Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH:17]=[O:18])=[N:2]1.[CH2:19]([Mg]Br)[CH:20]=[CH2:21]>O1CCCC1.C(OCC)C>[OH:18][CH:17]([CH2:21][CH:20]=[CH2:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1
Reactant: C=CC[Mg]Br
Reactant: O=CCc1ccccc1-c1noc2ccccc12
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2 g of 2-[2-(1,2-benzisoxazol-3-yl)-phenyl] acetaldehyde in 50 ml of tetrahydrofuran at -78° C. under a nitrogen atmosphere was added 10 ml of a 1 M solution of allyl magnesium bromide in diethyl ether. The solution was warmed to room temperature and stirred for a further 2 h then quenched by addition of 50 ml of saturated aqueous ammonium chloride. The aqueous layer was extracted with 150 ml then 100 ml of dichloromethane and the combined organic extracts dried over sodium sulfate and evaporated to give crude product which was purified by chromatography eluting with 20% ethyl acetate in hexane, affording 1 g of 3-[2-(2-Hydroxy-4-pentenyl)phenyl]-1,2-benzisoxazole, 1H-NMR (200 MHz, CDCl3) d 5.8 (CH=CH2).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:11])[CH3:10].O>CN(C=O)C.CCOC(C)=O>[Br:8][C:23]1[C:24]([NH2:27])=[N:25][CH:26]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([S:12]([CH:9]([CH3:11])[CH3:10])(=[O:13])=[O:14])=[CH:16][CH:17]=2)[N:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (1.926 g, 10.82 mmol) was added to a solution of 5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (3 g, 10.82 mmol) in DMF at ambient temperature. The reaction mixture was stirred at ambient temperature for 30 min and then added to a rapidly stirring water (50 ml). The precipitate was filtered off and dried in vacuo. The solid obtained was slurried in EtOAc, filtered off and dried in vacuo to provide 3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine used which was as such without further purification (8 g, 62%). 1H NMR (400.0 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.2 (d, 2H), 7.90 (d, 2H), 7.2 (s, 2H), 3.4-3.5 (m, 1H), 1.20 (d, 6H); LC/MS m/z 358.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15]OS(C)(=O)=O)=[CH:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccccc3)n2)ccc1F
Yield: 81.3 %

Procedure:
Following the procedure of Example 1(10), 2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 81.3%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][C:12](OC)=[O:13]>O1CCCC1>[C:16]1([CH:8]([OH:7])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CCCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCC(O)c1ccccc1
Reaction time: 1 h

Procedure:
A 2.0 M tetrahydrofuran solution of lithium aluminum hydride (2.80 mL, 5.60 mmol) was added to a tetrahydrofuran solution (10 mL) of methyl 5-oxo-5-phenylpentanoate (500 mg, 2.78 mmol) at 0° C. The reaction mixture was stirred for one hour and quenched with the sequential addition of water (0.2 mL), 10% sodium hydroxide solution (0.2 mL), and water (0.6 mL). It was concentrated in vacuo to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.32-1.42 (m, 1H), 1.46-1.55 (m, 1H), 1.56-1.64 (m, 2H), 1.70-1.78 (m, 1H), 1.78-1.88 (m, 1H), 3.63 (t, J=6.6 Hz, 2H), 4.68 (dd, J=5.7, 7.8 Hz, 1H), 7.25-7.30 (m, 1H), 7.32-7.35 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1)[CH3:31]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:18]=[C:17]([O:19][CH2:40][C:37]3[CH:36]=[CH:35][C:34]([C:33]([O:32][CH2:30][CH3:31])=[O:42])=[CH:39][CH:38]=3)[CH:16]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Product: CCOC(=O)c1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCN(C(=O)OCC)CC3)c2)cc1
Yield: 83.5 %

Procedure:
Using 0.52 g (1.31 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]-piperazine-1-carboxylic acid ethyl ester and 4-bromomethyl-benzoic acid ethyl ester (0.318 g, 1.31 mmol) and following the procedure of Example 42(b) affored 0.61 g of the required product. Percentage purity (LCMS): 60.0% (M+1)=557.2+1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
A mixture of tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (1 g, 2.25 mmol, 1.00 equiv), (4-phenoxyphenyl)boronic acid (530 mg, 2.48 mmol, 1.10 equiv), sodium carbonate (480 mg, 4.53 mmol, 2.01 equiv) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol, 0.03 equiv) in 1,4-dioxane (60 mL) and water (15 mL) was stirred under nitrogen at 90° C. for 24 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was dissolved in 500 mL of dichloromethane. The resulting solution was washed with 200 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 700 mg (64%) of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[C:13]2[C:8]([CH:9]=[C:10]([Cl:19])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[S:28])=[CH:25][CH:24]=1>>[Cl:19][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:27](=[S:28])[C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:31][CH:30]=1)([C:3]#[N:4])[CH3:20])[C:14]=2[O:15][CH2:16][CH2:17][CH3:18]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CCCOc1c2ccc(Cl)cc2nn1CC(C)(N)C#N
Product: CCCOc1c2ccc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-3-propoxy-2H-indazol-2-yl)-2-methylpropionitrile (104 mg, described in Example 124) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (88 mg, 46%). MS (ES): M/Z [M+H]=497. 1H NMR: (400 MHz, CHLOROFORM-d): 1.14 (t, J=7.4 Hz, 3H), 1.90 (s, 3H), 1.92-2.04 (m, 2H), 4.51 (d, J=14.2 Hz, 1H), 4.56-4.70 (m, 2H), 4.82 (d, J=14.2 Hz, 1H), 6.92 (dd, J=9.1, 1.7 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.62 (dd, J=9.1, 0.5 Hz, 1H), 7.79 (dd, J=8.3 Hz, 2H), 7.91-7.99 (m, 2H) and 9.17 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:8]1=[S:26])C.O.[OH-].[Li+].O.Cl>O1CCOCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:11][N:7]([CH2:6][CH2:5][C:4]([OH:27])=[O:3])[C:8]2=[S:26])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)propionic acid ethyl ester (1 eq) and lithium hydroxide hydrate (1.2 eq) is dissolved in 1,4-dioxane:water (4/1:v/v) and allowed to stir at room temperature for 3 hours. The reaction mixture is neutralized with aqueous 2N HCl and extracted with ethyl acetate. The organics are dried and concentrated under vacuum to give 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)propionic acid.
Reaction SMILES: C(N=C=S)C=C.[CH2:7]([N:10]1[C:14]([SH:15])=[N:13][N:12]=[C:11]1[OH:16])[CH:8]=[CH2:9].Br[C:18]1[S:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=1>>[CH2:7]([N:10]1[C:14]([S:15][C:18]2[S:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=2)=[N:13][N:12]=[C:11]1[OH:16])[CH:8]=[CH2:9]
Reactant: C=CCn1c(O)nnc1S
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: C=CCN=C=S
Product: C=CCn1c(O)nnc1Sc1ncc([N+](=O)[O-])s1

Procedure:
The title compound was prepared in a similar manner described in Example 6 starting with allyl isothiocyanate. 4-Allyl-3-hydroxy-5-mercapto-1,2,4-triazole was reacted with 2-bromo-5-nitrothiazole as in Example 6. Crystallization from ethanol and water gave 4-allyl-3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]-1,2,4-triazole as a yellow solid.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=2)[N:28]=1>>[C:36]([NH:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]2[N:28]=[C:24]([NH:23][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([S:11]([N:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH2:2]4)(=[O:12])=[O:13])=[CH:15][CH:16]=3)[S:25][CH:26]=2)=[CH:30][CH:31]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: CC(=O)Nc1ccc(-c2csc(NC(=O)c3ccc(S(=O)(=O)N4CCCc5ccccc54)cc3)n2)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with N-(4-(2-aminothiazol-4-yl)phenyl)acetamide (57 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-60% EtOAc in hexanes to give N-(4-(4-acetamidophenyl)thiazol-2-yl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 28 mg (22%). 1H-NMR: 10.02 (s, 1H), 8.20 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.67-7.58 (m, 4H), 7.24-7.18 (m, 1H), 7.14-7.08 (m, 2H), 3.84-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.06 (s, 3H), 1.66-1.59 (m, 2H).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:27])[OH:26])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[Cl:38][C:39]1[C:40]2[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([N:8]([CH3:28])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:26])[OH:27])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:44]([C:43]2[S:42][C:41]3[CH:47]=[CH:48][CH:49]=[CH:50][C:40]=3[C:39]=2[Cl:38])=[O:45])[CH2:13][CH2:14]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of boronic acid 4 (1.95 g, 4.99 mmol) in DCM (20 mL) is treated with DIPEA (1.04 mL, 5.98 mmol), followed by 3-chlorobenzo[b]thiophene-2-carbonyl chloride (1.38 g, 5.98 mmol) in one portion. The resulting solution is stirred 16 h at RT. LC/MS at this juncture showed the reaction had reached completion. The reaction mixture is washed with water (3×10 mL) and brine (1×10 mL). The organic layer is dried over MgSO4 and the solvent removed in vacuo to afford the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cn(Cc2ccccc2)c2ccccc12
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(Cc3ccccc3)c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as starting compound and 6-bromo-1-(1-benzyl-1 H-indol-3-yl)-1-hexanone were reacted and treated in the same manner as in Example 199 to give 0.43 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-benzyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[C:6]([O:14]C(=O)C)=[CH:5]1)(=[O:3])[CH3:2].S([O-])([O-])=O.[Na+].[Na+]>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[C:6]([OH:14])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cn(C(C)=O)c2ccc(Br)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)n1cc(O)c2cc(Br)ccc21
Temperature: 80 °C
Yield: 81.5 %

Procedure:
1-acetyl-5-bromo-3-acetoxyindole (1.0 g, 3.38 mmol) and sodium sulfite (1.0 g, 7.94 mmol) were mixed in 20 ml water. After heated for 3 hours at 80° C., the reaction mixture was cooled down to room temperature, and then extracted with ethyl acetate (50 ml×2). The combined organic phases were dried and evaporated to obtain a solid as white needles (1-acetyl-5-bromo-3-hydroxyindole) (0.7 g, yield: 82%; mp: 180-182° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:15]3[S:19][C:18]([C:20](O)=[O:21])=[CH:17][CH:16]=3)[CH2:14][CH:13]=[CH:12][CH2:11]2)[CH:5]=[C:4]([CH3:23])[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:20]([C:18]1[S:19][C:15]([C:10]2([CH2:9][O:8][C:6]3[CH:5]=[C:4]([CH3:23])[C:3]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)=[C:2]([CH3:1])[CH:7]=3)[CH2:11][CH:12]=[CH:13][CH2:14]2)=[CH:16][CH:17]=1)=[O:21]
Reactant: COC(=O)CCN
Reactant: Cc1cc(OCC2(c3ccc(C(=O)O)s3)CC=CC2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(C2(COc3cc(C)c(-c4ccc(C(F)(F)F)cc4)c(C)c3)CC=CC2)s1
Yield: 65.4 %

Procedure:
To a mixture of 5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-thiophene-2-carboxylic acid (0.204 g, 0.433 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.0665 g, 0.476 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.0716 g, 0.530 mmol) in DMF (4.0 mL) is added N, N-diisopropylethylamine (0.240 mL, 1.37 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.106 g, 0.553 mmol) and stirred overnight. The reaction mixture is poured into H2O (10 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide 3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.158 g, 65%) as a white foam. MS (ES): 556.3 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]1[CH2:30][CH2:29][C@:28]([CH:34]([CH3:36])[CH3:35])([C:31](O)=[O:32])[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:18]([O:22][C:23](=[O:24])[NH:25][C@@H:26]1[CH2:30][CH2:29][C@:28]([CH:34]([CH3:35])[CH3:36])([C:31]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[C:4]([C:14]([F:17])([F:15])[F:16])[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)=[O:32])[CH2:27]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(C(F)(F)F)cc(N2CCNCC2)n1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)n1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazine (280 mg, 1.1 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (460 mg, 1.7 mmol) in methylene chloride (30 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.60 g, 1.4 mmol), and triethylamine (0.20 g, 2.0 mmol). After being stirred overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to provide the desired product (200 mg, 35.1%). LCMS calculated for C25H37F3N4O3: (M+H) 499.3; found 499.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:18]2[CH2:19][CH2:20][C:15]([F:21])([F:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(Br)cc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC1(F)CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 60 °C
Yield: 50.9 %

Procedure:
A suspension of 1-bromo-4-(3-bromopropoxy)benzene (1.85 g, 6.29 mmol), 4,4-difluoropiperidine hydrochloride (1.0 g, 6.34 mmol) and potassium carbonate (2.17 g, 15.7 mmol) in acetonitrile (100 mL) was heated to 60° C. overnight, then concentrated in vacuo. The residue was partitioned between ether and saturated aqueous sodium bicarbonate. The layers were separated; the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography on an analogix SF40-80g column (hexanes/ethyl acetate=7:3) afforded the title compound as a clear oil (1.07 g, 50%). LCMS m/z 334.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.90-2.08 (m, 6 H) 2.47-2.64 (m, 6 H) 3.99 (t, J=6.34 Hz, 2 H) 6.75-6.81 (m, 2 H) 7.34-7.40 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[K+].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21]>C(OCC)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:20]=[O:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=Cc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-bromoindole (5.0 g) was added to a stirred suspension of potassium hydride (2.92 g) in diethyl ether (100 ml) at 0° C. The reaction mixture was stirred for 15 mins, cooled to −78° C. before tert-butyl lithium (31.5 ml) was added, and after 30 minutes dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 18 hrs and then poured into ice-cold 1N HCl the layers were separated and the aqueous was extracted with ethyl acetate (×3). The combined organic layers were washed with saturated sodium bicarbonate solution, brine, dried MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with Dichloromethane/Methanol (97/3, v/v) to afford a white solid (1.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[CH3:22][O:23][C:24]1[C:29]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ncccc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1cncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 61.1, 90 mg, 0.25 mmol), 2-methoxypyridin-3-ylboronic acid (45.9 mg, 0.300 mmol), K2CO3 (69.1 mg, 0.500 mmol), PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol), water (0.6 mL) and dioxane (3 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 60° C. for 1 h. The RM was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 15 g, EtOAc) to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.1 min, m/z=390.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3H) 7.19 (dd, J=7.23, 4.89 Hz, 1H) 7.40 (d, J=8.99 Hz, 2H) 7.89 (m, J=9.00 Hz, 2H) 7.97 (dd, J=7.43, 1.96 Hz, 1H) 8.28 (dd, J=5.08, 1.96 Hz, 1H) 8.46 (t, J=2.15 Hz, 1H) 8.97 (d, J=1.95 Hz, 1H) 9.08 (d, J=2.35 Hz, 1H) 10.64 (s, 1H).