Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH2:13][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH:29]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:12]1[O:11][N:10]=[C:9]([CH:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13]1
Reactant: O=CCCCC1CC(C=Cc2ccccc2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCNCC1CCCCC1CC(C=Cc2ccccc2)=NO1
Yield: 78.6 %

Procedure:
4-[3-(2-Phenylvinyl)-4,5-dihydroisoxazol-5-yl]butanal (23.4 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 28.7 mg (73.2%) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12]>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Cl)cnc1N
Reactant: O=C(O)CO
Product: OCc1nc2cc(Cl)cnc2[nH]1

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.67 g of 5-chloro-2,3-diaminopyridine (prepared as described in Preparation 62) and 18.6 g of glycolic acid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 8.83 g of the title compound, melting at 209-211° C.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:26][C:27]([F:40])([F:39])[C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][N:29]=1>>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:36]2[CH2:35][CH2:34][N:33]([C:31]3[S:32][C:28]([C:27]([F:39])([F:26])[F:40])=[N:29][N:30]=3)[CH2:38][CH2:37]2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 34 %

Procedure:
Prepared in analogy to example 1 (b) from 2-morpholin-4-yl-5-nitro-benzoic acid (Example A27) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a brown solid (yield 34%). MS (m/e): 473.4 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26](Cl)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 1-(4-Trifluoromethoxy-phenyl)-piperazine and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (74%%, yellow solid, MS (m/e): 481.2 (M+H, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:30][C:27]3[CH:28]=[N:29][C:24]([N:21]4[CH2:20][CH2:19][O:18][CH2:23][CH2:22]4)=[CH:25][CH:26]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCOCC4)nc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 73-1 (40 mg, 0.18 mmol), 6-morpholinopyridin-3-amine (40 mg, 0.22 mmol) and HATU (80 mg, 0.21 mmol) in 2 mL DMF was added DIEA (104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give the title compound 73 as white solid. MS m/z 389.19 (M+1); 1H NMR 400 MHz (DMSO-d6) δ11.30(s, 1H), 8.82(d, 1H, J=6.4 Hz), 8.57(d, 1H, J=2.4 Hz), 8.35(m, 1H), 8.24(dd, 1H, J1=6.4 Hz, J2=1.6 Hz), 8.19(dd, 1H, J1=10.0 Hz, J2=2.8 Hz), 8.02(m, 2H), 7.63(m, 2H), 7.42(d, 2H, J=9.6 Hz), 3.87(s, 2H), 3.75(m, 4H), 3.66(m, 4H), 2.80(s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][N:3]=1.[F-:18].[Cs+]>CS(C)=O.O>[F:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][N:3]=1
Reactant: Fc1ccc2c(OCC3CC3)cnc(Cl)c2c1
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2c(OCC3CC3)cnc(F)c2c1
Temperature: 145 °C
Yield: 65.8 %

Procedure:
To a solution of 1-Chloro-4-(cyclopropylmethoxy)-7-fluoroisoquinoline (0.7 g, 2.78 mmol) in DMSO (5 mL) was added cesium fluoride (1.0 g, 6.95 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.43 g, 65%) as white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.35-8.33 (m, 1H), 7.77-7.74 (d, J=12 Hz, 1H) 7.73 (t, J=8 Hz, 1H), 7.52-7.51 (d, J=4 Hz, 1H), 4.10-4.08 (d, J=8 Hz, 2H), 1.42-1.40 (m, 1H), 0.74-0.69 (m, 2H), 0.49-0.46 (m, 2H); MS: MS m/z 237.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][OH:27].[CH2:28]([O:30][C:31]([C:33]1[O:34][C:35]2[CH:41]=[CH:40][C:39](O)=[CH:38][C:36]=2[CH:37]=1)=[O:32])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH2:28]([O:30][C:31]([C:33]1[O:34][C:35]2[CH:41]=[CH:40][C:39]([O:27][CH2:26][C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]5[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]6[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=6)[CH2:14]5)[C:6]=4[C:2]=3[CH3:1])=[CH:38][C:36]=2[CH:37]=1)=[O:32])[CH3:29]
Reactant: Cc1c(CO)oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c12
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OCc3oc4cccc(OCC5CCCN(Cc6cccnc6)C5)c4c3C)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
[3-Methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-yl]-methanol (107 mg), 5-hydroxybenzofuran-2-carboxylic acid ethyl ester (60 mg), triphenylphosphine (100 mg) and azodicarboxylic acid diethyl ester (70 μl) were dissolved in THF (7 ml). The solution was stirred overnight at room temperature. A white precipitate separated out. The precipitate was filtered out and the filtrate was evaporated to dryness. The residue was separated by silica gel column chromatography developed by dichloromethane-methanol to give 5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-carboxylic acid ethyl ester (48 mg) as a colorless oil. FAB-MS: m/z 555 (MH+); 1H-NMR (CDCl3): δ 1.25-2.23 (7H, m), 1.43 (3H, t, J=7 Hz), 2.24 (3H, s), 2.78 (1H, m), 2.95 (1H, m), 3.47 (1H, d, J=13 Hz), 3.57 (1H, d, J=13 Hz), 3.89 (2H, m), 4.44 (2H, q, J=7 Hz), 5.10 (2H, s), 6.55 (1H, d, J=8 Hz), 7.04 (1H, d, J=8 Hz), 7.14 (1H, dd, J1=9 Hz, J2=2 Hz), 7.23 (3H, m), 7.47 (1H, m), 7.48 (1H, s), 7.66 (1H, br d, J=7 Hz), 8.48 (1H, br d, J=5 Hz), 8.53 (1H, br s).
Reaction SMILES: CCCCC(N([C@H](C(O)=O)C(C)C)CC1C=CC(C2C=CC=CC=2C2NN=NN=2)=CC=1)=O.Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[N:51]([C:52]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:50]=[N:49][N:48]=2)=[CH:37][CH:36]=1.[CH2:71]([O:78][C:79](=[O:85])[C@H:80]([CH:82]([CH3:84])[CH3:83])[NH2:81])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[CH2:71]([O:78][C:79](=[O:85])[C@H:80]([CH:82]([CH3:83])[CH3:84])[NH:81][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[N:51]([C:52]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:50]=[N:49][N:48]=2)=[CH:37][CH:36]=1)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Product: CC(C)[C@H](NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)OCc1ccccc1

Procedure:
According to U.S. Pat. No. 5,399,578, Valsartan can also be prepared by reaction of 4-bromomethyl-2′-(1-triphenylmethyltetrazol-5-yl)biphenyl (VI) with L-valine benzyl ester to produce N-[[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]-methyl]-L-valine benzyl ester (VII), followed by treatment with valeryl chloride to produce N-(1-oxopentyl)-N-[[2′-(1-triphenylmethyltetrazol-5-yl)[1,1′-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (VIII). Compound (VIII) is deprotected under acidic conditions to produce N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (IX), which is then hydrogenated in presence of Pd/C catalyst to give finally Valsartan. The process is shown in scheme II, below:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=3)[S:10][C:3]=12.[OH-].[Na+].Cl>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=3)[S:10][C:3]=12
Reactant: COC(=O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of methyl 2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylate (0.200 g, 0.62 mmole), prepared by the method described in PC10795A, section A, example 26, in EtOAc (5 ml) was added 1N aqueous NaOH solution (1.85 ml, 1.85 mmole). The reaction mixture was stirred at 50° C. for 1 h, cooled to room temperature, diluted with H2O (10 ml) and acidified with 1N HCl to pH˜2. The resulting solution was extracted with 10% MeOH in CH2Cl2 (5×10 ml), dried over MgSO4 and concentrated and dried under vacuum to give yellow solid (0.181 g, 98%). 1H NMR (300 MHz, DMSO-d6) □7.67 (1H, d, J=5.09 Hz) 8.41 (1H, s) 8.65 (1H, s) 8.71 (1H, bs); ESIMS (MH+): 309.95.
Reaction SMILES: S(N)(N)(=O)=O.[C:6]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22]O)[CH2:11]1)(=[O:8])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][C:48]([NH:50][S:51]([NH2:54])(=[O:53])=[O:52])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[C:6]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@@H:12]([CH2:22][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[S:51](=[O:52])(=[O:53])[NH2:54])[CH2:11]1)(=[O:8])[CH3:7]
Reactant: CC(=O)S[C@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)NS(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NS(N)(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)S[C@H]1C[C@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)N(C(=O)OC(C)(C)C)C1

Procedure:
Preparation of a sulfamide compound To a solution of (2R,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) in tetrahydrofuran (THF), triphenylphosphine (PPh3), N-t-butoxycarbonylsulfamide (BSMD), and azodicarboxylic acid diethyl ester (DEAD) are successively added under ice cooling. The conditions for this reaction are shown in Table 2, Step A-6. The reaction mixture is diluted with toluene, concentrated, diluted with toluene, and the formed crystals are filtered off. The filtrate is concentrated. The residue is purified by silica gel column chromatography to give (2R,4S)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino)methylpyrrolidine. NMR δ(CDCl3) ppm: 1.41(s, 9H), 1.55(s, 9H), 1.19 to 2.0(m, 2H), 2.35(s, 3H), 3.32(dd, J=11.4 Hz, J=8.2 Hz, 1H), 3.6 to 3.9(m, 3H), 3.9 to 4.1(m, 1H), 4.5(m, 1H), 6.15(s, 2H). IR ν (KBr) cm-1 : 3420, 3320, 1706, 1686, 1666.
Reaction SMILES: C(N)(=O)C1C=CC=CC=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@@:17]([NH:36][C:37](=[O:48])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)([C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([F:35])[CH:26]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][C:12]=1[OH:49].Br[C:51]([CH3:57])([CH3:56])[C:52]([O:54][CH3:55])=[O:53].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@:17]([C:25]2[CH:30]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:28]=[C:27]([F:35])[CH:26]=2)([NH:36][C:37](=[O:48])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=2)[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][C:12]=1[O:49][C:51]([CH3:57])([CH3:56])[C:52]([O:54][CH3:55])=[O:53]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(O)c1)c1cccc(C(F)(F)F)c1
Agent: NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)c2cccc(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 180 °C
Yield: 29 %

Procedure:
A solution of (R)—N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide benzamide, prepared as described in Example 264, (226 mg, 0.4 mmol), methyl 2-bromo-2-methylpropanoate (0.10 mL) and K2CO3 (326 mg, 2.36 mmol) in DMF (1 mL) was heated at 180° C. under microwave condition for 1200 seconds. The reaction mixture was allowed to cool, diluted with EtOAc and the organic layer was washed with H2O (2×), saturated NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO flash chromatography (silica gel, hexanes/EtOAc) to give (R)-methyl 2-(2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)benzamido)ethyl)phenoxy)-2-methylpropanoate (Example 273, 76 mg, yield: 29%). LCMS: RT=2.26 min [M+H] 666.4 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[C:7]=1[CH3:8]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cc1c(Cl)ncnc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)ncnc1Nc1ccc(OC(F)(F)F)cc1
Yield: 84 %

Procedure:
4,6-Dichloro-5-methylpyrimidine (534.6 mg, 3.3 mmol) and 4-trifluoromethoxy aniline (661 mg, 3.6 mmol) were dissolved in EtOH and DIEA (625 uL, 3.6 mmol) was added and the mixture was refluxed for 4 h. It was then cooled, concentrated and work-up with ethyl acetate. The organic layer was separated and dried (Na2SO4). Concentrated and purified by silica-gel column chromatography (Ethyl acetate/hexane). 800 mg (84% Yield), MS m/z 304.14 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15](=O)[NH2:16])[CH:14]=1)(=[O:8])[CH3:7]>CN(C)C=O>[C:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1cncc(C(N)=O)c1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1cncc(C#N)c1
Yield: 48.5 %

Procedure:
Phosphorus oxychloride (2.75 g) was added to a solution of 3-acetyl-5-carbamoylpyridine (2.8 g) in N,N-dimethylformamide (30 ml) with cooling on an ice-water bath. The mixture was stirred with cooling for 1.5 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (150 ml) and the mixture was extracted with ethyl acetate (100 ml). The extract was dried with magnesium sulfate and then evaporated. The residue was chromatographed on a silica gel column eluting with chloroform to afford 3-acetyl-5-cyanopyridine (1.21 g).
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:20])[CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([NH:1][CH:2]([CH:10]([OH:20])[CH:11]([NH:19][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NS(C)(=O)=O
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A solution of the resultant compound of Example 12 (0.049 mmol) and 0.032 ml (0.29 mmol) of 4-methylmorpholine in 1 ml of dichloromethane was cooled to 0° C. and treated with 0.008 ml (0.10 mmol) of methanesulfonyl chloride. After 0.5 h, the solution was washed with 10% aqueous citric acid, dried over Na2SO4, and concentrated. Flash chromatography using 5% methanol in chloroform gave 2.6 mg (13%) of the desired compound. 1H NMR (CDCl3) δ 2.16 (s, 3H), 2.34 (s, 3H), 2.93 (m, 4H), 3.41 (d, J=4 Hz, 1H), 3.7-3.8 (m, 2H), 3.92 (m, 1H), 5.06 (d, J=9 Hz, 1H), 5.42 (d, J=9 Hz, 1 H), 7 2-7.4 (m, 10H). Mass spectrum (M+NH4)+ =444.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=S.C([O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1)C.CS(Cl)(=O)=O>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]([OH:24])=[O:14])=[CH:17][C:18]=2[N:23]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 48 h

Procedure:
A mixture of 1,3-dichloro-2-isothiocyanato-benzene (4.50 g, 22.1 mmol) in 50 mL dichloromethane was added to a stirred solution of 3,4-diamino-benzoic acid ethyl ester (4.00 g, 22.2 mmol) in 100 mL dichloromethane. After stirring for 2 days the mixture was concentrated i.vac. The residue was taken up in 200 mL dichloromethane. TEA (7.0 mL, 49.9 mmol) and DMAP (100 mg, 0.8 mmol) were added. A mixture of methanesulfonyl chloride (1.70 mL, 22.0 mmol) in 50 mL dichloromethane was added to the solution and stirred overnight. The mixture was concentrated i.vac. The residue was taken up in methanol and 4 M NaOH (aq) was added. After stirring overnight at ambient temperature the mixture was heated to reflux for 2 h and concentrated i.vac. The residue was taken up in water and methanol and neutralized with HCl (aq). The mixture was filtered and washed with water.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1)(=[O:4])=[O:3].[F:14][C:15]([F:36])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:36][C:15]([F:14])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](/[CH:25]=[C:12]2/[C:8]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:9][C:10](=[O:13])[S:11]/2)[CH2:21][CH2:20]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CS(=O)(=O)CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CS(=O)(=O)CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of 4-{[2-(methylsulfonyl)ethyl]amino}-1,3-thiazol-2(5H)-one (1.39 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.77 g) in 2-propanol (20 mL) was added piperidinium acetate (757 mg). The reaction mixture was stirred at 80° C. for 3 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (1.6 g).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].C(N(CC)CC)C>ClCCl>[O:30]([C:28]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[C:13]3[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=3[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=2[CH:16]=1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)Oc3ccccc3)cc1[C@@H](NC(C)=O)CC2
Yield: 79 %

Procedure:
A solution of N-acetyl colchicinol (0.35 g; 0.98 mmol), phenyl chloroformate (145 μl; 1.08 mmol) and triethylamine (150 μl; 1.08 mmol) in dichloromethane (20 ml) was stirred at ambient temperature for 1 hour. The mixture was washed with water and the organic phase evaporated. The residue was purified by flash chromatography, eluting with ethyl acetate/petroleum ether (80/20) to give N-[(5S)-3-phenoxycarbonyloxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide as a foam.