Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.NC1C=C(C2N=CN(C)C=2C2SC3N=CN=C(N)C=3C=2)C=CC=1.[CH2:47]([N:54]=[C:55]=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:55]([NH:54][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:56])=[CH:3][CH:4]=3)[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Cn1cnc(-c2ccc(N)cc2)c1-c1cc2c(N)ncnc2s1
Reactant: O=C=NCc1ccccc1
Agent: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Product: Cn1cnc(-c2ccc(NC(=O)NCc3ccccc3)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 186 but using 6-[4-(4-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 112) in place of 6-[4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 110) and using benzyl isocyanate in place of phenyl isocyanate. Yellow solid (10 mg, 36%);
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[O:29]1[C:38]2[C:33](=[CH:34][C:35](/[CH:39]=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:41](=[O:42])/[CH:40]=[CH:39]/[C:35]4[CH:34]=[C:33]5[C:38](=[CH:37][CH:36]=4)[O:29][CH2:30][CH2:31][CH2:32]5)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc2c(c1)CCCO2
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)CCCO3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and (2E)-3-(3,4-dihydro-2H-chromen-6-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a yellow solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C33H40N4O3: 541 (M+H). Found: 541
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])=[C:19]([F:30])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]=[O:18])[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:37]([CH2:39]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:38]>CO>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])=[C:19]([F:30])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][C:17]4[O:18][CH:39]=[N:37][CH:38]=4)[C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CC=O)c1F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(Cl)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2Cc2cnco2)c1F
Yield: 50.9 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3-(2-oxo-ethyl)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (0.020 g, 0.046 mmol) is dissolved in methanol (2 mL). Potassium carbonate (0.013 g, 0.093 mmol) and 1-isocyanomethanesulfonyl-4-methyl-benzene (0.010 g, 0.051 mmol) are added. The reaction mixture is stirred at reflux for 16 hours under N2, then concentrated under reduced pressure. The residue is dissolved in ethyl acetate and poured into a separatory funnel and washed with water and brine. The combined aqueous layers are reextracted with ethyl acetate (2×). The combined ethyl acetate layers are dried (Na2SO4,) and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography (eluting with 15:1 methylene chloride:methanol) to yield 0.011 g (50%) of the desired product. MS APCI (+) m/z 470, 472 (M+, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 10.51 (br s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.23 (s, 1H), 7.15 (d, 1H), 6.92 (dd, 1H), 6.31 (d, 1H), 6.11 (br s, 1H), 5.45 (s, 2H), 3.62 (d, 2H), 2.40 (s, 3H), 0.87 (m, 1H), 0.49 (m, 2H), 0.20 (m, 2H). 19F NMR (376 MHz, CDCl3) −134.54 (s).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:7])[C:4](Cl)=[O:5].[NH:8]([C:10]1[C:18]2[O:17][CH:16]([CH3:19])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[NH2:9].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:19][CH:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:8][NH:9][C:4]([N:3]([O:2][CH3:1])[CH3:7])=[O:5])[C:18]=2[O:17]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1Cc2cccc(NN)c2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)NNc1cccc2c1OC(C)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.9 g of N-methoxy-N-methylcarbamic chloride was added drop-by-drop (over 5 minutes) to a mixture of 6.6 g of 1D, 125 ml of THF and 5.2 g of N,N-diisopropyl-N-ethylamine, at -10° C. The mixture was stirred for 1 hour at 0° C., and then mixed with ice water. The resulting mixture was extracted with ether, the extract was dried (MgSO4) and the solvent was evaporated, to give 1-(2,3-dihydro-2-methylbenzofuran-7-yl)-4-methoxy-4-methylsemicarbazide (1E), as an amber syrup.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10])#[N:2].[CH2:12](O)[CH2:13][CH2:14]O>C(Cl)Cl>[O:10]1[CH2:14][CH2:13][CH2:12][O:11][B:9]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: OCCCO
Reactant: N#Cc1ccccc1B(O)O
Solvent: ClCCl
Product: N#Cc1ccccc1B1OCCCO1
Reaction time: 20 h
Yield: 57.2 %

Procedure:
49.0 g (334 mmol) 2-cyanobenzeneboronic acid and 25.9 g (340 mmol) 1,3-propanediol were dissolved in 1 L CH2Cl2 with stirring in a 2 L round bottom flask for 20 h. The solution was then poured over a filter with suction to remove gummy solids. The filtrate was then dried with anhydrous MgSO4 to remove residual water, filtered and evaporated of solvent to give light-colored oil. The oil was then dissolved in CH2Cl2 and purified on a silica gel plug using CH2Cl2 as eluent. The product fractions were evaporated down to give the product as clear oil (35.7 g, 57.2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:35])=[C:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:3]=1
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a solution of methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate (173 mg, 0.39 mmol) in CH2Cl2 (5 ml) was added mCPBA (142 mg, ˜0.59 mmol). The reaction was stirred at room temperature for 1 hour, and was directly loaded on Celite, purified by flash column chromatography on silica gel (30-70% EtOAc in hexane) to yield the title compound (40 mg, 22%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 90 °C
Yield: 39.2 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethylamine (81 mg, 0.32 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (83 mg, 0.35 mmol) and DIPEA (162 μL, 0.95 mmol) in n-butanol (1 mL) was heated at 90° C. in a sealed vial for 65 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which and with MeOH followed by 2M NH3/MeOH (purification by SCX cartridge repeated three times). The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) and then triturated with MeOH to afford 176 as an off-white solid (47 mg, 40%). LCMS (Method K): RT 2.75 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.65 (1H, s), 8.79 (1H, d, J=2.46 Hz), 8.61 (1H, s), 8.15-7.91 (4H, m), 7.71 (1H, dd, J=8.80, 4.84 Hz), 7.55-7.46 (1H, m), 7.11 (1H, td, J=9.33, 2.43 Hz), 6.93 (1H, dd, J=8.91, 2.44 Hz), 5.49 (1H, s), 1.62 (3H, d, J=6.83 Hz)
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].P(OC)(OC)(OC)=O>>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH3:14])[CH:1]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: [K+]
Solvent: COP(=O)(OC)OC
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 80 °C
Yield: 92.1 %

Procedure:
In an apparatus similar to Example 1, 15.2 g (0.083 mol) of syringaldehyde and 15.0 g (0.11 mol) of potassium carbonate were heated to 105° C. under nitrogen and 15 ml (0.12 mol) of trimethyl phosphate were added over 10 minutes. The mixture was maintained at about 80° C. for 3 hours then cooled to 45° C. and quenched with 50 ml of H2O. The tan solid which precipitated was collected, washed with 3×50 ml of water and dried to give 15 g (92%) of 3,4,5-trimethoxybenzaldehyde.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])=[O:10])=[CH:7][N:8]=1)[CH3:2].[OH:18]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])=[O:10])=[CH:7][N:8]=1)=[O:18])[CH3:2]
Reactant: C=CCCCCNC(=O)c1cnc(SCC)s1
Reactant: OO
Solvent: CC(=O)O
Product: C=CCCCCNC(=O)c1cnc(S(=O)CC)s1

Procedure:
In this preparation a mixture of 0.064 mole of 2-ethylthio-5-(hex-5-enylaminocarbonyl)thiazole; 40 ml. of 30% aqueous hydrogen peroxide and 200 ml. of acetic acid is stirred at a temperature of from 40° to 50° C for four hours. The mixture is concentrated by evaporation of a large portion of the acetic acid, under vacuum, at room temperature (about 20° C) and the resulting residue poured into 500 ml. of ethyl acetate and then washed with aqueous sodium bicarbonate solution until no acetic acid is present in the organic layer. The ethyl acetate layer is then separated, dried with anhydrous magnesium sulfate, filtered, and the resulting filtrate evaporated to dryness, under vacuum, affording 2-ethylsulfinyl-5-(hex-5-enylaminocarbonyl)thiazole.
Reaction SMILES: C[O:2][C:3](=[O:45])[C@@H:4]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=3[CH:16]=2)[CH3:14])=[CH:8][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:30][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:22]3[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:29])[C:17]=3[CH:16]=2)[CH3:14])=[CH:10][CH:11]=1)[C:3]([OH:45])=[O:2])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(C)Oc1ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S)-2-(2-Benzoylphenylamino)-3-(4(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphtalen-2-yl)-ethoxy)-phenyl)-propionic acid methyl ester (100 mg; 0.17 mmol) in THF (12 ml) was added a solution of lithium hydroxide (16 mg; 0.37 mmol) in water (8 ml). The reaction mixture was stirred at room temperature for 4 hours and 1 N HCl was added to pH 6. The mixture was extracted with methylene chloride (2×50 ml). The combined organic phases were dried and evaporated. The product was crystallized as the L-lysine salt from methanol-hexanes. Yield 95 mg. Compound 4.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=2)[CH:11]=[CH:10][N:9]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:13]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NC1CCCC1
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Product: Clc1cc(-c2ccnc(NC3CCCC3)n2)ccn1

Procedure:
Cyclopentylamine (3 mL) was combined with 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Example 6, Step A) (300 mg, 1.3 mmol) and stirred at 55° C. for 2 hours. The resulting suspension was filtered, and the collected solid was oven dried at 50° C. in vacuo to give 340 mg of the title compound as a brown solid.
Reaction SMILES: [I-:1].[NH:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][N+](C)(C)C.[C:12]1([P:18]([C:25]2C=CC=CC=2)[C:19]2C=CC=CC=2)C=CC=CC=1>C(#N)C>[I-:1].[NH:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][P+:18]([CH3:25])([CH3:19])[CH3:12]
Reactant: C[N+](C)(C)Cc1ccc[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CC#N
Product: C[P+](C)(C)Cc1ccc[nH]1
Yield: 152.7 %

Procedure:
Subsequently, to a suspension of (pyrrol-2-yl)methyl trimethylammonium iodide (7.59 g, 28.52 mmol) obtained above in acetonitrile (60 ml) was added triphenylphosphine (8.98 g, 34.2 mmol) with stirring, and the resulting mixture was stirred at 80° C. for 6 hours. After cooling, the reaction mixture was concentrated to about one-half of its initial volume, to which was added ethyl acetate (100 ml). The crystals precipitated were collected by filtration, washed with ethyl acetate and dried in vacuo to afford (pyrrol-2-yl)methyl trimethylphosphonium iodide (12.33 g, yield: 92%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[F:28][C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:31]2[CH2:32][CH2:33][C@H:29]([F:28])[CH2:30]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CC[C@H](F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (135 mg, 0.477 mmol) in MeOH (4768 μL) was added DIPEA (208 μL, 1.192 mmol), then (S)-3-fluoropyrrolidine (46.7 mg, 0.524 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solvent was removed and the residue applied to Silica gel and eluted with an EtOAc/Hex gradient to afford two diasteriomers (Hp1 and Hp2). Hp1: LC-MS (M+H)+=336.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.06-7.13 (2H, m), 6.93-7.00 (2H, m), 5.32 (1H, td, J=52.57, 3.17 Hz), 4.17 (1H, dd, J=9.16, 5.49 Hz), 4.06-4.14 (1H, m), 3.98-4.06 (1H, m), 3.76-3.90 (2H, m), 3.25 (1H, ddd, J=15.11, 8.55, 6.26 Hz), 3.08-3.16 (1H, m), 2.51-2.60 (1H, m, J=13.20, 9.12, 9.12, 6.41 Hz), 2.32-2.42 (1H, m), 2.00-2.17 (2H, m). Hp2: LC-MS (M+H)+=336.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.06-7.14 (2H, m), 6.94-7.02 (2H, m), 5.25-5.40 (1H, m), 3.99-4.24 (3H, m), 3.75-3.92 (2H, m), 3.19-3.28 (1H, m), 3.10-3.19 (1H, m), 2.57 (1H, dddd, J=13.24, 8.74, 8.55, 4.58 Hz), 2.31-2.43 (1H, m), 1.94-2.17 (2H, m)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10](I)([CH3:12])[CH3:11].C(OC1C=C(CCN)C=CC=1)(C)C>>[CH:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:12])[CH3:11]
Reactant: CC(C)I
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)Oc1cccc(CCN)c1
Product: CC(C)Oc1cccc(C=O)c1

Procedure:
3-Isopropoxybenzaldehyde was prepared from 3-hydroxybenzaldehyde and isopropyl iodide analogous to the procedure described in Example 361. By using the procedure of Example 151 this aldehyde was transformed to 2-(3-isopropoxyphenyl)ethylamine, which was reacted with the product of Example 103, following the procedure of Example 105 to give the titled product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:10]=[N:9][N:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:7]=1.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>>[F:1][C:2]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:10]=[N:9][N:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:15][CH2:16]2)[N:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(OCc2cnn(C3CCNCC3)n2)c(F)c1
Product: CC(C)OC(=O)N1CCC(n2ncc(COc3ccc(S(C)(=O)=O)cc3F)n2)CC1

Procedure:
The title compound was synthesized using 4-[4-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-[1,2,3]triazol-2-yl]-piperidine (Intermediate 7) and isopropyl chloroformate in a manner similar to that described in Example 35. 1H NMR (CDCl3): δ 7.66 (3H, m), 7.27 (1H, m), 5.30 (2H, s), 4.94 (1H, m), 4.63 (1H, m), 4.20 (2H, m), 3.04 (3H, s), 2.19 (2H, m), 2.17 (2H, m), 1.25 (6H, d).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[C:12]([OH:21])=[CH:11]1)[CH3:9].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:21][C:12]1[C:13](=[O:20])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]([CH2:8][CH3:9])[CH:11]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1cc(O)c(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1cc(OS(C)(=O)=O)c(=O)c2ccccc21

Procedure:
Triethylamine (5.6 ml) was added to a stirred suspension of 1-ethyl-3-hydroxy-4-quinolone (3.74 g) and methanesulphonyl chloride (2.3 ml) in dichloromethane (80 ml) and the resultant solution was stirred for 90 minutes. The solution was washed with water (50 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue crystallised from industrial methylated spirit (10 ml) to give the novel compound 1-ethyl-4-oxo-1,4-dihydro-quinol-3-yl methanesulphonate, m.p. 141°-143°.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1.[H-].[Na+].[CH2:23](Br)[CH3:24].O>CN(C)C=O>[CH2:23]([N:5]1[C:4](=[O:20])[CH2:3][CH:2]([CH3:1])[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[N:6]1)[CH3:24]
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2C
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1N=C(c2ccc3c(c2)CCC(=O)N3C)C(C)CC1=O
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 5.4 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one in 50 ml of dimethylformamide was added 1.1 g of 50% sodium hydride. After stirring for about 30 minutes, 2.4 g of ethyl bromide was added and the mixture was stirred at about 40° C. for one hour. The reaction mixture was poured into 200 ml of water and extracted with 100 ml of ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 3.7 g of 6-(2-ethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one as colorless crystals, melting at 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:27]([Si:31]([CH3:41])([CH3:40])[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36](O)[CH2:35][CH2:34]1)([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:12][C@H:36]1[CH2:37][CH2:38][C@@H:33]([O:32][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:40])[CH3:41])[CH2:34][CH2:35]1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)ccc1O[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of methyl 5-chloro-2-hydroxybenzoate (2.07 g, 11 mmol) and diisopropyl azodicarboxylate (2.98 g, 14 mmol) (Aldrich) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added a mixture of trans-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol (3.2 g, 14 mmol) and triphenylphosphine (3.64 g, 14 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into water, extracted with ethyl acetate (3×). The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (5% EtOAc;hexanes) to give cis-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzoic acid methyl ester as a yellow oil (Yield 4.0 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(-c2ccccc2)cn1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc(-c2ccccc2)cn1

Procedure:
Synthesized using compound 71b (724 mg, 4.25 mmol), NBS (832 mg, 4.68 mmol) and DBPO (52 mg, 0.21 mmol) in carbon tetrachloride according to Method A. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Product was used directly in the next step without further characterization. Yellow solid. Yield: 571 mg, 54%. (ESI): m/z=250.80 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH3:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C1C=CN=CC=1)C.ClCCCl>[C:16]([O:12][C:11]1[C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[CH:2]([CH3:1])[CH3:3])(=[O:18])[CH3:17]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(=O)Oc1c(C(C)C)cc(C=O)cc1C(C)C

Procedure:
3,5-bis(1-methylethyl)-4-hydroxybenzaldehyde is acetylated with acetic anhydride in refluxing 1,2-dichloroethane, in the presence of DMAP, to provide 4-acetoxy-3,5-Bis(1-methylethyl)benzaldehyde. This material is converted by the method of example 2 into the title compound, obtained as a white solid, mp 95°-97° after recrystallization from hexane.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:31])C(=O)C1.O>C1COCC1>[Br:31][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:23])=[CH:2][CH:3]=3)[S:11][C:10]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2sc3ccccc3c2-c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 80.5 %

Procedure:
2.5 g (1 eq, 7.9 mmol) of 2,3-di-p-tolyl-benzo[b]thiophene and 14 g (10 eq, 79 mmol) of NBS were dissolved in 200 ml of THF in a 500 ml-round-bottomed flask and stirred for 6 hours. 50 ml of water was added to the solution to terminate the reaction, and the organic phase was extracted using brine and methylene chloride. The extracted organic phase was dried using anhydrous magnesium sulfate and filtered to remove the solvent. A resulting solid was recrystallized using methylene chloride and hexane, dissolved in a small amount of THF, and separated using column chromatography (silica and hexane) to obtain 2.5 g (71%) of a yellow solid.