Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:22])([O:18][CH:19](Cl)[CH3:20])[O:2][CH2:3][CH2:4][CH:5]([CH3:17])[CH:6]([O:13][N+:14]([O-:16])=[O:15])[CH:7]([O:9][N+:10]([O-:12])=[O:11])[CH3:8].[CH2:23]([C:27]1[N:28]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]3[N:53]([C:54]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[N:52]=[N:51][N:50]=3)=[CH:39][CH:38]=2)[C:29]([C:33]([OH:35])=[O:34])=[C:30]([Cl:32])[N:31]=1)[CH2:24][CH2:25][CH3:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([C:27]1[N:28]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]3[N:53]([C:54]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[N:52]=[N:51][N:50]=3)=[CH:41][CH:42]=2)[C:29]([C:33]([O:35][CH:19]([O:18][C:1]([O:2][CH2:3][CH2:4][CH:5]([CH3:17])[C@@H:6]([O:13][N+:14]([O-:16])=[O:15])[C@H:7]([O:9][N+:10]([O-:12])=[O:11])[CH3:8])=[O:22])[CH3:20])=[O:34])=[C:30]([Cl:32])[N:31]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Cl)OC(=O)OCCC(C)C(O[N+](=O)[O-])C(C)O[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4R,5R))-3-methyl-4,5-bis(nitrooxy)hexyl 1-chloroethyl carbonate (1.01 g, 3.26 mmol) was added to a stirred solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 3, 3.32 g, 4.88 mmol) and Cs2CO3 (2.40 g, 7.33 mmol) in DMF (18 mL). The solution was stirred at room temperature overnight. The mixture was diluted with a solution of NaH2PO4 5% (40 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (4×20 mL) and brine. The residue was purified by flash chromatography (Biotage SP1, SNAP 100 g column, TLC method: n-Hexane/EtOAc 7:3, RE 0.45) affording the title compound that was used in the next step without any further characterization.
Reaction SMILES: FC1C=CC(COC2C=CC(CO)=CC=2)=CC=1.C[O:19][C:20](=[O:47])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:33][CH:32]=2)=[CH:25][C:24]=1[CH3:46]>>[F:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][O:37][C:34]2[CH:33]=[CH:32][C:31]([CH2:30][S:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:20]([OH:47])=[O:19])=[C:24]([CH3:46])[CH:25]=3)=[CH:36][CH:35]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(F)cc3)cc2)cc1C
Agent: OCc1ccc(OCc2ccc(F)cc2)cc1
Product: Cc1cc(SCc2ccc(OCc3ccc(F)cc3)cc2)ccc1OCC(=O)O

Procedure:
Preparation of [4-(4-Fluoro-benzyloxy)-phenyl]-methanol (compound 57A) The title compound was prepared in the manner analogous to Example 14A using 1-bromomethyl-4-fluoro-benzene and 4-hydroxymethyl-phenol. MS m/z 215 (M-OH). Step 2. Preparation of 1-(4-Chloromethyl-phenoxymethyl)-4difluoro-benzene (compound 57B) The title compound was prepared in the manner analogous to Example 3B using 57A. MS m/z 215 (M-Cl). Step 3. Preparation of {4-[4-(4-Fluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (compound 57C) The title compound was prepared in the manner analogous to Example 1F using 57B and 2C. MS m/z 427 (M+1). Step 4. Preparation of {4-[4-(4-Fluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid (compound 57) The title compound was prepared in the manner analogous to Example 1 using the product from Example 57C. mp 154-155° C.; IR (KBr) cm−1: 3060, 2925, 1727, 1495, 1228, 1156; 400 MHz 1H NMR (DMSO-d6): δ 13.00 (br(s), 1H), 7.37-7.48 (m, 2H), 6.99-7.22 (m, 6H), 6.80-6.90 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 4.98 (s, 2H), 4.61 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 411 (M−1). Anal. Calc'd for C23H21FO4S: C, 66.97; H, 5.13; found: C, 66.64; H, 4.88.
Reaction SMILES: Br[C:2]1[C:3](=[O:31])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:58][C:59]1[CH:60]=[C:61](B(O)O)[CH:62]=[CH:63][C:64]=1[F:65]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:25][CH2:26]4)=[CH:7][CH:8]=3)[C:3](=[O:31])[C:2]=2[C:62]2[CH:61]=[CH:60][C:59]([F:58])=[C:64]([F:65])[CH:63]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(Cl)cc2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2ccc(F)c(F)c2)=C3c2ccc(Cl)cc2)CC1
Yield: 50 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(4-chlorophenyl)-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (50%).
Reaction SMILES: CN1C=CN=C1.[Cl:7][C:8]1[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1.CS(Cl)(=O)=O.[NH2:21][CH2:22][CH:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C:36]3=[O:41])=[CH:31][CH:30]=2)[CH2:24]1>ClCCl.O>[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:21][CH2:22][CH:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C:36]4=[O:41])=[CH:31][CH:30]=3)[CH2:24]2)=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NCC1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(NCC1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
1-Methylimidazole (24.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5° C. and the resulting solution was stirred for 10 minutes. A solution of methanesulfonyl chloride (12 g, 0.105 mol) in dichloromethane (40 ml) was added to the above solution at −5° C. The resulting solution was stirred for 1 hour at −5° C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of racemic 4-[4-[5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (29.1 g, 0.1 mol). The reaction mixture was stirred for 2 hours at 25-30° C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85° C. for 3 to 4 hours to produce 39.1 g of pure racemic 5-chloro-N-[[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl]thiophene-2-carboxamide as a white crystalline solid (Theoretical Yield: 90%; Purity by HPLC: 99.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[O:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[O:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[OH:9])=[CH:11]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2ccoc2)c1O
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
2-Bromo-6-methylphenol (800 mg, 4.28 mmol), 3-furan boronic acid (574 mg, 5.13 mmol), sodium carbonate (1400 mg, 12.8 mmol) and Pd2(dppf)2Cl2 (699 mg, 0.82 mmol) were dissolved in dimethoxyethane/water 10 mL/10 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(furan-3-yl)-6-methylphenol (273 mg, 26%).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].[F-].[K+].[Br:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>CS(C)=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2Br)c1
Temperature: 110 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
To a solution of 4-(difluoromethoxy)-3-hydroxy benzaldehyde (8.6 g, 0.046 mol) in dimethylsulphoxide (15 mL) was added potassium fluoride (5.36 g, 0.092 mol) at room temperature. Then it was refluxed to 100-120° C. To this 2-bromo-1-fluoro-4-nitrobenzene (20.3 g, 0.093 mol) in dimethylsulphoxide (10 mL) was added dropwise at 100-120° C. The heating was continued for 5 hours. The reaction mixture was poured into the crushed ice and stirred for 1 hour. Then the aqueous layer was decanted. The solid obtained was dissolved in ethyl acetate (500 mL). The organic layer was washed with water (3×200 mL). The organics were dried over sodium sulphate and filtered. The solvents were removed in vacuum to give the crude product. The product was purified by column chromatography by using gradient (0-2) % of ethyl acetate in hexane. The solid obtained was washed with hexane and dried. Yield—66%. 1H-NMR (DMSO-d6) δ: 7.06 (d, 1H), 7.23-7.41-7.59 (t, 1H), 7.67 (d, 1H), 7.82 (d, 1H), 7.96-7.98 (m, 1H), 8.20-8.23 (m, 1H), 8.61 (d, 1H), 9.97 (s, 1H); HPLC (purity): 99.5%; Mass calculated for C14H8BrF2NO5-388.1, observed—388.1; Rf—0.47 (Ethyl acetate:Hexane (3:7).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:44][CH2:45][C:46]([NH:48][CH:49]1[CH2:52][N:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:50]1)=[O:47]>O1CCOCC1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11]([NH:44][CH2:45][C:46]([NH:48][CH:49]2[CH2:52][N:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:50]2)=[O:47])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Reactant: Oc1cc(C(F)(F)F)nc2ccc(C(F)(F)F)cc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2cc(C(F)(F)F)nc3ccc(C(F)(F)F)cc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of commercially available 2,6-bis(trifluoromethyl)quinolin-4-ol (291 mg, 1.04 mmol) in dry dioxane (5 mL) was treated sequentially with TEA (0.36 mL, 2.58 mmol) and PyBrOP (586 mg, 1.26 mmol). After stirring 1 hour at room temperature under argon, a solution of tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (352, 1.54 mmol), prepared as described in Example 1, Step E in dry dioxane (5 mL) was introduced and the reaction mixture was stirred overnight at room temperature. After concentration in vacuo, the residue was purified by flash chromatography (silica gel, 0-5% MeOH/ethyl acetate) to afford the product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70](NCC4C=CC=CN=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[NH2:100][CH2:101][C:102]1[CH:107]=[CH:106][N:105]=[CH:104][CH:103]=1>>[ClH:45].[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:100][CH2:101][C:102]4[CH:107]=[CH:106][N:105]=[CH:104][CH:103]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCc1ccncc1
Agent: Cl
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccncc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol. (Intermediate FC) using a procedure analogous to 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[((1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113), by replacing 2-aminomethyl pyridine with 4-aminomethylpyridine. MS (ES+) m/e 729.55 (MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([F:44])([F:43])[C:21]1[CH:22]=[C:23]([C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[C:34]([CH3:41])[CH:33]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.[F:45][C:46]([Si](C)(C)C)([F:48])[F:47]>O1CCCC1.C(OCC)(=O)C>[F:19][C:20]([F:43])([F:44])[C:21]1[CH:22]=[C:23]([C:31]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[C:34]([CH3:41])[CH:33]=2)([OH:42])[C:46]([F:48])([F:47])[F:45])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (0.2 ml) was added to a solution of 3′,5′-bis-trifluoromethyl-3-methyl-4-nitrobenzophenone (1.4 g) and trifluoromethyltrimethyl-silane (1.0 g) in tetrahydrofuran (20 ml) in an ice bath and stirred at room temperature for 8 hours. The reaction solution was diluted with ethyl acetate and washed with water and a saturated salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was dissolved in tetrahydrofuran (20 ml) and, by adding 2N hydrochloric acid (2 ml), stirred at room temperature for 30 minutes. After diluting with ethyl acetate and washing with water and a saturated salt solution and after drying over anhydrous magnesium sulfate, the solvent was distilled off. Then the residue was purified by silica gel column chromatography to obtain 1-(3,5-bis-trifluoromethylphenyl)-2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethanol (0.8 g).
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH3:39][O:40][C:41]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:42]=1[CH:43]=[CH:44]C(O)=O>>[CH3:39][O:40][C:41]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:42]=1[CH:43]=[CH:44][C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:27])[CH2:20][O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:17]
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1
Product: COc1ccc(OC)c(C=CC(=O)N[C@@H](COC(C)(C)C)C(=O)NCCc2ccc(O)c(O)c2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-seryl]dopamine (572 mg, 1.1 mmol, example 42, step A) as described for example 42 (step B) using 2,5-dimethoxycinnamic acid (345 mg, 1.7 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using 10% EtOAc/CH2Cl2/1% AcOH and 50% EtOAc/CH2Cl2 as the eluent. The title compound was obtained as a yellow powder (300 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[CH2:20]([Mg]Br)[CH3:21]>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)([OH:8])[CH2:20][CH3:21])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(CC)c2ncc(Br)s2)CC1
Reaction time: 1 h

Procedure:
A solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (500 mg, 1.444 mmol) in THF (6 mL) was cooled to −60° C. Ethylmagnesium bromide (3.0 M in THF, 481 μl, 1.444 mmol) was added dropwise and the resulting mixture was stirred for 1 hour. The mixture was diluted with water and EtOAc and the layers were separated. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (5-80% EtOAc/Hexanes) to afford racemic-trans-ethyl 4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylate as a yellow solid. The racemic mixture was purified by super critical fluid chromatography (Chiral Technology AD-H 2.1×25 cm, 5 uM, 30%/70% Methanol/CO2 with a 14 minute run time) to afford enantiomer 1 and enantiomer 2 as clear oils. Enantiomer 1 (retention time=7.24 min): MS ESI calc'd. for C12H22BrNO3S [M+H]+ 376, 378. found 376, 378. 1H NMR (500 MHz, DMSO-d6) δ 7.75 (s, 1H), 5.62 (s, 1H), 3.99 (q, J=7.0, 2H), 2.20-0.80 (m, 15H), 0.68 (t, J=6.9, 3H). Enantiomer 2 (retention time=10.18 min): MS ESI calcd for C17H26BrNO3S [M+H]+ 376, 378. found 376, 378. 1H NMR (500 MHz, DMSO-d6) δ 7.75 (s, 1H), 5.62 (s, 1H), 3.99 (q, J=7.0, 2H), 2.20-0.8 (m, 15H), 0.68 (t, J=6.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](Cl)=[N:15][N:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[N:15][N:14]=1
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1-c1nnc(Cl)c2ccccc12
Temperature: 65 °C
Yield: 87.6 %

Procedure:
5-Chloro-2-methylindole (0.74 g, 2.26 mmol) and 1,4-dichloro-phthalazine (0.45 g, 2.26 mmol) were treated with 30 mL of 1,2-dichloroethane and 3.2=mol of AlCl3 (427 mg). The resulting suspension was heated to 65° C. overnight. The reaction was cooled and quenched with 3 mL water. The resultant precipitate was filtered and dried under vacuum to give 0.65 g of the sub-title compound. MS: ESI (negative): 326, 328 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH3:45])([CH3:44])[C:35]([NH:37][S:38]([CH:41]2[CH2:43][CH2:42]2)(=[O:40])=[O:39])=[O:36])=[C:6]([CH:8]2[CH2:13][C:12](=O)[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:47]>C1COCC1.C1(C)C=CC=CC=1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:33][C:34]([CH3:45])([CH3:44])[C:35]([NH:37][S:38]([CH:41]4[CH2:42][CH2:43]4)(=[O:39])=[O:40])=[O:36])[CH2:13][C:12](=[S:47])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(=O)(=O)C2CC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=S)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(=O)(=O)C2CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 88.5 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-4′-[5-chloro-2-(2-cyclopropanesulfonylamino-1,1-dimethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (12 mg, 0.018 mmol) and P2S5 (12 mg, 0.054 mmol) in THF (1 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM layers were combined and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (11 mg).
Reaction SMILES: O[CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].S(=O)(=O)(O)O.[CH2:18]1[O:22][CH:21]([CH:23]([OH:26])[CH2:24]O)[C@@H:20]([OH:27])[CH:19]1[OH:28].C1O[C@@H]2[C@@H](O)CO[C@@H]2[C@@H]1O>>[CH2:11]1[O:12][C@@H:5]2[C@H:3]([OH:4])[CH2:2][O:8][C@@H:7]2[C@@H:9]1[OH:10].[CH2:24]1[O:27][C@@H:20]2[C@@H:19]([OH:28])[CH2:18][O:22][C@@H:21]2[C@H:23]1[OH:26]
Reactant: OCC(O)C1OCC(O)[C@@H]1O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Agent: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Product: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 125 °C
Reaction time: 2 h

Procedure:
A reaction was carried out wherein sorbitol and sulfuric acid (0.5% by weight of the starting sorbitol) were combined in a reaction vessel. The vessel was heated to 125° C. and run under a vacuum of about 10-20 millibar. Samples of the reaction mixture were taken at regular intervals and assayed for sorbitol, sorbitan, mannitan, and isosorbide. The results are shown in FIG. 1. The sorbitol concentration decreases smoothly as a function of time to approximately zero after about 120 minutes (the sorbitol line is believed to include also mannitol and iditol which, in turn, react to give isomannide or isoidide). The concentration of sorbitan increases and then decreases as it is first condensed from sorbitol and then converted to isosorbide. Isosorbide is formed at a reasonable rate only after significant amounts of sorbitan have been produced. As the sorbitan is consumed, isosorbide becomes the major compound in the reaction mixture. The reaction mixture also contains small amounts of mannitan and iditan.