chloro-1,3-dihydro-indol-2-one (82 mg, 0.3 mmol) (from Example 6b supra), 4-bromomethyl-2,6-dichloro-pyridine (85.3 mg, 0.35 mmol) (Maybridge), potassium iodide (59.2 mg, 0.35 mmol) and potassium carbonate (89.2 mg, 0.645 mmol) in acetone (3 mL) was heated at 60° C. for 3 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a light brown solid. (Yield 60 mg, 45%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:29])[CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]([OH:29])[CH2:25][N:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 40.2 %

Procedure:
Following general procedure A-1, {6-bromo-4-[4-(2-(dimethylamino)-1-hydroxyethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (50 mg, 0.110 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (30 mg, 0.165 mmol) to afford the desired product (23 mg, 40%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) 9.41 (s, 1H), 8.22 (dd, J=8.8, 2.0 Hz, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.23 (s, 1H), 7.09-7.02 (m, 1H), 5.20 (dd, J=10.6, 3.8 Hz, 1H), 3.31-3.20 (m, 2H), 3.03 (s, 3H), 2.97 (s, 3H), 2.89-2.80 (m, 1H), 1.25-1.14 (m, 4H); ESI MS m/z 520 [C29H27ClFN3O3+H]+; HPLC 94.8% (AUC), tR=11.31 min.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][OH:5].[Na].[Cl:8][C:9]([Cl:13])([Cl:12])[C:10]#[N:11]>C(O)(=O)C>[NH2:11][C:10]1([C:9]([Cl:13])([Cl:12])[Cl:8])[O:6][CH2:1][CH:2]=[CH:3][CH2:4][O:5]1
Reactant: OC/C=C\CO
Reactant: N#CC(Cl)(Cl)Cl
Agent: [Na]
Solvent: CC(=O)O
Product: NC1(C(Cl)(Cl)Cl)OCC=CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To cis-2-butene-1,4-diol (22.28 g, 252.9 mmole) there was added a catalytic amount of sodium followed by a slow addition at ~0° C. of trichloroacetonitrile (110 g, 3 equivalents). Upon completion of the trichloroacetonitrole addition, the solution was stirred at room temperature for 16 hours. The solution was acidified with 1 ml glacial acetic acid and stirred for 15 minutes. The resulting solution was distilled under reduced pressure (0.25 mm Hg) and several fractions were collected at different temperatures. The minor fraction (9.71 g) collected between 98°-110° was characterized as the cyclic title product. IR (KBr): 3430-3350, 3040, 2940-2920, 1607, 1110 and 825 cm-1. 1H NMR was consistent with the indicated structure.
Reaction SMILES: C1(C(OCCC)CO)C=CC=CC=1.[CH2:14]([O:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][OH:21])[CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>C1CCCCC1>[CH2:14]([O:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:20]=[O:21])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOC(CO)c1ccccc1
Agent: CCCOC(CO)c1ccccc1
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCOC(C=O)c1ccccc1
Yield: 68 %

Procedure:
The procedure in Example 3 was repeated except that 180.25 g of 2-phenyl-2-propoxyethanol was replaced with 194 g of 2-butoxy-2-phenylethanol and 540 g of toluene was replaced with 580 g of cyclohexane, to obtain 130.5 g of 2-butoxy-2-phenylethanal (yield: 68%).