Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:45])([CH3:44])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]4[N:30]5[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C:29]5=[N:28][N:27]=4)=[CH:22][C:21]=2[O:42][CH3:43])=[CH:12]3)[CH:6]=[N:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:43][O:42][C:21]1[CH:22]=[C:23]([C:26]2[N:30]3[CH2:31][CH2:32][NH:33][CH2:34][C:29]3=[N:28][N:27]=2)[CH:24]=[CH:25][C:20]=1[NH:19][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]([CH3:45])([OH:1])[CH3:44])[CH:8]=1)=[CH:18][CH:17]=2
Reactant: COc1cc(-c2nnc3n2CCN(C(=O)OC(C)(C)C)C3)ccc1Nc1cc2cc(-c3cnn(CC(C)(C)O)c3)ccc2cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nnc3n2CCNC3)ccc1Nc1cc2cc(-c3cnn(CC(C)(C)O)c3)ccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a solution of tert-Butyl 3-(4-(6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)isoquinolin-3-ylamino)-3-methoxyphenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (Example 55, 29 mg, 0.047 mmol) in DCM (10 mL) at 0° C. was added TFA (0.35 mL). The reaction was stirred at room temperature for 16 hours before concentrating in vacuo. The residue was purified by elution through an SCX-2 column using 2M NH3/MeOH to afford the title compound as a yellow solid (17.5 mg, 72%).
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([CH2:58][OH:59])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>>[OH:59][CH2:58][C:55]1[CH:56]=[CH:57][C:52]([C:49]2[CH:48]=[CH:47][C:46]([NH:45][C:11]([C:13]3[CH:14]=[C:15]([S:19]([C:22]4[CH:23]=[C:24]5[C:29](=[C:30]([CH3:32])[CH:31]=4)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]5[NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=4)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:51][CH:50]=2)=[CH:53][CH:54]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: Nc1ccc(-c2ccc(CO)cc2)cc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CO)cc6)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using (4′-amino-[1,1′-biphenyl]-4-yl)methanol in place of 8-aminooctanol. ES/MS calcd. for C38H33N4O6S+ 673.2. Found m/z=673.2 (M+H)+.
Reaction SMILES: F[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[F:14].[CH3:15][C@H:16]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>>[CH3:15][C@H:16]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:5]3[C:6]([CH3:9])=[N:7][O:8][C:4]=3[C:3]=2[F:14])[CH2:17]1
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: Cc1noc2c(F)c(F)c(C=O)cc12
Product: Cc1noc2c(F)c(N3C[C@H](C)C[C@H](C)C3)c(C=O)cc12

Procedure:
Starting materials: 6,7-difluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 374) and (3S,5R)-3,5-dimethylpiperidine (HCl Salt).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[C:11]=2[F:19])O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[C:11]=2[F:19])[CH:7]=1
Reactant: COc1ccc(C(O)c2cc(Br)ccc2Cl)c(F)c1F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Reaction time: 16 h
Yield: 72.4 %

Procedure:
(5-bromo-2-chloro-phenyl)-(2,3-difluoro-4-methoxy-phenyl)methanol 2d (5.1 g, 14.1 mmol) was dissolved in 40 mL methylene chloride, followed by addition of triethyl silane (6.75 mL, 42.3 mmol) and dropwise addition of boron trifluoride diethyl ether (3.57 mL, 28.2 mmol). The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was partitioned after 20 mL saturated sodium carbonate solution were added. The aqueous phase was extracted with dichlormethane (20 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound 1-[(5-bromo-2-chloro-phenyl)methyl]-2,3-difluoro-4-methoxy-benzene 2e (3.55 g, white solid), yield: 72.4%. 1H NMR (400 MHz, CDCl3): δ 7.36-7.33 (m, 1H), 7.30-7.27 (m, 2H), 6.81-6.79 (m, 1H), 6.73-6.69 (m, 1H), 4.00 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].[H][H]>CO.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: [H][H]
Reactant: COC(=O)CN(C(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CN(C(=O)C(F)(F)F)c1ccc(N)cc1
Yield: 100 %

Procedure:
The compound from step b above (3.05 g, 10 mmol) was dissolved in a mixture of methanol (100 mL) and methylene chloride (15 mL) and hydrogenated in the presence of 10% palladium on activated carbon (700 mg) using a hydrogen balloon at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (2.74 g, ˜100%) which was used direct for the next step. 1H NMR (400 MHz, CDCl3) δ: 7.13 (d, 2H), 7.63 (d, 2H), 4.36 (s, 2H), 3.78 (s, 3H), 3.65 (brs, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:21]([N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: BrCC=Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccccc2)c1=O
Yield: 92.1 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and cinnamyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 92.1%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([C:15]1[CH:16]=[C:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:12]([OH:17])=[CH:13][CH:14]=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Oc1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(O)c(-c2ccccc2)c1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
At ambient temperature, to a stirred suspension of aluminum chloride (2.0 g, 15.0 mmol) in CH2Cl2 (20 mL) was added 2-phenylphenol (1.28 g, 7.53 mmol). After 30 min, the reaction was cooled to 0° C. To the reaction was added dropwise a solution of 2-chlorobenzoyl chloride (0.94 mL, 7.42 mmol) in CH2Cl2 (20 mL). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched into crushed ice (100 g) diluted with sat. aq. KH2PO4 (100 mL) and extracted with CH2Cl2. The organic extracts were dried (Na2SO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with a 3 & 10% EtOAc/pet. ether step gradient to give 0.5g (21%) of the title compound as an off white solid, mp 194-198° C. 1H NMR (DMSO-d6) δ 7.07 (dd, 1H), 7.33 (tt, 1H), 7.40 (tt, 2H), 7.46-7.49 (m, 4H), 7.51-7.59 (m, 4H), 10.8 (s, 1H). mass spectrum (EI) m/z 308 (M+).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>[Zn+2].[I-].[I-]>[CH2:23]([O:22][CH:15]([O:19][CH2:20][CH3:21])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:24]
Reactant: C#CCCCCCCCCCCCC
Reactant: CCOC(OCC)OCC
Agent: [I-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCC#CC(OCC)OCC

Procedure:
Tetradecyne (100 g), (EtO)3CH (200 ml) and ZnI2 (15 g) were heated together (bath temperature 170°-175°) with distillative removal of ethanol (~90 minutes). The reaction mixture was evaporated in vacuo (bath temperature 80°) to remove excess (EtO)3CH. The residue was distributed between CH2Cl2 and water. The CH2Cl2 phase was separated, washed with aqueous NaHCO3, dried (Na2SO4) and evaporated in vacuo to provide a light brown oil. Yield: 135.4 g. This product was shown to be virtually pure by TLC and PMR and it was used as such in subsequent reactions.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:38])[CH2:36][OH:37])[NH:30][C:29](=[O:39])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:38])[CH2:36][OH:37])[NH:30][C:29](=[O:39])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 86.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1 H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol) was dissolved in 2 mL of ethanol under stirring at room temperature, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 9f (25.1 mg, 0.112 mmol) was then added to the solution. Upon completion of the addition, the mixture was stirred until all dissolved, and piperidine (50 μL, 0.5 mmol) was then added to the reaction solution. Upon completion of the addition, the reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-N-{5-fluoro-3-[5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide 9 (51 mg, yield 80%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25]([S:28](Cl)(=[O:30])=[O:29])[CH2:26][CH3:27]>>[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:28]([CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 33 from ethyl 3-amino2-benzoyl-6-chloro-1H-indole-1-carboxylate (Example 1, step 2) and 1 -propanesulfonyl chloride.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12](=[NH:14])[NH2:13])[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].CN(C)[CH:18]=[C:19]([Br:22])[CH:20]=O.CCO>CO>[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12]2[N:13]=[CH:20][C:19]([Br:22])=[CH:18][N:14]=2)[CH2:11][CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CN(C)C=C(Br)C=O
Reactant: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ncc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
(1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (1.0 g, 4.2 mmol) (prepared according to the procedure described in patent application WO 2009/070485 A1) and 3-dimethylamino-2-bromo-propenal (1.1 g, 6.4 mmol) are added to EtOH (2 mL) in a pressure tube. The reaction vessel is capped and the mixture is heated at 80° C. for 24 hours. The mixture is cool to room temperature and methanol (20 mL) is added. The resulting solids are filtered and the filtrate is concentrated in vacuo. The residue is dissolved with CH2Cl2 (50 mL) and the solids are filtered. The filtrate is concentrated and the residue is purified by silica gel chromatography using a gradient of 0-50% EtOAc in hexanes to afford [1-(5-bromo-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester as a solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])=[CH:35][CH:34]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1
Yield: 81 %

Procedure:
A solution of 3-benzoyl-8-(trifluoromethyl)quinolin-4-yl trifluoromethanesulfonate (1.8 g, 4 mmol), 4-methoxyphenylboronic acid(1.0 g, 6.5 mmol), and K3PO4(3.0 g) in dioxane (50 ml) was heated to reflux. After, 4 hr, the reaction was cooled, filtered, concentrated to give an oil which was purified by column chromatography (eluent 10% EtOAc/Hex) to give a white solid (1.3 g Yield=81%); MS (ESI) m/z 408 ([M+H]+;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[NH:34][C:33]2=[O:41])[CH2:28][CH2:27]1>CN(C)C=O>[O:41]=[C:33]1[N:32]([CH:29]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:31][CH2:30]2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Yield: 13.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7.2 g), triethylamine (3.6 cc) and 1-(4-piperidinyl)-2-benzimidazolinone (5.6 g) in dimethylformamide (100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification 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 ethanol (95-5 vol) as eluant, and recrystallization from boiling acetonitrile (200 cc), 2-{3-[4-(2-oxo-1-benzimidazolinyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.6 g) is obtained, m.p. 253° C.
Reaction SMILES: [OH-:1].[Na+].CC(O)(C)CN[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[N:17]=[N:18][N:19]=[C:9]2[C:8]=1[N+:20]([O-:22])=[O:21]>O>[N+:20]([C:8]1[C:9]2[N:10]([N:17]=[N:18][N:19]=2)[C:11]2[C:16]([C:7]=1[OH:1])=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:22])=[O:21]
Reactant: [OH-]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12

Procedure:
Aqueous sodium hydroxide (30 g of 50%) was added to a suspension of 2-methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol (34.0 g, 0.1125 mole, Example 3) in water (500 mL). The mixture was heated on a steam bath and the solid dissolved rapidly. The solution was heated for about 30 minutes and then upon stirring a solid began to precipitate. The mixture was made acidic with 6N hydrochloric acid. The resulting solid was isolated by filtration; washed in succession with water, ethanol and ether; then dried under vacuum at 100° C. to provide 23.2 g of crude product as a pale yellow/green solid. A sample (3.2 g) was recrystallized initially from methanol/dichloromethane and then from toluene to provide 4-nitrotetrazolo[1,5-a]quinolin-5-ol. Analysis: Calculated for C9H5N5O3: % C, 46.76; % H, 2.18; % N, 30.29. Found: % C, 46.85; % H, 2.23; % N, 29.91.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCCCO2)=[C:18]([F:28])[C:17]=1[O:29][CH3:30].[F-].[K+].C(#N)C>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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:29][CH3:30])[C:18]=2[F:28])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Temperature: 70 °C
Yield: 76 %

Procedure:
A 250 mL three-neck flask with a reflux condenser, a nitrogen inlet and a thermocouple was charged with methyl 4-amino-3,6-dichloro-5-fluoropicolinate (9.965 g, 41.7 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (12.74 g, 52.1 mmol) and KF (4.84 g, 83 mmol). Acetonitrile (78 mL) and water (26 mL) were added. The reaction mixture was purged with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2; 1.477 g, 2.10 mmol, 5 mol %) was added, and the solution was heated to 70° C. under nitrogen for 2 h. Upon cooling to room temperature, a precipitate formed which was filtered and washed with water. The precipitate was dissolved in EtOAc (ca 500 mL) and washed with water and then brine. The organic layer was dried (MgSO4) and the solvent was removed using a rotary evaporator to give an orange solid, which was dried in vacuum oven at 50° C. (11.46 g, 76% yield): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 164.85 (s), 153.11 (d, J=252.5 Hz), 146.29 (s), 144.52 (d, J=4.3 Hz), 143.74 (s), 142.75 (dd, J=227.1, 14.0 Hz), 136.38 (d, J=13.4 Hz), 128.58 (d, J=3.2 Hz), 125.87 (s), 125.54 (d, J=3.5 Hz), 122.89 (dd, J=13.8, 4.0 Hz), 113.01 (d, J=3.0 Hz), 61.61 (d, J=4.2 Hz), 52.70 (s); ESIMS m/z 364 ([M+H]+). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](N3CCCCC3)[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1.C[OH:30]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][C:11](=[O:30])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1
Reactant: CO
Solvent: O
Product: CN1CCC(=C2c3ccccc3CC(=O)c3ccccc32)CC1

Procedure:
This enamine product is then hydrolyzed by refluxing with stirring in 150 ml. 10% in water and 75 ml. of methanol. The methanol is then removed by evaporation of the reaction mixture on a rotary evaporator. The residual material containing the desired product is made alkaline by adding solid NaHCO3 until no more CO2 is evolved. The residue is then extracted with toluene and ether. The combined extracts containing the product are dried over anhydrous MgSO4, filtered, and the solvents removed with a rotary evaporator. There remains a dark brown residual oil which when seeded crystallizes slowly. This product is collected and recrystallized from hexane two times to give 1-methyl-4-(10,11-dihydro-10-oxo-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 138°-140°C. Three more recrystallizations from hexane gives product, m.p. 141°-142°C.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][C:7]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)([CH3:10])[CH2:6][CH2:5]1)[CH3:2].[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][C:7]([N:11]2[CH2:16][CH2:15][CH:14]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13][CH2:12]2)([CH3:10])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1CCC(C)(N2CCC(=O)CC2)CC1
Reactant: CCOC(=O)/C=C/c1ccc(C)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)/C=C/c1ccc(C)cc1NC1CCN(C2(C)CCC(OCC)CC2)CC1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
1-[4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8) (0.350 g, 1.462 mmol)+ethyl (2E)-3-(2-amino-4-methylphenyl)-2-propenoate (D142) (0.1 g, 0.487 mmol) were placed in a microwave vial with 1,2-dichloroethane (DCE) (0.974 mL) and stirred for 10 mins. Sodium triacetoxyborohydride (0.387 g, 1.827 mmol) was added and the mixture heated at 140° C. for 10 mins. LCMS of the crude reaction mixture showed product (67% by u.v.). The reaction was quenched with NaHCO3 (10 mL, sat. aq) and then extracted with DCM (3×20 mL). The organic phases were combined, dried (phase sep. cartridge) and passed through a SCX-3 cartridge, eluting with DCM/MeOH to remove any neutral/acidic by-products. The product was eluted from the cartridge with 0.5 M NH3/MeOH to give a dark yellow oil. The crude product was purified by column chromatography using a 5 g cartridge and eluting with DCM-8% NH3/MeOH/DCM to give the product as a bright yellow/green oil (0.117 g, 56%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCCC1
Yield: 84.2 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) was reacted with cyclohexanecarbonyl chloride (0.52 mL, 3.9 mmol) to provide 1.16 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclohexanecarboxamide as a light brown solid, m.p. 201.7-202.5° C.