Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=1[O:15][CH3:16].[S:27]1[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[S:29].CCO>CCOC(C)=O>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[C:33]2[S:27][C:28](=[S:29])[NH:30][C:31]2=[O:32])=[CH:9][C:8]=1[O:15][CH3:16]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 14 h
Yield: 22 %

Procedure:
To a flask was added 4-(2,4-bis(trifluoromethyl)benzyloxy)-3-methoxybenzaldehyde from Step A (164 mg, 433 μmol), rhodanine (58 mg, 433 μmol), absolute EtOH (7 mL), and TEA (120 μL, 870 μmol). The reaction solution was allowed to stir at 65° C. for 14 h. The reaction solution was diluted with EtOAc (100 mL), washed with sat. NH4Cl (75 mL×3), dried over Na2SO4, filtered, and concentrated to ⅓ the original volume. The yellow precipitates were isolated by filtration under reduced pressure, washed with EtOAc (50 mL) and Et2O (50 mL) to afford the title compound (47 mg, 23%). 1H NMR (DMSO-d6) δ 13.25 (1H, br s), 7.90 (1H, d, J=8.1 Hz), 7.86 (1H, s), 7.80 (1H, d, J=8.60 Hz), 7.48 (1H, s), 6.99 (1H, dd, J=2.0 Hz, 8.6 Hz), 6.96 (1H, d, J=2.0 Hz), 6.86 (1H, d, J=8.3 Hz), 5.35 (2H, s), 3.88 (3H, s); MS (ESI) 494 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([OH:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:14]([O:17][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of the alcohol from Step 2 (0.19 g, 0.59 mmol) and benzyl bromide (0.10 mL, 0.88 mmol) in DMF (4 mL) at 0° C. was added Cs2CO3 (0.29 g, 0.88 mmol). The mixture was stirred at RT for 1 hour, and then saturated NH4Cl solution and H2O were added. The product was extracted with 1:1 EtOAc:Et2O and the organic layer was washed with H2O and brine. After drying (MgSO4), filtering, and removal of solvent, the crude product was purified by flash chromatography (1:2 EtOAc:hexane) to give a tan coloured foam (0.23 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([N:17]([OH:32])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.[CH3:33][NH:34][CH2:35][CH2:36][OH:37]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([N:17]([OH:32])[C:14]2[CH:15]=[CH:16][C:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[N:34]([CH2:35][CH2:36][OH:37])[CH3:33])=[CH:12][CH:13]=2)=[O:19])=[CH:22][C:23]=1[C:28]([F:29])([F:31])[F:30]
Reactant: CNCCO
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N(O)c1ccc(-n2cnc3c(Cl)ncnc32)cc1
Product: CN(CCO)c1ncnc2c1ncn2-c1ccc(N(O)C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-chloropurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-1-hydroxyurea and 2-methylamino-ethanol by using the same techniques as in Example 53.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:23])[CH:9]=2)[N:4]=1.ClC1C2C(=CC=C(F)C=2)N=C(CCl)[N:26]=1.COC1C=CC(NC)=CC=1>CC(O)C.Cl.C(Cl)Cl>[NH2:26][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:23])[CH:9]=2)[N:4]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccc(F)cc23)cc1
Reactant: Fc1ccc2nc(CCl)nc(Cl)c2c1
Agent: CNc1ccc(OC)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(N(C)c2nc(CN)nc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
(2-Chloromethyl-6-fluoro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 4-chloro-2-chloromethyl-6-fluoroquinazoline (265 mg, 1.15 mmol) and (4-methoxy-phenyl)-methyl-amine (175 mg, 1.26 mmol) in i-PrOH (10 mL) was treated with HCl (12 M, 4 drops) and stirred overnight at rt. The reaction was diluted with CH2Cl2 and washed with 5% NaOH. The organics were dried (MgSO4), concentrated and purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%, 20 min) to provide 258 mg (68%) of the title compound. 1H NMR (DMSO-d6) δ 7.83 (dd, 1H), 7.62 (ddd, 1H), 7.25-7.33 (m, 2H), 7.02-7.10 (m, 2H), 6.47 (dd, 1H), 4.75 (s, 2H), 3.81 (s, 3H), 3.54 (s, 3H); LC-MS (ESI+; 332 ([M+H]+)).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:27]([C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1)#[N:28].[OH-].[Na+]>CC(N(C)C)=O.CC(OC)(C)C>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:35][C:31]4[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=4)[C:27]#[N:28])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:20][CH2:19][CH2:18]1
Reactant: N#Cc1cccc(O)c1
Reactant: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: COC(C)(C)C
Product: N#Cc1cccc(Oc2ccc(C(=O)N3CCCN(C4CCC4)CC3)cn2)c1
Temperature: 125 °C
Reaction time: 20 h

Procedure:
To a solution of (6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone (101.0 g, 343.8 mmol) in dimethylacetamide (1.1 L) was added Cs2CO3 (224 g, 687.6 mmol) and m-cyanophenol (81.9 g, 687.6 mmol). The resulting mixture was warmed to 125° C. and stirred for 20 h. After cooling to room temperature, the resulting mixture was filtered and acetic acid (1.5 L) was added to the filtrate. The resulting mixture was concentrated under reduced pressure to yield a brown residue which was taken up into MTBE (1.5 L) and 1N NaOH(aq) (1.5 L). The resulting layers were thoroughly mixed and then separated. The organic extract was dried over magnesium sulfate, filtered, and concentrated to yield the title compound as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.N1CCCCC1.C1(O)C=CC=CC=1>CO.C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C(C(=Cc1ccc(Cl)cc1)c1ccccc1)c1ccc(O)cc1
Reaction time: 8 h
Yield: 24.9 %

Procedure:
9.4 g (0.0443 mole) of 1-(4-hydroxyphenyl)-2-phenylethanone, 6.23 g (0.0443 mole) of 4-chlorobenzaldehyde and 3.53 g (0.0415 mole) of piperidine in 19.3 ml of methanol was stirred at 35° and then kept overnight. It was worked up as under Example IA to give 14.5 g (83%) of crude product. 14 g (0.0333 mole) of the crude phenol was mixed with 140 ml of glacial acetic acid and refluxed for 4 hours. Work up as under Example IB followed by recrystallization from methanol gave 3.7 g (34%) of pure product, m.p. 179°-181°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: BrCCC1CCOCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CCC2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 4-(2-bromo-ethyl)-tetrahydro-pyran (described in US 2004220214) gave the title compound. ES-MS m/e (%): 479.5(M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:40]=[O:41]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:40]=[O:41])=[N:3][CH:4]=1
Reactant: COc1ccc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-methoxyphenyl)thio]methyl]-4-methylpyridine (1.08 g, 2.48 mmol) in toluene (30 ml), a hexane solution of n-butyllithium (1.54 M, 1.77 ml, 2.72 mmol) was added in an argon atmosphere at −78° C. The reaction mixture was stirred for 30 minutes at −40° C., and then cooled again to −78° C., and N,N-dimethylformamide (0.221 ml, 2.72 mmol) was added thereto. After stirring the reaction mixture for 2 hours, water was added thereto at the same temperature, and the mixture was allowed to warm to room temperature. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:1 was concentrated under reduced pressure to obtain the title compound (597 mg, 1.55 mmol, 63%) as a yellow oily substance.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]=[CH:9]2)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[O:14]=[C:13]1[N:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:3][CH2:4]2)[CH:9]=[N:10][CH:11]=[CH:12]1
Reactant: O=C1CCC(n2cnccc2=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cnccc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 3-(4-oxo-cyclohexyl)-3H-pyrimidin-4-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:36])([F:35])[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:28][C:24]([C:23]([F:36])([F:22])[F:35])=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as an off-white crystalline solid (yield 52%). MS (m/e): 532.3 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([N:18]3[CH:22]=[C:21]([C:23]4[C:24]5[CH:31]=[CH:30][NH:29][C:25]=5[N:26]=[CH:27][N:28]=4)[CH:20]=[N:19]3)[CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)[C:3]=1[CH3:32].[F:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>O>[N:26]1[C:25]2[NH:29][CH:30]=[CH:31][C:24]=2[C:23]([C:21]2[CH:20]=[N:19][N:18]([CH:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:4]4[C:3]([CH3:32])=[C:2]([NH:36][C:35]5[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=5[F:33])[N:7]=[CH:6][N:5]=4)[CH2:9][CH2:10]3)[CH2:15][C:16]#[N:17])[CH:22]=2)=[N:28][CH:27]=1
Reactant: Cc1c(Cl)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reactant: Nc1ccccc1F
Solvent: O
Product: Cc1c(Nc2ccccc2F)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Yield: 27.8 %

Procedure:
A solution of 3-[1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.010 g, 0.022 mmol from step 3 in example 146) and 3 mg TSA.H2O in 2-fluoro-aniline (95 microL, 1.0 mmol) was heated at 160° C. for 1.7 hours. The reaction was purified by preparative-LCMS (pH 10) to give 3.2 mg white solid (50% yield). 1H NMR (400 MHz, DMSO): δ 12.07 (1H, s); 8.78 (1H, s); 8.61 (1H s); 8.37 (1H, s); 8.02 (1H, s); 7.99 (1H, s); 7.55 (1H, d); 7.38 (1H, m); 7.1.5 (1H, m); 7.06 (2H, m); 6.95 (1H, s); 4.57 (1H, m); 3.61 (1H, m); 3.45 (1H, m); 3.27 (2H, m); 2.7 (1H, m); 2.58 (1H, m); 2.02 (1H, m); 1.98 (3H, s); 1.82 (1H, m); 1.3 (2H, m); (1.01 (1H, m). LCMS (M+1): 523.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(NC1C=CC(S(=O)(=O)N)=CC=1)=S)[CH2:9][C:10]([OH:12])=[O:11].C(OC(NCCCCCCCCN(CC1C=CC=CN=1)CC(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: NS(=O)(=O)c1ccc(NC(=S)NCCCCCCCCN(CC(=O)O)Cc2ccccn2)cc1
Agent: CC(C)(C)OC(=O)CN(CCCCCCCCNC(=O)OC(C)(C)C)Cc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCCCCN(CC(=O)O)Cc1ccccn1

Procedure:
2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylphenyl)thioureido)octyl)amino)acetic acid. A solution of tert-butyl 2-((8-(tert-butoxycarbonylamino)octyl)(pyridin-2-ylmethyl)amino)acetate (0.449 g, 1.0 mmol) in DCM (4 mL) and TFA (4.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to afford 2-((8-aminooctyl)(pyridin-2-ylmethyl)amino)acetic acid. A solution of the above product 2-((8-aminooctyl)(pyridin-2-ylmethyl)amino)acetic acid, 4-isothiocyanatobenzenesulfonamide (0.278 g, 1.3 mmol) in CH3CN (40 mL) and DIPEA (3.0 mL) was stirred at 50° C. under nitrogen for 48 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by Amberchrom™ eluting with acetonitrile/water to give 2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylphenyl)thioureido)octyl)amino)acetic acid (0.500 g) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.11 (s, 1H), 7.94 (td, J=7.6, 1.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.57 (d, J=7.6 Hz, 1H), 7.50-7.47 (m, 1H), 7.26 (s, 2H), 4.53 (s, 2H), 4.14 (s, 2H), 3.44-3.40 (m, 2H), 3.14-3.08 (m, 2H), 1.64-1.24 (m, 1 H); ESMS m/z: 508.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Fc1cccc(F)c1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3c(F)cccc3F)cc2)c1C
Yield: 21.4 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.1 g, 0.28 mmol) in dimethoxyethane (4 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,6-difluorobenzene (0.084 g) and 2.0 M aqueous sodium carbonate (1 mL, 2 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,6-difluoro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.027 g, 21%) as a solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:10](Cl)(=O)[CH:11]=[CH2:12]>CC(C)=O>[C:1]1([O:7][CH2:12][CH:11]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)Cl
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Into a reaction vessel equipped with a stirrer, thermometer, and reflux condenser 94 g (1.0 mol) of phenol, 40 g (1.0 mol) of NaOH, and 210 g of acetone were introduced. With stirring the contents, the internal temperature was elevated to 40° C. Subsequently, 76 g (1.0 mol) of acryloyl chloride was added dropwise thereto over 1 hour. After completion of the dropwise addition, the reaction mixture was further kept at 40° C. for 2 hours and reacted thereby. The reaction product was filtered to remove the NaCl yielded as a by-product, and the acetone was thereafter removed under reduced pressure to obtain 134 g of allyl phenyl ether.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([NH:42][C@H:43]([C:48](O)=[O:49])[CH2:44][C:45](=[O:47])[NH2:46])=[O:41].ON1C=CC=CC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:74][S:75]([OH:78])(=[O:77])=[O:76]>C(OCC)(=O)C.O.O1CCCC1>[CH3:74][S:75]([OH:78])(=[O:77])=[O:76].[C:18]([NH:17][C:15]([C@@H:14]1[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6][N:5]1[CH2:4][C@@H:3]([OH:22])[C@@H:2]([NH:1][C:48](=[O:49])[C@H:43]([CH2:44][C:45](=[O:47])[NH2:46])[NH:42][C:40]([C:31]1[CH:32]=[CH:33][C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=1)=[O:41])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Agent: O=c1ccccn1O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Yield: 95.9 %

Procedure:
125.9 g (312 mmol) of 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-t-butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, 94.6 g (328 mmol) of N-(2-quinolylcarbonyl)-L-asparagine and 3.5 g (31 mmol) of 1-hydroxy-2(1H)-pyridone were treated with a mixture of 75 ml of tetrahydrofuran and 1925 ml of ethyl acetate. A solution of 70.9 g (344 mmol) of dicyclohexylcarbodiimide in 500 ml of ethyl acetate was subsequently added dropwise at 25° within 30 minutes while stirring. The reaction mixture was stirred for 10 hours. Then, 50 ml of water of low ion contents were added and the suspension was cooled to 2°-3° and stirred at this temperature for 1 hour. The dicyclohexylurea was then filtered off and washed on the filter with 2 500 ml portions of ethyl acetate. The filtrates were combined and treated slowly at 50° with a solution of 32.5 g (338 mmol) of methanesulphonic acid and 250 ml of ethyl acetate. The suspension was subsequently stirred at 20° for 14 hours. The crystals were then filtered off under suction, washed with a total of 600 ml of ethyl acetate and subsequently dried at 45°/2000 Pa for 24 hours. 229.5 g (95%) of N-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide methanesulphonate having a HPLC content of 97.1% were obtained.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[C:33]([CH3:34])=[N:32][CH:31]=[N:30]1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[C:33]([CH3:34])=[N:32][CH:31]=[N:30]3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1F
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.84 min; Mass spectrum (ESI+): m/z=454 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:16])([CH2:13][O:14][CH3:15])[CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:12][CH2:11][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([OH:16])[CH2:13][O:14][CH3:15]
Reactant: COCC(O)(CC#N)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC(O)(CCN)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
To a solution of (3RS)-3-(3,4-dichlorophenyl)-3-hydroxy-4-methoxybutanenitrile (5.56 g) in THF (100 mL) was added lithium aluminum hydride (812 mg) by small portions at room temperature. The mixture was stirred at room temperature for 10 min, and the reaction mixture was quenched with water. The precipitate was filtered off, and washed with THF. The filtrate was concentrated, 0.1 N aqueous potassium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (NH, eluent; hexane:ethyl acetate (0%-100%)) to give the title compound (3.02 g).