Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[C:9]1(=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=O.Cl.N([O-])=O>CO>[C:9]1(=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[N:1][OH:2]
Reactant: CC(C)CCON=O
Reactant: O=C1Cc2ccccc2C1=O
Agent: Cl
Agent: O=N[O-]
Solvent: CO
Product: O=C1C(=NO)Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
Isoamyl nitrite (15 ml, 108 mmol) was added to a solution of indan-1,2-dione (12 g, 90 mmol) in MeOH (380 ml) at 45° C. followed by concentrated HCl (12 ml) dropwise over 5 minutes. The reaction mixture was stirred for 3 hours at room temperature. Excess isoaamyl nitrite (1 ml) and concentrated HCl (1 ml) was added and the suspension stirred for a further 15 minutes. On cooling to room temperature a white precipitate formed. The precipitate was filtered off and washed with cold MeOH (40 ml) followed by Et2O (40 ml) to afford indan-1,2-dione-2-oxime (6.2 g, 43%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:26])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])=[O:15])[CH2:6][CH2:5]2.[O:28]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:28][C:7]([CH3:26])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:27])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCN1CCCC1=O)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCN2CCCC2=O)=C(C)C1=O
Yield: 100.1 %

Procedure:
Oxidation as described in protocol B, using 113.2 mg (0.302 mmol) of 6-hydroxy-2,5,7,8-tetramethyl-N-(3-(2-oxopyrrolidin-1-yl)propyl)chroman-2-carboxamide and 364.6 mg CAN (0.665 mmol) yielded 118 mg of 2-hydroxy-2-methyl-N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C@H:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C@H:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[CH:38][CH:39]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1-trifluoroacetyl-1H-1-benzazepine-4-carboxamide (180 mg) in ethanol (30 ml) was added sodium borohydride (10.0 mg) at room temperature and stirred for 2 hours. To the reaction solution was further added sodium borohydride (10.0 mg), and the mixture was stirred for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:2) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 82) (141.4 mg) as yellow amorphous.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]([CH3:12])[CH2:10]O)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]([CH3:12])[CH2:10][Cl:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(CO)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(CCl)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of an optically-active compound of [benzyl-(2-hydroxy-1-methylethyl)-amino]acetic acid tert-butyl ester (160.0 g) in chloroform (640 ml) cooled to 0° C. was added dropwise thionyl chloride (50.0 ml), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to 0° C. Then, thereto were added saturated aqueous sodium bicarbonate solution (1000 ml) and chloroform (100 ml), and the mixture was stirred. The separated organic layer was washed with saturated aqueous sodium chloride solution (500 ml), and the aqueous layer was extracted with chloroform (450 ml) again. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (172.9 g).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:5]=2[O:4]1.[F:21][C:22]([F:27])([F:26])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15]([C:22]([F:27])([F:26])[F:21])[CH:16]=[CH:17][C:5]=2[O:4]1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 150 °C
Reaction time: 5.5 h
Yield: 59.8 %

Procedure:
A mixture of 1.00 g of ethyl 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylate, 0.84 g of potassium trifluoroacetate, 1.18 g of cuprous iodide, 4 ml of toluene and 10 ml of N,N-dimethylformamide was heated with stirring at 150° C. for 5.5 hours in a nitrogen gas atmosphere while removing toluene. The reaction mixture was added to a mixed solution of 2N hydrochloric acid and ethyl acetate, and an insoluble material was separated by filtration using celite. The organic layer was separated from the filtrate, and the aqueous layer was extracted with ethyl acetate. The resulting organic layers were combined, washed with a brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (an eluting solvent, ethyl acetate:hexane =10:1) to obtain 0.51 g of ethyl 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylate as an oily substance.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.[C:53]1([N:59]=[C:60]=[O:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([C:60]([NH:59][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:61])[CH2:48][CH2:47]1
Reactant: O=C=Nc1ccccc1
Reactant: Clc1cnc2nc1Nc1ccc(OCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)N1CCC(COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(piperidin-4-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 40% yield. LCMS for C30H31ClN7O2 (M+H)+: m/z=556.1.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CCNC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CCN(C(=O)N(C)C)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 163) (99 mg, 0.23 mmol) and NEt3 (35 μL, 0.25 mmol) in DMF (2 ml) was added dimethylcarbamoyl chloride (29 μL, 0.25 mmol). Reaction mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (42 mg, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (400 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.7 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (153 mg, 25%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].CN(C)C=O.I[CH2:22][CH2:23][CH2:24][CH:25]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:25]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:24][CH2:23][CH2:22][N:8]2[CH2:7][CH2:6][N:5]([C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:4]([CH2:3][O:2][CH3:1])[CH2:9]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Reactant: COCC1CNCCN1C(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COCC1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1C(=O)C(F)(F)F
Reaction time: 4 h
Yield: 94 %

Procedure:
To a stirred mixture of 6.05 parts of 2-(methoxymethyl)-1-(trifluoroacetyl)piperazine, 5.25 parts of N,N-diethylethananamine and 36 parts of N,N-dimethylformamide were added 11 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene]. Stirring was continued for 4 hours at 75° C. The reaction mixture was cooled and poured onto 400 parts of water. The product was extracted twice with 140 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated, yielding 11.5 parts (94%) of 4-[4,4-bis(4-fluorophenyl)butyl]-2-(methoxymethyl)-1-(trifluoroacetyl)piperazine as a residue (intermediate 60).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[CH2:25]([N:27]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A suspension of 1.5 g (0.0043 mol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 15 ml of dimethylformamide was treated with 1.6 g (0.022 mol) of diethylamine. After stirring at room temperature for 16 hrs. the solution obtained was freed completely from the solvents. The residue was chromatographed over silica gel with dichloromethane/methanol 9:1 as the eluent. There were obtained 1.33 g (81%) of 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 172°-174°.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([O:30]CC)=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[C:16]([NH2:34])[C:15]=2[F:35])[CH2:9]1)=O)(C)(C)C.[ClH:36]>C(O)(=O)C>[ClH:36].[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[C:16]([NH2:34])[C:15]=2[F:35])[CH2:9]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)c(N)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1c(F)c(OC2CCNC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
Ethyl 7-(t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3carboxylate (105 mg) was similarly treated using 0.5 ml of concentrated hydrochloric acid and 2 ml of acetic acid, whereby 38 mg of the title product was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([C:2]3[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=3)[CH2:26][CH2:27]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(Cc3ccc(F)cc3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-(4-fluorobenzyl)piperidine. MS (+ESI) m/z 385 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1>>[OH:31][C:25]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[CH2:30][CH2:29][CH2:28][N:27]([C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:26]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)C(c3ccccc3)c3ccccc3)C2)c1

Procedure:
The compound of Example 29 was prepared according to the general preparation protocol A from diphenylacetyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[S:8]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22](=[O:23])[CH:21]=[C:20]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:19]2)=[CH:14][CH:13]=1)([OH:11])(=[O:10])=[O:9].[C:31]([OH:34])(=O)[CH3:32]>>[CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:1][C:2]1[C:21]2[C:22](=[O:23])[N:18]([C:15]3[CH:14]=[CH:13][C:12]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:17][CH:16]=3)[NH:19][C:20]=2[N:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31](=[O:34])[CH:32]=1
Reactant: O=c1cc(Nc2ccccc2)[nH]n1-c1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cc(=O)n(-c2ccccc2)c2[nH]n(-c3ccc(S(=O)(=O)O)cc3)c(=O)c12

Procedure:
1-(4-Sulfophenyl)-3-anilinopyrazolin-5-one triethylamine salt (8.6 g) and 3.5 g of ethyl acetacetate were added to 50 ml of glacial acetic acid and refluxed with heating for 8 hours, and then the reaction solution was concentrated to about 1/3 of the volume. Isopropanol (80 ml) was added thereto to deposit crystals which was then recrystallized from methanol to obtain 3.5 g of 4-methyl-7-phenyl-2-(4-sulfophenyl)pyrazolo[3,4-b]pyridine-3,6-dione triethylamine salt. These crystals (3 g), 0.9 g of glutacondialdehyde dianil hydrochloride, 1.3 ml of triethylamine, 1.1 ml of acetic anhydride and 20 ml of N,N-dimethylformamide were mixed and stirred at room temperature for one hour and then at 50° C. for 2 hours. The reaction solution was cooled to room temperature and a solution of 1.8 g of potassium acetate in 10 ml of methanol, followed by one hour stirring. The deposited crystals were recovered by filtration and recrystallized from a methanol-water mixed solvent (methanol/water=3/1) to obtain 1.1 g of Compound 33 as dark bluish, green crystals. Melting point 300° C. or more, λmaxCH3OH =767 nm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].O1CCCC1>C(OCC)(=O)C>[CH2:17]([O:24][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1ccc(OCc2ccnc(Cl)c2)cc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(OCc2ccnc(OCc3ccccc3)c2)cc1
Yield: 99.3 %

Procedure:
A mixture of 2-chloro-4-[(4-fluorophenoxy)methyl]pyridine (845 mg, 3.55 mmols), benzyl alcohol (0.48 mL, 4.62 mmols), sodium hydride (60% oiliness, 170 mg, 4.26 mmols) and tetrahydrofuran (20 mL) was refluxed for 16 hours. Cooling the reaction liquid to room temperature, ethyl acetate was added thereto, followed by washing with saturated aqueous sodium hydrogencarbonate solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil, FLASH 40+M, hexane:ethyl acetate=10:0-17:3) to provide the title compound (1.09 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.[C:17](Cl)(Cl)=[O:18]>>[N:1]([C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1)=[C:17]=[O:18]
Reactant: COc1cc(N)ccc1C(=O)OC(C)(C)C
Reactant: O=C(Cl)Cl
Product: COc1cc(N=C=O)ccc1C(=O)OC(C)(C)C

Procedure:
tert-Butyl 4-isocyanato-2-methoxy-benzoate was prepared from tert-butyl 4-amino-2-methoxy-benzoate and phosgene using the procedure of step 2 of Example 1.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:31]1[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: OB(O)c1cccnc1
Product: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(-c3cccnc3)nc21

Procedure:
4-(2-Chloro-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (50 mg) was reacted with pyridin-3-ylboronic acid via General Procedure A and purified via reverse phase HPLC to give 33.4 mg 137 as a white solid. MS (Q1) 473.3 (M)+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:27])[C:15](=[O:26])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[CH:17][C:7]2=1)(=[O:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)C>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:16]1[C:15](=[O:26])[N:14]([CH3:27])[C:8]2[N:9]([CH3:13])[C:10]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][C:4]([C:1](=[O:3])[CH2:2][C:31](=[O:30])[CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)=[CH:12][CH:11]=3
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: CCOC(=O)COC1CCCCO1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CC(=O)COC4CCCCO4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 80 above, with the compound from preparation 1.10E, 6-acetyl-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and (tetrahydropyran-2-yloxy)acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].C([Li])CCC.[I:20]I>C1COCC1>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:20])[CH:6]=1)[CH3:2]
Reactant: II
Reactant: CCOC(OCC)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(OCC)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred -78° C. solution of 3-bromobenzaldehyde diethyl acetal, prepared as in step 1, (1.0 g, 3.8 mmol) in THF (10 mL) was added n-butyllithium (1.7 mL, 4.25 mmol, 2.5M in hexanes). The cold reaction mixture was stirred 0.5 hours followed by the addition of a THF (5 mL) solution of iodine (1.09 g, 4.25 mmol). The ice bath was removed and the reaction allowed to warm to ambient temperature. Saturated NH4Cl was added and the mixture diluted with hexanes. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with 5% ethyl acetate-hexanes to afford 1.0 g of 3-iodobenzaldehyde diethyl acetal.