Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[NH:22]C(=O)C.Cl.[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[NH2:22]
Reactant: COC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87 mg of 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-acetylamino benzoic acid methylester are dissolved in 6 ml of methanol, treated with 1 ml of 4 N hydrochloric acid and stirred for 48 hours at room temperature. The mixture is neutralised by addition of 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel (hexane/ethyl acetate=6/1) yields the title compound as colourless crystals. mp: 50-55°.
Reaction SMILES: N1C=CC=C(C)C=1.[CH2:8]([O:10][N:11]=[C:12]([C:16]1[C:17](=[O:35])[CH2:18][CH:19]([C:23]2[C:24]([O:33][CH3:34])=[N:25][C:26]([S:31][CH3:32])=[N:27][C:28]=2[O:29][CH3:30])[CH2:20][C:21]=1[OH:22])[CH2:13][CH2:14][CH3:15])[CH3:9].[CH3:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39]>ClCCl>[CH3:36][C:37]([CH3:42])([CH3:41])[C:38]([O:22][C:21]1[CH2:20][CH:19]([C:23]2[C:28]([O:29][CH3:30])=[N:27][C:26]([S:31][CH3:32])=[N:25][C:24]=2[O:33][CH3:34])[CH2:18][C:17](=[O:35])[C:16]=1[C:12](=[N:11][O:10][CH2:8][CH3:9])[CH2:13][CH2:14][CH3:15])=[O:39]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(OC)nc(SC)nc2OC)CC1=O
Solvent: Cc1cccnc1
Solvent: ClCCl
Product: CCCC(=NOCC)C1=C(OC(=O)C(C)(C)C)CC(c2c(OC)nc(SC)nc2OC)CC1=O
Temperature: 25 °C

Procedure:
A solution of 3-picoline (40 mg) and 2-[1-ethoxyimino)butyl]-5-(4,6-dimethoxy-2-methylthio-5-pyrimidyl)cyclohex-2-en-1-one (2) (80 mg) in dichloromethane (10 ml) was treated with trimethylacetyl chloride with stirring at room temperature. After 2 hours the solution was washed with dilute hydrochloric acid (1M, 20 ml), separated, dried over anhydrous magnesium sulphate and evaporated under reduced pressure to give 3-trimethylacetyloxy-2-[1-(ethoxyimino)butyl]-5-(4,6-dimethoxy-2-methylthio-5-pyrimidyl)cyclohex-2-en-1-one (7) as a pale brown oil (100 mg) which was characterized by nuclear magnetic resonance spectroscopy.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]=4)[CH3:29])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 9, 0.5 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.35 g) in n-BuOH (10 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.45 g of desired product. MS (electrospray): 384 (M+1) for C18H18FN7O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.60 (s, 1H) 8.20 (m, 1H) 8.15 (m, 1H) 7.60 (m, 1H) 7.40 (s, 1H) 6.30 (d, 1H) 6.20 (s, 1H) 5.35 (m, 1H), 1.90 (m, 1H) 1.60 (d, 3H) 1.00 (m, 2H) 0.80 (m, 2H).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[C:14]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:19]=[CH:18][C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:22]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:16][CH:15]=1.I[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCCCCC>[C:14]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:19]=[CH:18][C:17]([N:20]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:22]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:16][CH:15]=1
Reactant: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3-c3ccccc3)cc2)cc1
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Product: COc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
Toluene (200 mL) was bubbled with nitrogen for 15 min, followed by addition of 10% t-Bu3P in hexane (2.9 mL, 1.0 mmol) and Pd2(dba)3 (1.1 g, 1.2 mmol). The mixture was bubbled with nitrogen for 15 min, then N-([1,1′-biphenyl]-4-yl)-[1,1′:3′,1″-terphenyl]-4′-amine (10.6 g, 26.5 mmol), 4-iodoanisole (11.2 g, 48.0 mmol), sodium tert-butoxide (3.5 g, 36.0 mmol) were added. The mixture was bubbled with nitrogen for 15 min and stirred for 16 h at room temperature. The reaction mixture was filtered through a silica pad and washed with toluene (containing 0.5% triethylamine). The solvent was removed in vacuo and the residue was purified by flash chromatography using 30-40% toluene/hexane (containing 0.5% triethylamine) to afford N-([1,1′-biphenyl]-4-yl)-N-(4-methoxyphenyl)-[1,1′:3′,1″-terphenyl]-4′-amine (12.5 g, 94% yield) as a white solid.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:29]#[C:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:29]([C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Nc1nc(I)nc2c1nc(NCc1ccccc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCCCC
Product: CCCCC#Cc1nc(N)c2nc(NCc3ccccc3)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-benzylaminoadenosine (11, 230 mg, 0.46 mmol) and 1-hexyn (2.23 mmol). The mixture was purified by column chromatography (EtOAc). Yield 146 mg (0.32 mmol, 70%), mp 141–143÷C; Rƒ 0.26 (5% MeOH in EtOAc); 1H NMR (DMSO-d6) δ 7.64 (t, 1H, J=6.10 Hz, NH), 7.36–7.18 (m, 5H, phenyl), 6.59 (bs, 2H, NH2), 5.92 (d, 1H, J=7.71 Hz, H-1′), 5.77 (t, 1H, J=4.85 Hz, OH-2′), 5.32 (d, 1H, J=6.74 Hz, OH-5′), 5.18 (d, 1H, J=4.18 Hz, OH-3′), 4.64 (q, 1H, J=4.64 Hz, H-2′), 4.58 (t, 2H, J=4.65 Hz, NHCH2), 4.09 (t, 1H, J=4.09 Hz, H-3′), 3.98 (d, 1H, J=1.60 Hz, H-4′), 3.62 (q, 2H, J=2.58 Hz, H-5′), 2.36 (t, 2H, J=6.92 Hz, ≡CCH2), 1.55–134 (m, 4H, CH2CH2), 0.89 (t, 3H, J=7.11 Hz, CH3); MS m/z 453 (M+H)+; Anal. (C23H28N6O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[C:4](Cl)[N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1>CC(O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][CH2:19][NH:18][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:22]1
Reactant: COC(=O)C(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CC(C)O
Product: COC(=O)C(C)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(Cl)nc21
Temperature: 85 °C

Procedure:
A mixture of methyl 2-(2,6-dichloro-9H-purin-9-yl)propanoate (b) (600 mg, 2.2 mmol), tryptamine (420 mg, 2.6 mmol) and 2-propanol (30 mL) was heated at 85° C. in a sealed tube for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (10 to 80% ethyl acetate in hexane eluant) to afford the title compound as a white solid. MS m/z 360.1 (M+1).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10](=[O:19])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)[CH:8]=[CH:9][C:2]=12.Br.C(=O)(O)[O-:22].[Na+]>CS(C)=O.O>[N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10](=[O:19])[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[O:22])[CH:8]=[CH:9][C:2]=12
Reactant: Cc1cccc(CC(=O)c2ccc3nsnc3c2)n1
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)C(=O)c2ccc3nsnc3c2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1-Benzo[1,2,5]thiadiazol-5-yl -2-(6-methyl-pyridin-2-yl)-ethanone (5.88 g, 21.8 mmol) was dissolved in dimethyl sulfoxide (50 ml) heated to 60° C. Hydrogen bromide (7.1 ml of a 48% solution in water) was added dropwise and the reaction stirred for 3 hours at 60° C. The cooled reaction was poured into water (100 ml) and the pH adjusted to pH 8 with saturated sodium bicarbonate solution. The organic product was extracted into ethyl acetate (3×100 ml), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure (5.19 g, 84%); 1H NMR (250 MHz, CDCl3) δ: 2.47 (3H, s), 7.40 (1H, d), 7.85 (1H, t), 8.06 (1H, d), 8.15 (1H, d), 8.28 (1H, d), 8.45 (1H, s); m/z(API) 284 (M+H+, 100%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:41][C:42](=[O:53])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH:51]=O)=[CH:45][CH:44]=1)C.C([SiH](CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].B(F)(F)F.CCOCC.FC(F)(F)C(O)=O.C(O)(=O)C>ClCCl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:51][CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([C:42]([OH:53])=[O:41])=[CH:44][CH:45]=2)=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)(=[O:28])=[O:29])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)NCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 51.7 %

Procedure:
N-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichlorophenyl)-methanesulfonamide (20.0 g, 34.25 mmol), 4-(3-Oxo-propyl)-benzoic acid ethyl ester (10.5 g, 50.97 mmol), triethylsilane (12.0 g, 103.5 mmol), magnesium sulfate (0.30 g), and dichloromethane (100 mL) were combined, stirred, and cooled to −20° C. A solution of boron trifluoride diethyl etherate (3.26 g, 22.96 mmol) in dichloromethane (10 mL) was added to the reaction mixture over 2 min. After 40 min, trifluoroacetic acid (1.95 g, 17.11) was added to the reaction mixture. After three hours, the reaction mixture was filtered cold through a celite pad into aqueous sodium bicarbonate (9 g/100 mL). The organic layer was concentrated to 60 g, then methanol (100 mL) was added. The solution was concentrated to 82 g. Methanol (40 mL) and aqueous sodium hydroxide (8.2 g of a 50% solution, 102.5 mmol) were added to the mixture. The mixture was stirred and warmed to 65° C. for 6 h. After cooling the reaction mixture to room temperature, acetic acid (6.2 g, 102.5 mmol) was added and the solvent (40 g) was removed. Toluene (200 mL) and water (50 mL) were added to the mixture. The organic layer was separated and washed with water (10 mL), then concentrated to 78 g. The solid product was collected by filtration after standing overnight, then recrystallized from 10 parts of toluene to give 13.2 g (52%) of the title compound. 1H NMR (DMSO-d6): δ12.80 (br.s, 1H), 7.89 (d, 2H, J=2 Hz), 7.59 (d, 1H, J=1.5 Hz), 7.53 (d, 1H, J=6 Hz), 7.48 (d, 1H, J=1.5 Hz), 7.38 (m, 9H), 7.20 (m, 5H), 6.77 (dd, 1H, J=6.9 & 1.5 Hz), 6.46 (d, 1H, J=6.9 Hz), 4.36 (s, 2H), 3.18 (m, 2H), 2.96 (m, 2H), 2.76 (m, 4H), 1.90(m, 2H). MS: 744 MW, 99.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:36])([F:35])[C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:34][C:32]3[S:33][C:29]([C:28]([F:36])([F:35])[F:27])=[N:30][N:31]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nnc(C(F)(F)F)s1
Yield: 18.7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine (0.059 g, 0.34 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.025 g of desired product. 1HNMR (DMSO-d6): δ 3.95 (s, 3H), 7.51 (t, J=9.0 Hz, 1H), 7.87-7.76 (m, 3H), 7.78 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 12.86 (br s, 2H); MS (m/z): 514.90 [M]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:13][CH:15]2[CH2:16][O:17]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: ClCC1CO1
Product: FC(F)(F)Oc1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethoxy-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH:38]1([CH2:41]Br)[CH2:40][CH2:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:41][CH:38]3[CH2:40][CH2:39]3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: BrCC1CC1
Product: COc1ccc(CC2c3cc(OCC4CC4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([CH3:28])[C:20]=1[CH3:29].C(O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([CH3:28])[C:20]=2[CH3:29])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(Br)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(OC)cc2)c(C)c1C
Temperature: 97.5 °C
Yield: 90.2 %

Procedure:
(4-methoxyphenyl)boronic acid (0.56 g, 3.70 mmol) and potassium carbonate (1.40 g, 10.11 mmol) were added to a solution of methyl 5-bromo-3,4-dimethylthiophene-2-carboxylate (9b, 0.8 g, 3.37 mmol) in a mixture of toluene:ethanol (10:30 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)palladium (0.19 g, 0.17 mmol) was added to the reaction mixture under nitrogen and the tube was sealed. The reaction mixture was heated at 95-100° C. for 2 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and was filtered through celite. The celite cake was washed with ethyl acetate (30 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was further purified by column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound 9c (0.84 g, 90%).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH3:41][CH:42]([C:44]1[S:45][C:46]([CH:50]=O)=[C:47]([CH3:49])[N:48]=1)[CH3:43]>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:50]/[C:46]1[S:45][C:44]([CH:42]([CH3:41])[CH3:43])=[N:48][C:47]=1[CH3:49]
Reactant: Cc1nc(C(C)C)sc1C=O
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C(C)C)nc1C)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
1,1,3,3-Tetramethylguanidine (55 μL, 0.44 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 100 mg, 0.20 mmol) in tetrahydrofuran (4 mL) at about −20° C. After 5 min, a solution of 2-(1-methylethyl)-4-methylthiazole-5-carboxaldehyde (Example 57; 38 mg, 0.225 mmol) in tetrahydrofuran (1 mL) was added. After 2 min, the cooling bath was removed and the solution was stirred at room temperature for 66 h. The solvent was evaporated and ethyl acetate (10 mL) and 10% aqueous acetic acid (5 mL) were added to the residue. The mixture was filtered to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(1-methylethyl)-4-methylthiazol-5-yl]propenoic acid methyl ester (65 mg, 62% yield) as a colorless solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23](=[O:26])[CH:24]=[CH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.C(N(CC)CC)C>[O:26]=[C:23]([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH:24]=[CH:25]/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(C(=O)O)c2ccccc12)OCc1ccccc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-1-naphthalenecarboxylic acid (100 g), benzylacrylate (96.8 g), triphenylphosphine (10.2 g) palladium(II) acetate (2 g), triethylamine (258 ml) and DMF (600 ml) are heated at 90-100° C. for 4-12 h (typically 10-12 h). Two further portions of palladium(II) acetate (20 g) are added at four hour intervals during the stir period. The mixture is treated with charcoal (3×15 g) at 50-80° C. (typically 70-80° C.) filtering after each charge at 40-45° C. The DMF is then distilled off at 80-90° C. under vacuum and the residue is cooled to 25-35° C. Dichloromethane (100 ml) and water (100 ml) are added to the residue and the mixture is acidified with concentrated hydrochloric acid and is stirred at 20-35° C. for about 30 min. The mixture is filtered, and the solid product dried. The residue is dissolved in a mixture of DMF (600 ml) then water (400 ml) at 90-100° C. and stirred for 1-1.5 h. The solution is filtered at 80-85° C., cooled to 20-35° C., and stirred for about 2 h. The product is filtered off and dried (dry weight 43 g).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13].[S:24](Cl)([CH3:27])(=[O:26])=[O:25].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:27][S:24]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])(=[O:26])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 10 °C

Procedure:
Triethylamine (20 mL, 144.6 mmol) was added to a solution of compound 54 (29.5 g, 119.9 mmol) in ethyl acetate (300 mL). The mixture was cooled to 10° C. in an ice bath. Then, a solution of mesyl chloride (10.2 mL, 131.8 mmol) in ethyl acetate (50 mL) was added dropwise at a temperature≦20° C. The resulting solution was stirred at room temperature for 3 h (TLC monitoring, eluent: hexane-ethyl acetate, 4:1). The reaction mixture was filtered to remove the precipitate—triethylamine hydrochloride. The filtrate was washed with aqueous NaHCO3, water, and evaporated. Yield of 55: 32.2 g (83%) as crystals.
Reaction SMILES: [CH3:1][N:2]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:3]1[CH:4]=[C:5]([O:21][C:22]([F:25])([F:24])[F:23])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C[N:36](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][N:2]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:3]1[CH:4]=[C:5]([O:21][C:22]([F:24])([F:25])[F:23])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:36])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
A mixture of {2-[7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (210 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (90 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. 1H-1,2,3-Benzotriazol-1-ol-ammonia complex (150 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) were added to the reaction mixture, and the mixture was further stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was purified by preparative HPLC to give the title compound (90 mg, yield 43%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 186-187° C. MS: 519 (MH+).