Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[N:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH2:6][C:4]1[N:3]=[N:2][S:1][CH:5]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1csnn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1csnn1
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
A solution of 1,2,3-thiadiazol-4-ylmethanol (0.75 g, 6.5 mmol) in dichloromethane (20 mL) was cooled to 5° C. under a nitrogen atmosphere and treated with triethylamine (1.018 mL, 7.3 mmol) and methanesulfonyl chloride (0.565 mL, 7.3 mmol). After 15 min, the ice-bath was removed and the reaction mixture was stirred for 2 h. The solution was washed with 1N hydrochloric acid solution (2×2 mL) and water, dried (MgSO4 +MgO) and concentrated. The residue was purified by chromatography (silica gel column 1.5×21 cm) with ether as eluting solvent to give 0.90 g (71%) of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:15])[CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:15][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC[C@@H](O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC[C@H](c2ccc(F)cc2)O1
Temperature: 40 °C
Reaction time: 16 h
Yield: 111 %

Procedure:
To a solution of (R)-methyl 4-(4-fluorophenyl)-4-hydroxybutanoate (1.7 g, 8.0 mmol) in DCM (40 mL) was added 8 drops TFA at room temperature. The reaction mixture was warmed to 40° C. and stirred for 16 h. Evaporation of the solvent gave a light yellow oil from which the product was isolated by Flash chromatography eluting with 0% to 30% ethyl acetate/hexane to give 1.6 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.[NH2:26][CH2:27][CH:28]1[CH2:37][CH2:36][C:31]2[N:32]=[C:33]([NH2:35])[S:34][C:30]=2[CH2:29]1>>[NH2:35][C:33]1[S:34][C:30]2[CH2:29][CH:28]([CH2:27][NH:26][C:20](=[O:21])[CH2:19][N:14]3[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][S:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)(=[O:10])=[O:9])[C:13]3=[O:23])[CH2:37][CH2:36][C:31]=2[N:32]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Reactant: NCC1CCc2nc(N)sc2C1
Agent: Br
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NCC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 6-(aminomethyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a pale solid.
Reaction SMILES: N([O-])=O.[Na+].[I:5][C:6]1[CH:7]=[C:8]([CH3:13])[C:9](N)=[N:10][CH:11]=1.[OH:14]S(O)(=O)=O.B(O)(O)O.[NH4+].[OH-]>>[I:5][C:6]1[CH:7]=[C:8]([CH3:13])[C:9]([OH:14])=[N:10][CH:11]=1
Reactant: Cc1cc(I)cnc1N
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: OB(O)O
Agent: [NH4+]
Product: Cc1cc(I)cnc1O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Sodium nitrite (0.708 g, 10.25 mmol) was added to a mixture of 5-iodo-3-methyl-pyridin-2-ylamine (2 g, 8.55 mmol) and H2SO4 (12 mL) at 0° C. The reaction mixture was stirred 15 min at 60° C., allowed to cool down, and poured onto crushed ice. Boric acid (1.057 g, 17.09 mmol) was added and the solution was quickly heated to 100° C. The reaction mixture was cooled down and neutralized with a saturated aq. NH4OH solution. The suspension was filtered to afford the crude title product (1.67 g, 7.11 mmol, 83% yield) as a brown solid. tR: 2.85 min (HPLC 1); tR: 0.62 min (LC-MS 2); ESI-MS: 236 [M+H]+ (LC-MS 2).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][C:9]=1[O:19][CH3:20])([O-])=O.C([O-])(O)=O.[Na+]>O>[NH2:5][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][C:9]=1[O:19][CH3:20]
Reactant: COc1cc2c(cc1[N+](=O)[O-])C(=O)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1N)C(=O)CCC2
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of acetic acid (20 mL) in H2O (100 mL), 7-nitro-6-methoxy-1-tetralone (2.21 g, 10.0 mmol) was added. The solution was heated to reflux for 1 hour, and then cooled down to rt. NaHCO3 (60 mL, saturated solution) was added, and the mixture was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated in vacuo to provide a red oil. 7-Amino-6-methoxy-1-tetralone (1.74 g, 9.1 mmol, 91%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 2.07 (m, 2H), 2.57 (t, J=6.5 Hz, 2H), 2.86 (t, J=6.0 Hz, 2H), 3.73 (b, 2H), 3.91 (s, 3H), 6.59 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH:21]1[CH2:25][O:24]C(C)(C)[O:22]1)[CH2:3][NH:4][C:5](=[O:20])[CH2:6][S:7](=[O:19])(=[O:18])[NH:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]>CO.O>[OH:1][CH:2]([CH:21]([OH:22])[CH2:25][OH:24])[CH2:3][NH:4][C:5](=[O:20])[CH2:6][S:7](=[O:18])(=[O:19])[NH:8][C:9]1[C:10]([F:17])=[CH:11][C:12]([F:16])=[CH:13][C:14]=1[F:15]
Reactant: CC1(C)OCC(C(O)CNC(=O)CS(=O)(=O)Nc2c(F)cc(F)cc2F)O1
Solvent: O
Solvent: CO
Product: O=C(CS(=O)(=O)Nc1c(F)cc(F)cc1F)NCC(O)C(O)CO

Procedure:
2.22 g (6 mmol) of 2-[N-(2,4,6-trifluorophenyl)sulfamoyl]-acetic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethyl-amide] is dissolved in a mixture of 10 ml of methanol and 5 ml of water, about 100 mg of cation exchanger Amberlyst 15 is added and it is warmed to boiling temperature in 1 hour. The ion exchanger is then filtered off and the filtrate is evaporated to dryness in a vacuum. 1.94 g (5.24 mmol) =87.3% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(F)cc2)c1Br
Yield: 71 %

Procedure:
4-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 30 from 5-amino-4-bromo-3-methylisoxazole and 4-fluorobenzenesulfonyl chloride in 71% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 142-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[CH:11]3[CH2:18][CH2:19][CH2:20][CH:10]3[C:9]=2[CH:8]=1)=[O:4].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[CH:11]3[CH2:18][CH2:19][CH2:20][CH:10]3[C:9]=2[CH:8]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc2c(c1)C1CCCC1C(=O)N2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc2c(c1)C1CCCC1C(=O)N2

Procedure:
2.73 g (10.1 mmol) of 8-(methoxycarbonylethenyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one is dissolved in 100 ml of ethyl acetate, and after 273 mg of 10% Pd-C and 0.1 ml of acetic acid are added, it is stirred for 24 hours in a hydrogen atmosphere. After filtration, the filtrate is concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate: 2.7 g.
Reaction SMILES: [N+]([O-])([O-])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14].[C:21]1([C:27](=O)[C:28]([C:33]#N)=[CH:29][N:30](C)C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C(O)C>[C:29]([C:28]1[C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][C:18]([NH:17][C:9]2[CH:10]=[C:11]([O:15][CH3:16])[C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=2)=[N:20][CH:33]=1)#[N:30]
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Reactant: CN(C)C=C(C#N)C(=O)c1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Nc2ncc(C#N)c(-c3ccccc3)n2)cc(OC)c1OC
Yield: 49.4 %

Procedure:
A mixture of 3,4,5-trimethoxyphenylguanidinium nitrate (1.44 g, 5.0 mmol), 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (1.0 g, 5.0 mmol) and sodium hydroxide (0.22 g, 5.5 mmol) in ethanol (20 ml) was heated at reflux for 18 h. On cooling the resulting precipitate was collected by filtration, washed with water and diethyl ether, then dried to give the title compound (895 mg) as a green solid m.p. 246°. δH (d6DMSO) 10.37 (1H, br s), 8.93 (1H, s), 7.99 (2H, m), 7.60 (3H, m), 7.25 (2H, m), 3.75 (6H, s) and 3.63 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]([CH3:24])[C:7]([Cl:23])([CH:22]=1)/[CH:8]=[C:9](/[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=1)\[C:10](O)=[O:11].C(Cl)(=O)C([Cl:28])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]([CH3:24])[C:7]([Cl:23])([CH:22]=1)/[CH:8]=[C:9](/[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=1)\[C:10]([Cl:28])=[O:11]
Reactant: COC1=CC(Cl)(/C=C(\C(=O)O)C2=CCc3ccccc32)C(C)C=C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COC1=CC(Cl)(/C=C(\C(=O)Cl)C2=CCc3ccccc32)C(C)C=C1

Procedure:
(Z)-5-Methoxy-2-methyl-1-chlorobenzylidene-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:11]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)cc1
Yield: 22.2 %

Procedure:
A solution of 1-benzyl-4-(4-nitrophenoxy)-4-phenylpiperidine (1.95 g, 5 mM), in methanol (100 ml) was hydrogenated over 5% Pd/C at atmospheric pressure and room temperature. After the theoretical uptake of hydrogen had occurred (about 2 hours), the catalyst was removed by filtration and the solvents removed under reduced pressure. Recrystallisation of the residue from IPA (twice) gave the title compound (400 mg), m.p. 124°-6° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([C:22](O)=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.O>[C:11]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C@@H:20]([C:22]([NH:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[O:23])[CH2:21]1)=[O:16])([CH3:13])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NNc2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a brown solution of (5-fluoro-pyridin-2-yl)-hydrazine (590 mg, 4.64 mmol), (R)-1-N—BOC-beta proline (Manchester Organics, 1.00 g, 4.64 mmol) and HOBt.H2O (71.1 mg, 0.464 mmol) in DCM (20 mL) at RT was added EDC (1.07 g, 5.57 mmol) (CARE: exotherm to ˜35° C.) and the resulting solution stirred at RT for 4 h. Water (20 mL) was added and the mixture shaken. The aqueous was extracted with DCM (20 mL), then the combined organics were passed through a hydrophobic frit and concentrated in vacuo to ˜1 mL volume. FCC, using 1-10% MeOH in DCM, gave the title compound as a pale brown foam (1.37 g, 91%). LCMS (Method 3): Rt 2.93 min, m/z 347 [MNa+].
Reaction SMILES: CS(C)=O.ClCCl.C(Cl)(=O)C(Cl)=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH2:21][OH:22])[CH:20]=1>C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH:20]=1)[CH:21]=[O:22]
Reactant: OCc1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=Cc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
18 ml (0.26 mol) of DMSO are introduced into 64 ml of dichloromethane and, at −78° C., 16.1 g (0.127 mol, 11.1 ml) of oxalyl chloride are added. After 30 min, a solution of 13.1 g (59 mmol) of (5-bromo-2-chlorophenyl)methanol in 100 ml of chloroform is added dropwise. After 20 min, 40 ml of triethylamine are added and the reaction mixture is slowly warmed to RT. After the addition of 50 ml of water the mixture is extracted several times with ethyl acetate. The combined organic phases are washed successively with 2N hydrochloric acid, water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The resulting solid is dried Yunder high vacuum to constant weight.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([OH:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a suspension of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (7.0 g) in methanol (70 ml), sodium borohydride (1.29 g) was added portionwise at 21°-30° C. and the whole was stirred for 1 hour. The solution was poured into ice water (210 ml) and the resulting precipitate was collected by filtration, washed with water and dried to give 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (6.81 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH2:48])=[CH:42][CH:41]=1>C(#N)C.C(N(CC)C(C)C)(C)C>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH:48][C:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])=[CH:13][CH:12]=2)=[O:11])=[CH:42][CH:41]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methoxy-2-oxoethyl)benzoic acid (1.00 g) in acetonitrile (50 ml), N,N-diisopropyl ethyl amine (2.63 ml), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.94 g) and 2-(4-chlorophenyl)ethylamine (790 ml) were added, and the mixed solution was stirred at room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure, and the resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=30 to 50%) to give methyl (4-{[2-(4-chlorophenyl)ethyl]carbamoyl}phenyl)acetate (2.02 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[CH:35][N:36]([CH2:38][CH2:39][O:40][CH3:41])[CH:37]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[CH:35][N:36]([CH2:38][CH2:39][O:40][CH3:41])[CH:37]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3cn(CCOC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(C)cc(-c3cn(CCOC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Cc3c(C)cccc3C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1Cc1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A mixture of methyl 3-[4-[[3-(2,6-dimethylbenzyl)benzyl]oxy]phenyl]propanoate (125 mg), 2N aqueous sodium hydroxide solution (3 mL) and ethanol (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated and added to a mixture of 1N hydrochloric acid aqueous solution (10 mL) and water (30 mL). The precipitated solid was collected by filtration, washed with water and hexane and dried to give the title compound (99 mg, yield 82%) as colorless crystals.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[C:25]([CH3:27])=[C:24]([CH3:28])[N:23]=[C:22]([NH2:29])[C:21]=2[N:20]=[CH:19]1>>[NH2:29][C:22]1[C:21]2[N:20]=[CH:19][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:26]=2[C:25]([CH3:27])=[C:24]([CH3:28])[N:23]=1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: Cc1nc(N)c2ncn(CCCCNC(=O)N[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 16-26, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 393.2425.
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[CH3:29][CH:30]1[CH2:32][O:31]1>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH2:29][CH:30]([OH:31])[CH3:32]
Reactant: CC1CO1
Reactant: CN(C)CCc1sc2ccccc2c1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(O)Cc1c(CCN(C)C)sc2ccccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 17.5 %

Procedure:
A solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (285 mg, 1 mmol) and TMEDA (181 uL, 1.2 mmol) in toluene (12 mL) was cooled to −78° C. n-BuLi (750 uL, 1.2 mmol, 1.6M in hexanes) was added and the reaction was stirred at −78° C. for 45 min. 2-Methyl-oxirane (280 uL, 4 mmol) was added at −78° C. and the reaction was allowed to slowly reach room temperature, while being stirred overnight. The reaction was quenched with NH4Cl, pH was adjusted with sat. NaHCO3 until pH ˜9, followed by an extraction with EtOAc (4×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. Silica gel column chromatography (eluent: dichloromethane with gradient up to dichloromethane/MeOH=97/3) afforded 46 mg of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-propan-2-ol (Compound 23-1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7][CH2:6]2)=[CH2:2].ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl>[O:19]1[CH2:2][CH:1]1[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7][CH2:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1)CCOC2=O
Solvent: ClCCl
Product: O=C1OCCc2cc(C3CO3)ccc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
6-Vinyl-3,4-dihydro-1H-isochromen-1-one (36.0 g, 207 mmol, 1.0 eq) was added into a 500 mL round bottom flask and dissolved in dichloromethane (500 mL). The solution was cooled to 0° C., added portion wise 3-chloroperoxybenzoic acid (98.0 g, 413 mmol, 2.0 eq). The mixture was then purged with N2 and stirred at r.t. for 18 hr. To above solution was added water (100 mL). The crude product was extracted with dichloromethane. The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (hexane/EtOAc 0-50%). The desired product was obtained. LC-MS (IE, m/z): 191.27 [M+1]+; 1H NMR (500 MHz, CDCl3, δ in ppm): 8.07 (1H, aromatic, d, J=8.1 Hz), 7.32 (1H, aromatic, d, J=8.0 Hz), 7.16 (1H, br-s, aromatic), 4.52 (2H, CH2—O—, t, J=5.7 Hz), 3.90 (1H, br-s), 3.20 (1H, m), 3.05 (2H, CH2—CH2—O—, t, J=5.7 Hz), 2.77 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(F)cc1
Product: CN(C)C=CC(=O)c1ccc(F)cc1

Procedure:
A mixture of 5.0 g. of p-fluoroacetophenone and 10 ml. of dimethylformamide dimethylacetal is refluxed for 4 hours. Evaporation gives an oil which crystallizes with the addition of hexane to give the product, m.p. 83.5°-84° C.
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13]2[C:8]([C:9](=[O:28])[CH:10]=[C:11]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:12]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH3:29])[CH:6]=1)C=C.CS(O)(=O)=O>CCO.CCOC(C)=O.[Pd]>[NH2:4][C:5]1[N:14]=[C:13]2[C:8]([C:9](=[O:28])[CH:10]=[C:11]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:12]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH3:29])[CH:6]=1
Reactant: C=CCNc1cc(C)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 80 °C
Yield: 135.6 %

Procedure:
Pd/C (30 mg, 1.75 mmol, 10%) was added to a 25 mL round bottom flask and was blanketed with argon. 7-(allylamino)-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (150 mg, 0.392 mmol) was dissolved in EtOH (2 mL) and was added to the Pd/C followed by methane sulfonic acid (0.041 mL, 0.63 mmol). The reaction was heated to 80° C. for 3 d at which time it was cooled to room temperature, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by Biotage silica gel chromatrography eluting with 100% EtOAc to provide 7-amino-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (182 mg, 41%) as a yellow solid: LCMS RT: 2.01 min, MH+: 343.3.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([Cl:13])[N:5]=1.Cl[CH2:15][O:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:15][O:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])=[C:6]([Cl:13])[N:5]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOP(=O)(COCOCCl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCOCn1cnc2c(Cl)nc(N)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride in mineral oil (1.4 g, 34.5 mmol) in DMF (100 mL) was added 2-amino-6-chloropurine (5.78 g, 34.2 mmol) and the mixture was stirred for 1 hr at 25° C. To the resulting yellow solution was added dropwise a solution of above chloromethoxy(diethylphosphonomethoxy)methane in DMF (20 mL) under nitrogen. After stirring 15 hr at 25° C., volatiles were removed in vacuo. The residual oil was suspended in ethyl acetate (100 mL), washed with water (30 mL), brine and dried (MgSO4). The solvent was removed under reduced pressure, and the residual oil was chromatographed on silica gel using CH2Cl2 /3% MeOH as eluent to give the title compound as a colorless oil: yield 3.0 g (23%).