Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[CH3:38][C:39]1[S:40]C(B2OC(C)(C)C(C)(C)O2)=C[N:43]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[S:40][C:39]([CH3:38])=[N:43][CH:6]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cc1ncc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)s1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (2-methylthiazol-5-yl)boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=518, obsd.=518).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[CH2:19](OC(OCC)OCC)C>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:19][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9](=[O:10])[C:3]=2[N:4]=1
Reactant: Nc1ccc(Br)nc1C(=O)Nc1ccccc1F
Reactant: CCOC(OCC)OCC
Product: O=c1c2nc(Br)ccc2ncn1-c1ccccc1F
Temperature: 130 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
A mixture of 3-amino-6-bromo-N-(2-fluorophenyl)picolinamide (160 mg, 0.516 mmol) in triethoxymethane (5 mL) was stirred at 130° C. for 15 h. The mixture was cooled to room temperature and extracted with ethyl acetate (10 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 6-bromo-3-(2-fluorophenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (75 mg, yield: 45%), which was used for the next step without further purification. MS (M+H)+:320/322
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH2:8][NH:9][C:10](=[O:32])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][CH2:19][CH2:20][NH:21]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)(C)(C)C.Br>CC(O)=O>[NH2:21][CH2:20][CH2:19][O:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:33][S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:6]([OH:43])=[O:5])=[O:32])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(COCCNC(=O)OCc2ccccc2)cc1)NS(=O)(=O)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NCCOCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1

Procedure:
Cbz-ester 15-4 (200 mg, 0.33 mmol) was treated with 4 mL 30% HBr in HOAc for 2 h then concentrated and purified by flash chromatography (silica, 50:1:1 EtOH/NH4OH/H2O) providing 15-5 as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[N:5]([CH2:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)[C:4]1=[O:26].C(N(CC)CC)C.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:43](Cl)=[O:44]>ClCCl>[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:43]([NH:2][C@H:3]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[N:5]([CH2:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)[C:4]1=[O:26])=[O:44]
Reactant: N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)c1cc2ccccc2[nH]1

Procedure:
On the other hand, to a suspension of (3S)-3-amino-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one hydrochloride in dry dichloromethane (50 ml) was added dropwise triethylamine (7.45 ml). To the mixture was added dropwise a solution of 2-indolylcarbonyl chloride obtained above under stirring and cooling below 10° C. After stirring under the same conditions for 2 hours, the mixture was washed with hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give (3S)-1,3-dihydro-3-(2 -indolylcarbonylamino)-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (5.3 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:7].[C:15]([O-:18])(=O)C.[Na+]>CN(C)C=O.O>[Cl:3][C:7](=[CH:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:15]=[O:18]
Reactant: CC(=O)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC(Cl)=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
β chlorocinnamaldehyde was prepared by the following method. Phosphoryl chloride (24 ml, 0.26 mol.) was slowly added to anhydrous dimethyl formamide (40 ml) maintaining a temperature of 0° C. and the resulting solution stirred for 30 minutes. Acetophenone (24 g 0.2 mol.) was also dissolved in anhydrous dimethyl formamide (25 ml) and the mixture slowly added to the phosphoryl chloride solution. Whilst stirring, the reaction mixture was allowed to attain room temperature, stirred for two hours and then poured into an agitated solution of sodium acetate (300 g) in water (750 ml), After stirring for 30 minutes the product was extracted into ether, the ether extracts were dried over magnesium sulphate and the ether was then removed to yield 28.8 g of crude product which was used without further purification as follows.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:48][CH3:49])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36]([CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[C:15]2[CH:44]=[CH:45][CH:46]=[CH:47][C:14]1=2.[ClH:50]>CO.C(OCC)C>[ClH:50].[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:48][CH3:49])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36]([CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[C:15]2[CH:44]=[CH:45][CH:46]=[CH:47][C:14]1=2
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)C2CCOCC2)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3c(Br)cccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
A solution of tert-butyl(S)-1-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (45 mg, 61 μmol) in methanol (500 μl) at room temperature was treated with a 2 M hydrochloric acid in diethyl ether solution (1.3 ml) and stirred for 3.5 h. The reaction was then concentrated in vacuo, dissolved in water and placed on a lyophilizer over night to afford (S)-N-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (36 mg, 88%) as a light yellow powder: LC-MS m/z 637 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([N:20]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([CH:32]=O)=[N:21]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([N:20]1[C:24]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:23][C:22]([CH2:32][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[N:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Product: Cc1ccc(-c2cc(CNCCN3CCN(c4ccccc4)CC3)nn2C(C)(C)C)cc1
Yield: 80 %

Procedure:
Compound 10 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:11])[CH2:9][CH3:10].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(N)Cc1sccc1Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](Cc1sccc1Cl)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Five grams of 3-chloro-2-(2-aminobutyl)thiophene is dissolved in 10 ml of methylene chloride in a 3-neck round bottomed flask blanketed with an inert atmosphere at 0° C. Pyridine (2.2 ml) is added in one portion followed by 2.05 ml of methanesulfonyl chloride. After warming to room temperature, the mixture is stirred for 4 hours before diluting with 100 ml of diethyl ether. The solution is poured into a separatory funnel and washed with water, dilute 2N HCl, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]methanesulfonamide (5.5 g) as an orange oil which solidifies upon standing in a refrigerator overnight. MS: m/z (EI, 70EV) 267 (5%). 1H NMR (200 MHz; CDCl3): δ 1.0 (3H, t, CH3), 1.6 (2H, m, CH2), 2.65 (3H, s, CH3), 3.0 (2H, m, CH2), 3.6 (1H, m, CH), 6.9 (1H, d, CH), 7.2 (1H, d, CH).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[Cl:13][C:14]1[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][N:19]=1>C(#N)C.CC(O)C>[Cl:13][C:14]1[C:15]2[N:16]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=3[F:12])[N:20]=2)[CH:17]=[CH:18][N:19]=1
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: Nc1nccnc1Cl
Solvent: CC(C)O
Solvent: CC#N
Product: Fc1ccc(-c2cn3ccnc(Cl)c3n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)ethanone (107.31 g, 442.89 mmol) and 3-chloropyrazin-2-amine (98.00 g, 756.5 mmol) in ACN (800 mL) was stirred at reflux for about 20 h. The reaction mixture was cooled to about 25° C. before the resultant solid was collected. The filtrate solvent was removed in vacuo to yield a brown solid. This filtration was done to negate the bumping associated with the removal of the ACN. The combined solids were then suspended in water (750 mL) and basified, whilst stirring, with 2N NaOH (750 mL). After about 30 min, the product was partitioned between DCM (9×1000 mL) and filtered from the insoluble material to aid extraction process. The organic extracts were combined and stirred with 2.5N HCl (4×750 mL). The organic layer was finally washed with 2.0N NaOH (500 mL) and water (2×500 mL), dried over MgSO4, and filtered through a Florisil® pad (3 inch diameter×3 inch depth) to remove origin material. The Florisil® pad was washed with repeated amounts of solvent until no product was detected by TLC. The organic solvent was removed in vacuo to yield a yellow solid. The solid was suspended in IPA (200 mL) at about 80° C. for about 15 min and then cooled to about 20° C. The solid was collected and washed with ice-cold IPA (2×40 mL), followed by petroleum ether [bp 30-60° C.] (3×80 mL) to remove impurities. The solid was dried in vacuo at about 70° C. overnight to yield the title compound as a yellow powdery solid (69.75 g, 57%): LC/MS (Table 1, Method g) Rt=2.70 min; MS m/z: 266.1 (M+H)+.
Reaction SMILES: C([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([N+:26]([O-])=O)[CH:14]=1.C(O)(=O)C>CC(O)C.O.[C].[Pd]>[NH2:26][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH3:5])[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Sodium formate (2.7 g) and 10% palladium-carbon (0.65 g) were sequentially added to a solution mixture of tert-butyl 4-(2-methoxyphenyl)-2-nitrobenzoate (3.3 g) in 2-propanol (40 mL), water (10 mL), and acetic acid (2.6 mL), followed by heating to reflux for 2 hours. The reaction mixture was cooled to room temperature, and then the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 3.0 g of tert-butyl 2-amino-4-(2-methoxyphenyl)benzoate as a white oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1F.[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.[Mg].[NH4+].[Cl-]>C1COCC1>[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]12[O:15][CH:16]([C:2]3[C:7]1=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:17]=[CH:18]2
Reactant: Fc1ccccc1Br
Reactant: c1coc(C2OCCO2)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=CC2(C3OCCO3)OC1c1ccccc12
Reaction time: 1 h
Yield: 77.1 %

Procedure:
2-Bromofluorobenzene (36.0 g, 0.222M) in THF (200 ml) was added dropwise over one hour to a refluxing mixture of the above furan (28.0 g, 0.200M) and magnesium turnings (5.4 g, 0.206M) in dry THF (200 ml) under nitrogen. After the addition was complete, refluxing was continued for one hour. The cooled mixture was then poured onto saturated NH4Cl solution (250 ml), the organic layer separated and the aqueous layer re-extracted with ether. The combined organic extract was washed with saturated NH4Cl solution, dried over anhydrous K2CO3 -Na2SO4 and concentrated in vacuo. The residue was purified on the Waters Prep 500 HPLC using two columns and eluting with EtOAc/hexane (1:4). A total of 33.3 g of 1-(1,3-dioxolan-2-yl)-1,4-epoxy-1,4-dihydronaphthalene was obtained as a pale yellow oil. Crystallization of the oil from hexane gave 32.5 g (75% yield) as white crystals, mp 48°-49° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([NH:19][NH2:20])=[O:16])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(c2ccccc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{30} (1.23 g, 6.06 mmol, 1 equiv.), anhydrous hydrazine (0.96 mL, 18.2 mmol, 3 equiv.), ethanol (12.1 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{30} (1.23 g, 87%) as a yellow oil. 1H-NMR (500 MHz, CDCl3): δ 8.20 (br s, 1H), 7.29-7.26 (m, 2H), 6.92 (d, 2H, J=8.0 Hz), 6.88 (t, 1H, J=7.0 Hz), 3.51 (br s, 2H), 3.20 (t, 4H, J=5.0 Hz), 3.16 (s, 2H), 2.70 (t, 4H, J=5.0 Hz), 1.23 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.2, 150.9, 129.1, 120.0, 116.1, 60.5, 53.6, 49.2.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH2:29]([OH:34])[CH2:30][CH2:31][C:32]#[CH:33]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:33]#[C:32][CH2:31][CH2:30][CH2:29][OH:34])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: Cc1sc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: C#CCCCO
Product: Cc1sc2cc(C#CCCCO)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 13.1, the Trifluoro-methanesulfonic acid 2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl ester was reacted with 4-pentyn-1-ol to yield the 5-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol as brown oil, MS: 374 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][CH:8]=[C:7]2O)[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([CH3:14])=[N:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc2c(O)ccnc2nc1C
Product: CCOc1cc2c(Cl)ccnc2nc1C

Procedure:
In a similar manner to Example B1, 6-ethoxy-7-methyl-1,8-naphthyridin-4-ol (2.15 g) and phosphorus oxychloride (25 ml) were heated at 60° C. for 1 hour to give 5-chloro-3-ethoxy-2-methyl-1,8-naphthyridine, m.p. 164° C.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43]([N:20]([CH2:19][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:36])=[CH:6][CH:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[CH2:23][CH2:22]1)=[O:44]
Reactant: COc1ccc(-c2ccc(C(=O)N(C)C)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(C(=O)N(C)C)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 59 (110 mg, 0.22 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (56 mg, 0.24 mmol) using Method D to give the title compound.
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)[CH3:8].B(F)(F)F.CCOCC>C(Cl)Cl>[SH:6][CH2:5][CH:2]1[CH2:3][O:4][C:7]([CH3:8])([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:1]1
Reactant: OCC(S)CS
Reactant: COC(=O)CCCC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCCC1(C)OCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2,3-dimercaptopropanol (2.8 g, 0.022 mol), methyl 4-acetylbutyrate (3.2 g, 0.022 mol) and boron trifluoride etherate (0.62 ml) in methylene chloride (70 ml). The crude product was chromatographed on silica gel using 10% ethyl acetate/hexane as eluent to give 0.91 g (16.5%) of product.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:25]1[CH2:30][CH2:29][CH:28]([Mg]Br)[CH2:27][CH2:26]1>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[O:25]1[CH2:30][CH2:29][CH:28]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[S:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27][CH2:26]1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Br[Mg]C1CCOCC1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: c1ccc2sc(Nc3ccc(Oc4nccnc4C4CCOCC4)cc3)nc2c1

Procedure:
To a round bottomed flask was added N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.3000 g, 0.846 mmol) dissolved in a mixture of THF (1.353 mL) and NMP (0.338 mL). Iron(III)acetylacetonate (0.015 g, 0.042 mmol) was added and the temperature was brought to 0° C. (Tetrahydro-2H-pyran-4-yl)magnesium bromide (3.70 mL, 2.96 mmol) was added dropwise to the reaction. The reaction was quenched with sat. ammonium chloride. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. LC showed formation of N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine and N-(4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in DCM, to provide N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 405.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.Cl>O1CCCC1>[CH2:15]([N:4]([CH2:1][CH:2]=[CH2:3])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([Br:24])[CH:26]=1)(=[O:33])=[O:32])(=[O:7])=[O:6])[CH:16]=[CH2:17]
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)c1cccc(Br)c1
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A mixture of N,N-diallyl-4-aminopyridine-3-sulfonamide (0.25 g, 1.0 mmol) and cesium carbonate (0.82 g, 2.5 mmol) in tetrahydrofuran (10 mL) was stirred for 5 min, 3-bromobenzenesulfonyl chloride (0.17 mL, 1.2 mmol) was added and the reaction was stirred at room temperature over night. Diluted hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography, using chloroform/methanol (95:5) as the eluent, gave the title compound in 72% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][Si](C(C)(C)C)(C)C)[CH:15]=1)=[O:12])=[O:5])[CH3:2]>C1COCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(O[Si](C)(C)C(C)(C)C)c1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(O)c1
Reaction time: 4 h

Procedure:
To the title B compound, (R)-1-[3-(t-butyl-dimethyl-silanyloxy)-phenylsulfanyl-carbonyl]-pyrrolidine-2-carboxylic acid ethyl ester (1.5 g, 3.66 mmol) in a flask at RT, is added 1 M solution of n-tetrabutylammonium fluoride (14.6 mL, 14.6 mmol) in THF and the reaction is stirred for 4 h. The reaction mixture is concentrated at reduced pressure, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The crude (R)-1-(3-hydroxy-phenylsulfanylcarbonyl)-pyrrolidine-2-carboxylic acid ethyl ester is used in the next step without further purification.
Reaction SMILES: [ClH:1].Cl.C1(C[N:10]2[CH2:16][CH:15]3[N:17](CC4C=CC=CC=4)[CH2:18][CH:11]2[CH2:12][CH2:13][CH2:14]3)C=CC=CC=1>[Pd].CO.O>[ClH:1].[ClH:1].[CH:15]12[NH:17][CH2:18][CH:11]([NH:10][CH2:16]1)[CH2:12][CH2:13][CH2:14]2
Reactant: c1ccc(CN2CC3CCCC2CN3Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: C1CC2CNC(C1)CN2
Yield: 184.7 %

Procedure:
A solution of 20.28 g (53.5 mmol) of 6,8-bis(phenylmethyl)-6,8-diazabicyclo[3.2.2]nonane dihydrochloride in 400 of 2:1 methanol-water was hydrogenated using 2.5 g of 20% Pd/C catalyst. The reaction mixture was filtered and evaporated to dryness. The residue was triturated with 2-propanol and filtered to give 9.84 g of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, mp 300°-310° dec (92%).