Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1Cl>CO.O>[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1[S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
71.6 g (0.58 mol) of benzyl mercaptan are dissolved in 2.9 l of methanol/water (8:2), and 79.8 g (0.58 mol) of potassium carbonate are added. At 0°-5° C., 170 g (0.58 mol) of 5-bromo-2-chloro-3-nitrobenzoic acid methyl ester are added in portions over a period of 2.5 hours with stirring. Stirring is then continued for a further 2 hours and the internal temperature is then raised to 20° C. The resulting precipitate is then isolated by filtration, washed with a small amount of water and subsequently with 500 ml of methanol/water. After drying, 208 g (94%) of pale yellow product are obtained. Recrystallisation from 400 ml of methanol gives 190 g (86% of the theoretical yield) of product having a melting point of 65°-66° C.
Reaction SMILES: FC1C=CC2O[C@H](C)[C@H]([N:13]([CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14](=[O:21])[C:15]([OH:20])([CH3:19])[C:16]([NH2:18])=[O:17])C(=O)N(CCO)C=2C=1>C(O)(C)C.CCCCCCC>[OH:20][C:15]([CH3:19])([C:16]([NH2:18])=[O:17])[C:14]([NH:13][CH2:22][C:23]([F:28])([F:29])[C:24]([F:27])([F:26])[F:25])=[O:21]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CCO)C(=O)[C@H]1N(CC(F)(F)C(F)(F)F)C(=O)C(C)(O)C(N)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CC(O)(C(N)=O)C(=O)NCC(F)(F)C(F)(F)F

Procedure:
0.31 g (1.0 mmol) N-[(6R,7S)-2-Fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide epimers were separated by chromatography on Chiralpak AD with isopropanol/heptane 15:85 to yield 0.11 g N-[(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide, entity A, MS m/e (%): 502.3 (M+H+, 100) and 0.08 g N-[(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-(R or S)-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide, entity B, MS m/e (%): 502.1 (M+H+, 100).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2([C:34]([NH2:36])=[O:35])[CH2:33][CH2:32]2)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2([C:34]([NH2:36])=[O:35])[CH2:32][CH2:33]2)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:37])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2Cl)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)CC1
Reaction time: 2.5 h
Yield: 25.9 %

Procedure:
Formaldehyde (37 wt % in H2O; 14 μL, 0.19 mmol) was added to a solution of 1-(2-(2-(5-chloro-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (7) (30 mg, 63 μmol) in MeOH (5.0 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature before the addition of sodium triacetoxyborohydride (53 mg, 0.25 mmol). Stirring was continued for 2.5 hours at room temperature before the volatiles were removed in vacuo and the resulting residue was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and the volatiles evaporated in vacuo. The residue was dissolved in acetone (0.5 mL) and petroleum benzine 40-60° C. (25 mL) was added. The resulting green precipitate was isolated by filtration and dried under high vacuum to give the title compound 8 as a green solid (8 mg, 26%); 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.34 (d, J=7.3 Hz, 1H), 7.30-7.23 (m, 3H), 7.12 (d, J=8.5 Hz, 2H), 5.55 (s, 1H), 5.25 (s, 1H), 3.13 (J m, 6H), 2.52-2.41 (m, 1H), 2.38 (s, 3H), 2.23 (t, J=11.8 Hz, 2H), 1.89 (dd, J=25.4, 12.3 Hz, 2H), 1.80 (d, J=12.3 Hz, 2H), 1.68 (s, 2H), 1.06 (s, 2H). LCMS-A: rt 4.611 min; m/z 491 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(NC(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
To a solution of ethyl 4-(4-aminopiperidin-1-yl)benzoate (1.65 g, 6.65 mmol) in CH2Cl2 (200 mL) was added Et3N (1.35 g, 13.3 mmol), followed by acetyl chloride (0.573 g, 7.3 mmol). The reaction mixture was stirred at room temperature for 5 minutes, washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated, to afford ethyl 4-(4-acetamidopiperidin-1-yl)benzoate as a white solid (1.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C=C(C)c1ccc(Cl)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A mixture of p-chloro-α-methylstyrene (15.7 g, 204 mmole), 20 milligrams (mg) platinum oxide, and 20 ml absolute ethanol was shaken on a Paar Hydrogenator for about 8 hours, beginning with an initial hydrogen pressure of 42 pounds-per-square-inch (psi). During this procedure, an additional 14 psi of hydrogen were added to the Hydrogenator reservoir. The mixture was then filtered and the solvent removed by careful distillation at atmospheric pressure. The residual material resulting was distilled using a water aspirator vacuum to yield 12.69 g (74% yield) of p-chlorocumene (bp 69°-74° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:16])([F:15])[C:9]1[S:13][CH2:12][C:11](=[O:14])[CH:10]=1.F[B-](F)(F)F.CO[N+:24]1[N:25]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1>C(#N)C.O>[CH3:29][C:27]1[C:28]([O:14][C:11]2[CH:10]=[C:9]([C:8]([F:16])([F:15])[F:7])[S:13][CH:12]=2)=[N:24][N:25]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=2)[N:26]=1
Reactant: CO[n+]1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Reactant: O=C1C=C(C(F)(F)F)SC1
Agent: CC(C)(C)[O-]
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 27 h

Procedure:
Potassium tert-butoxide (0.30 g, 2.6 mmol) and 5-trifluoromethylthiophene-3-one (0.44 g, 2.6 mmol) were dissolved in acetonitrile (4 mL). A solution of crude 1-methoxy-4-methyl-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazolium tetrafluoroborate (1:1) (i.e., the product of Example 1, Step B, 0.70 g, 2.0 mmol) in acetonitrile (4 mL) was added at once. The reaction mixture was stirred at 23° C. for 27 h. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (2×25 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0 to 5% ethyl acetate in hexanes to afford the title compound (0.105 g) as a colorless solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([OH:36])[C:34]#[CH:35].[Al]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:35]#[C:34][CH2:33][OH:36])=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCO
Reactant: O=C(c1ccc(I)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Product: O=C(c1ccc(C#CCO)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-iodophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Part A; 5.0 g, 9.0 mmol) was treated with propargyl alcohol (1.05 mL, 18.1 mmol) and Pd(PPh3)2Cl2 (190 mg, 0.27 mmol). The reaction vessel was covered with aluminum foil to keep out light, and CuI (35 mg, 0.18 mmol) was added. After stirring overnight at ambient temperature, the reaction mixture was filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (SiO2; 4% MeOH in CHCl3, saturated with NH4OH) gave 4.32 g (8.97 mmol; quantitative) of the title product as a light brown foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH2:6])=[S:5].Cl[CH:8]([C:19](=O)[CH2:20][CH2:21][CH3:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[C:19]([CH2:20][CH2:21][CH3:22])[N:6]=1
Reactant: COCC(N)=S
Reactant: CCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: CCCc1nc(COC)sc1Cc1ccc([N+](=O)[O-])cc1
Yield: 25.7 %

Procedure:
A mixture of 1.2 g of methoxythioacetamide and 3 g of 2-chloro-1-(4-nitrophenyl)hexan-3-one is heated at 90°-100° C. for 4 hours and then cooled and taken up with ethyl acetate. The solution obtained is passed over animal charcoal and then evaporated. The brown oil obtained is purified on a silica column (eluent: 6/4 cyclohexane/ethyl acetate) to give 0.9 g of 2-methoxymethyl-4-propyl-5-(4-nitrobenzyl)thiazole in the form of a brown oil, which is used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26]>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].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:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
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: Cc1ccccc1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 29.2 %

Procedure:
Pd(PPh3)4 (60 mg, 0.052 mmol) in a 100 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (100 mg, 0.26 mmol) in toluene (15.6 mL), Na2CO3 (2 N, 7.8 mL), and 4-cyanophenylboronic acid (76.5 mg, 0.52 mmol). The mixture was refluxed under Ar for 3-5 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (31 mg, 29%) as a racemic product. 1H-NMR (CDCl3): 2.18 (m, 1H), 2.29 (t, 1H), 3.13 (s, 3H), 5.90 (d, 1H), 7.05 (d, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.38 (m, 2H), 7.45 (m, 2H), 7.50-7.64 (m, 3H), 7.82-7.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)=[N:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)C1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.6 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (400 mg, 1.4 mmol), 2-piperidin-4-yl-propan-2-ol (242 mg, 1.7 mmol), and 4 Å molecular sieves (1.5 g) in 1,2-dichloroethane (20 mL) was stirred at RT for 6 h. Sodium triacetoxyborohydride (593 mg, 2.8 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si—PPC, (10% MeOH in EtOAc): EtOAc, gradient 0:100 to 20:80) to afford the title compound as an orange solid (344 mg, 60%). 1H NMR (400 MHz, CDCl3): δ 3.98-3.93 (6 H, m), 3.85 (5 H, m), 3.08 (2 H, m), 2.28 (2 H, m), 1.79 (2 H, m), 1.48 (3 H, m), 1.23-1.21 (6 H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][O:11][CH2:12][C:13](O)=[O:14].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:13](=[O:14])[CH2:12][O:11][CH3:10])=[N:6][CH:7]=1
Reactant: COCC(=O)O
Reactant: NCc1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of (5-bromopyridin-2-yl)methanamine (358 mg, 1.914 mmol), 2-methoxyacetic acid (0.191 mL, 2.488 mmol), BOP-reagent (1101 mg, 2.488 mmol) and diisopropylethylamine (1.003 mL, 5.74 mmol) in DMF (8 mL) was stirred at rt for 2 hr. The reaction mixture was partitioned between EtOAc (60 ml) and saturated NaHCO3 solution (60 ml). The organic layer was washed with 10% LiCl solution (2×50 ml) and brine (50 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an orange oil that was chromatographed on a 24 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford N-((5-bromopyridin-2-yl)methyl)-2-methoxyacetamide (337 mg, 1.301 mmol, 68.0% yield) as an orange oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.62 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.4, 2.4 Hz, 1H), 7.44 (d, J=4.8 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 4.56 (d, J=5.5 Hz, 2H), 3.97 (s, 2H), 3.45 (s, 3H). MS (ES+) m/z: 259.0, 261.0 (M+H); LC retention time: 0.907 min (analytical HPLC Method O).
Reaction SMILES: Br.Br.[NH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:14])[CH2:7][CH2:6]1.[NH2:22][C:23]1[C:31]([Cl:32])=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([O:33][CH3:34])[CH:24]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[NH2:22][C:23]1[C:31]([Cl:32])=[CH:30][C:26]([C:27]([NH:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[O:14])[CH2:7][CH2:6]2)=[O:28])=[C:25]([O:33][CH3:34])[CH:24]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC1CCN(CCC(=O)c2ccc(O)cc2)CC1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCC(=O)c2ccc(O)cc2)CC1
Yield: 35.9 %

Procedure:
4-Aminomethyl-1-(3-(4-hydroxyphenyl)-3-oxopropyl)piperidine dihydrobromide (9.00 g) as a starting compound, 4-amino-5-chloro-2-methoxybenzoic acid (4.28 g), triethylamine (8.82 ml), 1-hydroxybenzotriazole (3.00 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (4.27 g) were reacted and purified in the same manner as in Example 270 to give 3.40 g of 4-amino-5-chloro-2-methoxy-N-((1-(3-(4-hydroxyphenyl)-3-oxopropyl)piperidin-4-yl)methyl)benzamide, m.p. 191°-193° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19].O=P(Cl)(Cl)Cl>>[Cl:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:16]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccncc2)nc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccncc2)nc2ccccc12
Yield: 60 %

Procedure:
2-Pyridin-4-ylquinazolin-4(3H)-one (1 mmol) and PCl5 (1.5 mmol) were suspended in POCl3 (12 mmol). The reaction mixture was brought to reflux over 4 h. The solvent was concentrated to dryness and the amorphous residue was partitioned with ethyl acetate and ice water. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with 10% Na2CO3 and brine and dried over magnesium sulfate. The filtrate was concentrated and dried in vacuo to afford the desired product as a brown solid. (60% yield). 1H NMR (400 MHz, d6-DMSO): δ 8.84 (d, 2H), 8.36 (d, 2H), 8.12 (m, 2H), 7.88 (m, 2H). MS (EI) for C13H8ClN3: 242 (MH+).
Reaction SMILES: [C:1]1([C@@H:7]([OH:16])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH:19]=1>C1C=CC=CC=1.CCOCC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20]2([O:9][C@H:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:16]2)[CH:19]=1
Reactant: O[C@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: CC1=CC(=O)CCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1=CC2(CCC1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Temperature: 115 °C
Yield: 99.9 %

Procedure:
(1R,2R)-1,2-diphenyl-1,2-ethanediol (150 g, 699 mmol) and 3-methyl-2-cyclohexen-1-one (77 g, 699 mmol) were suspended in benzene (1398 mL) and treated with PPTS (4.39 g, 17.48 mmol). The flask was fitted with a Dean-Stark trap filled with benzene and a condenser. The reaction was heated to 115° C. for 3 days, and then the reaction was cooled to ambient temperature and diluted with ether. The mixture was washed with saturated aq NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated to give a red/orange liquid (214 g, 100% yield). The liquid was used without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]([O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2)=[O:15])([CH3:12])[CH3:11].CO>ClCCl>[Cl:1][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([NH:16][C:14]([O:13][C:10]([CH3:9])([CH3:11])[CH3:12])=[O:15])[CH:18]=2)[NH:22][C:21]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
N-Chlorosuccinimide (0.044 g, 0.329 mmol) to a suspension of ethyl 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.100 g, 0.329 mmol) in dichloromethane (5 mL). Methanol (2 mL) was added to complete solution. The mixture was stirred at room temperature overnight. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (0.082 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 9.31 (br. s., 1H), 7.80 (br. s., 1H), 7.28-7.32 (m, 2H), 4.31 (q, 2H), 1.44 (s, 9H), 1.25-1.35 (m, 3H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][C:36](O)=[O:37])=[CH:34][C:29]=2[O:28][CH2:27]1>>[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][C:36]([NH:25][C@H:22]3[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]4[CH2:15][CH2:16][CH:11]([C:10]5[C:5]6[O:4][CH2:3][O:2][C:6]=6[CH:7]=[CH:8][CH:9]=5)[CH2:12][CH2:13]4)[CH2:24][CH2:23]3)=[O:37])=[CH:34][C:29]=2[O:28][CH2:27]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (21.8 mg, 54.1%), MS (ISP) m/z=493.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-(benzo[d][1,3]dioxol-5-yl)acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:16][Si:15]([C:13]#[C:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2)([CH3:18])[CH3:17]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2cc(O)ccc2c1
Temperature: 70 °C

Procedure:
To a mixture of 6-bromonaphthalen-2-ol (3.8 g, 17.04 mmol), ethynyltrimethylsilane (7.08 ml, 51.1 mmol), (PPh3)2PdCl2 (1.79 g, 2.56 mmol), TEA (12 ml, 85 mmol) in THF (12 ml) was added copper(I) iodide (0.324 g, 1.70 mmol). The resulting mixture was heated at 70° C. in oil bath overnight and cooled. To the mixture was added silica gel (40 g) and the resulting mixture was dried on vacuum. The gel powder was loaded on a silica gel column, eluted with DCM to provide compound 110A.