Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(Cl)(=O)C([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([Cl:19])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A stirred solution of 10.0 g (0.04 mole) of (+)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid in 100 ml of toluene was heated to 80° C. To this solution at 80° C. was added dropwise over 10 minutes a solution of 10.5 g (0.08 mole) of oxalyl chloride in 5 ml of toluene, and the whole heated at 80° C. for 26 hours. The toluene and excess oxalyl chloride were removed by distillation to give a residual oil which was distilled under reduced pressure using a Kugelrohr distilling system to give 8.2 g of (+)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride; b.p. 85° C./0.09 mm. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]1([O:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:10]1([O:16][CH:17]2[CH2:18][CH2:19][N:20]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:21][CH2:22]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCC(OC2CCNCC2)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(OC3CCCCC3)CC2)cc1
Yield: 53.9 %

Procedure:
A solution of 4-fluorobenzonitrile (1.50 g), 4-(cyclohexyloxy)piperidine (2.40 g) and potassium carbonate (3.3 g) in DMF (30 ml) was stirred at 90-95° C. for 6 hours. The reaction mixture was poured into water (100 ml) and extracted twice with a mixture of ethyl acetate and n-hexane (80 ml:30 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (6:1 v/v-5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-[4-cyclohexyloxypiperidin-1-yl)benzonitrile (1.90 g).
Reaction SMILES: [OH-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=1)=O.[N+]([O-])(O)=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1>CC(O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]2[N:31]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=3)[CH:6]=[CH:5][N:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: N=C(N)Nc1cccc(Cl)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1

Procedure:
31 mg (0.78 mmol) of sodium hydroxide are added to a suspension of 150 mg (0.7 mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 165 mg (0.71 mmol) of 3-chloro-phenyl-guanidine nitrate in 1.5 ml of 2-propanol. After stirring under reflux for 18 hours, the reaction mixture is cooled and filtered and the material retained on the filter is washed thoroughly with water. After drying (60°, HV), N-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine is obtained; m.p. 196°-198°, Rf =0.67 (methylene chloride:methanol=95:5), FAB-MS: 317 (M+ +1).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1[C:16]1[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:18][CH:19]=[CH:20][CH:21]=1.C1COCC1.[OH-].[Na+].Cl>CO.O>[CH2:23]([O:22][C:17]1[C:16]([C:5]2[CH:6]=[C:7]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:8]([O:10][CH3:11])=[CH:9][C:4]=2[C:3]([OH:30])=[O:2])=[CH:21][CH:20]=[CH:19][N:18]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 70 °C
Yield: 96.9 %

Procedure:
step 3—To a suspension of 66 (960 mg, 2.36 mmol) in MeOH (15 mL), H2O (10 mL), and THF (10 mL) was added NaOH (1.00 g, 23.6 mmol). The reaction mixture was heated at 70° C. overnight and gradually became homogeneous. The mixture was cooled to 0° C., acidified to pH 3 with 1.0 M aq HCl and thrice extracted with EtOAc. The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford 895 mg (97%) of 2-(2-benzyloxypyridin-3-yl)-4-tert-butyl-5-methoxybenzoic acid (68) as a beige solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1.O>CS(C)=O.C(OCC)(=O)C>[N+:8]([C:4]1[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(N2CCC(N3CCOCC3)CC2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
1-Fluoro-3-nitro-benzene (1.00 g, 0.00709 mol) and Potassium carbonate (1.47 g, 0.0106 mol) were dissolved in Dimethyl sulfoxide (7.50 mL) and 4-Piperidin-4-yl-morpholine (2.41 g, 0.0142 mol) was added. The reaction was allowed to stir overnight at 90° C. Upon completion of the reaction, the mixture was diluted with ethyl acetate and was poured over water. Combined extracts were then washed with brine and the organics were dried over magnesium sulfate, filtered and reduced. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 1.60 g of 4-[1-(3-Nitro-phenyl)-piperidin-4-yl]-morpholine.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[N:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1nccc(Cl)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-chloro-2-methylpyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.196, m/z=446; 1H NMR (CD3OD) 0.92 (s, 3H), 1.27 (s, 3H), 1.58 (d, 3H), 2.12 (s, 2H), 2.23 (m, 1H), 2.51-2.66 (m, 2H), 2.70 (s, 3H), 3.07 (m, 1H), 5.59 (m, 1H), 7.09 (d, 2H), 7.16-7.42 (m, 5H), 7.65 (d, 1H), 7.89 (d, 2H), 8.61 (d, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.N1C=CC=CC=1>ClCCl>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C:10]([CH2:9][NH:8][C:1](=[O:3])[CH3:2])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
Acetic anhydride (2.59 mL, 2.81 g, 27.5 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 4-aminomethyl-1-t-butoxycarbonyl-4-phenylpiperidine (7.96 g) and pyridine (3.03 mL, 2.97 g, 37.5 mmol) in dichloromethane (100 mL) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, aqueous sodium hydrogen carbonate (saturated, 100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×100 mL), aqueous sodium hydrogen carbonate (saturated, 100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (50:50 increasing to 100:0) to give the title compound as an off-white solid (5.96 g, 72% from 4-cyano-4-phenylpiperidine hydrochloride), δH (250 MHz, CDCl3) 7.45-7.26 (5H, m), 5.00 (1H, br m), 3.67 (2H, m), 3.45 (2H, br m), 3.21 (2H, m), 2.08 (2H, m), 1.88 (3H, s), 1.78 (2H, m), and 1.43 (9H, s).
Reaction SMILES: C1C2C3C=CC=CC=3CCCCC=2C(CO)=CC=1.ClC(C(F)(F)F)=C[C@@H]1[C@H](C(Cl)=O)C1(C)C.[Cl:34][C:35]([C:62]([F:65])([F:64])[F:63])=[CH:36][C@@H:37]1[C@H:39]([C:40]([O:42][CH2:43][C:44]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[C:48]=3[CH:47]=[CH:46][CH:45]=2)=[O:41])[C:38]1([CH3:61])[CH3:60]>>[Cl:34][C:35]([C:62]([F:63])([F:64])[F:65])=[CH:36][CH:37]1[CH:39]([C:40]([O:42][CH2:43][C:44]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[C:48]=3[CH:47]=[CH:46][CH:45]=2)=[O:41])[C:38]1([CH3:61])[CH3:60]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1cccc2c1CCCCc1ccccc1-2
Agent: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: OCc1cccc2c1CCCCc1ccccc1-2
Product: CC1(C)C(C=C(Cl)C(F)(F)F)C1C(=O)OCc1cccc2c1CCCCc1ccccc1-2

Procedure:
In the manner of Example I, but substituting 5,6,7,8-tetrahydrodibenzo[a,c]cyclooctene-4-methanol and cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride, (5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate was prepared.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]=[S:29]1(=[O:44])[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:40])[C:38]5[CH:42]=[CH:43][C:35]([N:32]6[CH2:31][CH2:30][S:29](=[O:44])(=[O:28])[CH2:34][CH2:33]6)=[CH:36][CH:37]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(N2CCS(=O)(=O)CC2)cc1

Procedure:
The title compound, white solid (129 mg, 91%), MS (ISP) m/z=568.4 [(M+H)+], mp 261.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-benzoic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1([OH:12])[CH2:11][NH:10][CH2:9]1.[F:13][C:14]1[C:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](F)=[O:18]>>[F:13][C:14]1[C:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:16]([C:17]([N:10]2[CH2:11][C:8]([C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]3[OH:1])([OH:12])[CH2:9]2)=[O:18])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: OC1CCCCC1C1(O)CNC1
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)([C@@H]2CCCC[C@@H]2O)C1

Procedure:
The compounds of examples 25a and 25b were synthesized starting from benzyl 3-hydroxy-3-(2-oxycyclohenyl)azetidine-1-carboxylate prepared according to the procedure given in example 25. The ketone was reduced to give benzyl 3-hydroxy-3-(2-hydroxycyclohexyl)azetidine-1-carboxylate as a mixture of racemic diastereomers which were subjected to hydrogenation to afford 3-(2-hydroxycyclohexyl)azetidin-3-ol. 3-(2-hydroxycyclohexyl)azetidin-3-ol was then carried forward in a coupling step with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl fluoride in the usual manner. The coupled material thus obtained was purified by preparative reverse phase HPLC where fraction 1 was tentatively assigned as (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(trans)-2-hydroxycyclohexyl]azetidin-3-ol (Example 25a) and fraction 2 was tentatively assigned as (±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(cis)-2-hydroxycyclohexyl]azetidin-3-ol.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(C3C=C4C(C(C)=NN4C)=CC=3)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:38]([O:42][C@@H:43]([C:49]1[C:67]([CH3:68])=[CH:66][C:52]2[N:53]=[C:54]([C:56]3[CH:61]=[CH:60][N:59]4[C:62]([CH3:65])=[N:63][N:64]=[C:58]4[CH:57]=3)[S:55][C:51]=2[C:50]=1[C:69]1[CH:74]=[CH:73][C:72]([Cl:75])=[CH:71][CH:70]=1)[C:44]([O:46]CC)=[O:45])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C@@H:43]([C:49]1[C:67]([CH3:68])=[CH:66][C:52]2[N:53]=[C:54]([C:56]3[CH:61]=[CH:60][N:59]4[C:62]([CH3:65])=[N:63][N:64]=[C:58]4[CH:57]=3)[S:55][C:51]=2[C:50]=1[C:69]1[CH:70]=[CH:71][C:72]([Cl:75])=[CH:73][CH:74]=1)[C:44]([OH:46])=[O:45])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4c(C)nnc4c3)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccn4c(C)nnc4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a manner similar to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid, but using (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzo[d]thiazol-6-yl)acetate instead of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C27H26ClN4O3S: 521.0 (M+H+); Found: 521.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J=7.3 Hz, 1H), 8.42 (s, 1H), 7.97 (d, J=7.5 Hz, 2H), 7.74-7.67 (m, 1H), 7.66-7.58 (m, 3H), 5.28 (s, 1H), 2.85 (s, 3H), 2.64 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:42])([F:41])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:41])[F:42])=[CH:35][CH:34]=3)(=[O:39])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)Cc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and [(4-trifluoromethylphenyl)-methyl]sulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (11%); 1H NMR (d6-DMSO) δ 11.69 (br s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.57–7.09 (m, 15H), 6.87 (d, J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 4.86 (s, 2H), 2.37 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 576 (M+H+).
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:14][C:15](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]C>>[CH2:7]([N:14]=[C:15]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCNC(=N)N
Reactant: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in part A of Example 18, and using 3.44 g. of sodium, 30.9 g. of n-heptylguanidine sulfate, and 19.1 g. of n-hexyl isocyanate, there was obtained 26.2 g. of 1-n-heptylamidino-3-n-hexylurea having the structural formula ##EQU63## as a white crystalline solid which melted at 68°-72°C. The solubility of this base in a dilute acidic solution (prepared by mixing 0.36 ml. of N/2 hydrochloric acid and 9.64 ml. of water) at 25°C. was less than 0.25 per cent. In 95 per cent ethyl alcohol at 25°C. it was soluble to the extent of 5 per cent (w/v); a precipitate formed when the 5 per cent alcoholic solution was diluted with four volumes of water.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[N:1]1([CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: OC(CCCn1cnc2cnc3ccccc3c21)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(CCCn1cnc2cnc3ccccc3c21)c1ccccc1

Procedure:
By the general method described in Step 6 of Example 1, 4-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-ol) (7.2 g, 22.7 mmol) was oxidized with DMSO (2.70 g, 34.0 mmol), oxalyl chloride (3.20 g, 25.0 mmol), and triethylamine (6.90 g, 68.1 mmol) to provide 4-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one (4.08 g) as a light yellow solid after chromatography on silica gel (elution with 10% methanol in dichloromethane).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C.O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1
Reactant: CNc1ccc(O)cc1
Reactant: Clc1ccc2oc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CN(c1ccc(O)cc1)c1nc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the sulfate salt of 4-(N-methylamino)phenol (0.008 mol, 2.76 g) in methyl ethyl ketone (25 ml) containing pure potassium carbonate (0.008 mol, 1.1 g) was warmed to reflux and a solution of 2,5-dichlorobenzoxazole (0.016 mol, 3.0 g) in methyl ethyl ketone (25 ml) was added dropwise over 2 hours. The resulting mixture was heated at reflux for a further hour, stood overnight, then stirred at room temperature for a further 8 hours. The solvent was then evaporated leaving a white solid. This was treated with a mixture of water (25 ml) and saturated aqueous sodium carbonate solution (25 ml). The solid was collected, washed with water, dried by suction and recrystallised three times from boiling toluene. Yield 1.4 g, mp 216°-217° C.; ir and pmr spectra and analysis consistent with assigned structure.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].CN(C=O)C>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:22]1[CH:23]=[CH:24][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=1)[C:11]([CH3:12])=[CH:10]2
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2nc(Cl)c(C)cc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc3ccc(OC)cc3cc2C)cc1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 25 %

Procedure:
To a mixture of 2-chloro-6-methoxy-3-methylquinoline (100 mg, 0.482 mmol), 4-(methoxycarbonyl)phenylboronic acid (184 mg, 1.02 mmol), TEA (0.35 mL, 2.41 mmol), and PdCl2(dppf) (35 mg, 0.048 mmol) was added 2 mL of DMF under argon. The mixture was then stirred for 2.5 h at 120° C. in a microwave reactor. The crude mixture was then diluted with water (25 mL) and extracted with EtOAc (25 mL×2). The organics were washed with brine (50 mL), dried over sodium sulfate, and concentrated to yield 250 mg of crude material. The crude was purified via column chromatography with a gradient of 5% EtOAc in hexanes to 80% EtOAc in hexanes to yield 37 mg (25% yield) of methyl 4-(6-methoxy-3-methylquinolin-2-yl)benzoate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][C:14]([O:17][C:18]([CH3:24])([CH3:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:28][CH2:29][C:30]1[C:35]([N:36]2[N:45]=[CH:44][C:43]3[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=3)[C:37]2=[O:51])=[CH:34][CH:33]=[CH:32][C:31]=1[B-](F)(F)F)(=O)C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCO>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[N:12]=[N:13][C:14]([O:17][C:18]([CH3:24])([CH3:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:30]=1[CH2:29][OH:28])[N:45]=[CH:44]2)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Reactant: CN(C)CC(C)(C)Oc1ccc(Nc2cc(Cl)nn(C)c2=O)nn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Solvent: O
Product: CN(C)CC(C)(C)Oc1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nn1
Temperature: 115 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
In a 15 mL microwave reaction vial was added 6-chloro-4-(6-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridazin-3-ylamino)-2-methylpyridazin-3(2H)-one (75 mg, 213 μmol, Eq: 1.00), n-BuOH (6 ml) and water (1.5 ml). To the mixture was added potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (101 mg, 213 μmol, Eq: 1.00) under argon. X-PHOS (10.6 μA, 31.9 μmol, Eq: 0.15) and potassium phosphate tribasic (99.3 mg, 468 μmol, Eq: 2.2) was added followed by bis(dibenzylideneacetone)palladium (9.17 mg, 15.9 μmol, Eq: 0.075). The tube was sealed under argon and heated in an oil bath at 115° C. for 3 hrs then stirred at room temperature overnight. To this mixture was added 100 mg NaOH in 1 mL distilled water. The mixture was warmed in an oil bath at 50° C. for 3 hrs then stirred at room temperature overnight. The crude reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The combined organic extracts were concentrated and absorbed onto silica gel. The crude material was purified by LC chromatography eluting with 0-5% (10% NH4OH in MeOH) in 1/1 EtOAc/heptane to afford 67 mg (47%) of the title compound as a pale yellow solid. Mp: 140-145° C. 1H NMR (300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 1.67 (s, 6H), 2.37 (s, 6H), 2.80 (s, 2H), 3.80 (t, J=6.2 Hz, 1H), 3.92 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 6.90 (d, J=9 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 7.43-7.65 (m, 5H), 8.20 (s, 1H), 8.28 (d, J=2.5, 1H), 8.55 (s, 1H). LCMS (ES): 643(M+H), RT=1.942 min.