Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1[O:9][C:8](=[O:10])[C@@:7]([C@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)(C)(C)C.[BH4-].[Na+]>CO.C(OCC)C>[OH:22][CH:19]1[CH2:20][CH2:21][C@H:17]([C@@:7]([OH:6])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=[O:9])[CH2:18]1
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@H]2CCC(=O)C2)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C(O)[C@](O)(c1ccccc1)[C@H]1CCC(O)C1
Reaction time: 0.5 h
Yield: 118.9 %

Procedure:
To a solution of 169 mg of (2R,5R)-2-(t-butyl)-5-[(1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one in 2 ml of methanol, 71 mg of sodium borohydride was added under cooling with ice, followed by stirring for 30 minutes at the same temperature. The reaction mixture was diluted with diethyl ether, washed with water and then brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 157 mg of the title compound was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]#[N:31])[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22].[NH2:32][OH:33]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:25][CH2:26][CH:27]([C:30]([NH2:31])=[N:32][OH:33])[CH2:28][CH2:29]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][C@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22]
Reactant: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(C#N)CC2)cc1F
Reactant: NO
Solvent: CCO
Product: C[C@H]1CC[C@H](c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(C(N)=NO)CC2)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To s solution of 1-[3-fluoro-4-[[(3S)-3-methyl-1,1-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-piperidine-4-carbonitrile Stereoisomer A (1.37 g, 3.12 mmol, prepared as described in Example 5) in ethanol (15 mL) was added hydroxylamine (50 mass % in water, 0.29 mL, 9.4 mmol) and the reaction was stirred at 60° C. for 2 hours. The solution was concentrated and purified by preparative HPLC to give 1-[3-fluoro-4-[[(3S,6R)-3-methyl-1,1-dioxo-6-phenyl-thiazinan-2-yl]methyl]phenyl]-N′-hydroxy-piperidine-4-carboxamidine Stereoisomer A (1.1 g, 75% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.82-8.76 (s, 1H), 7.48-7.43 (m, 2H), 7.42-7.33 (m, 3H), 7.32-7.26 (m, 1H), 6.82-6.76 (m, 1H), 6.72-6.65 (m, 1H), 5.36-5.26 (s, 2H), 4.49-4.42 (m, 1H), 4.42-4.36 (m, 1H), 4.31-4.23 (m, 1H), 4.15-4.01 (m, 1H), 3.80-3.67 (m, 2H), 2.72-2.59 (m, 2H), 2.46-2.36 (m, 1H), 2.21-2.04 (m, 2H), 1.84-1.74 (m, 3H), 1.73-1.57 (m, 3H), 1.12-1.04 (d, J=6.8 Hz, 3H); LCMS [M+1]+=475.2.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[OH-].[Na+].Cl>O.C(O)C.ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:25][CH:24]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 152.5 °C

Procedure:
A mixture of (±)-cis-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4-(trifluoromethyl)-phenyl)chromane (0.30 g, 0.60 mmol) and anhydrous pyridine hydrochloride (3.50 g, 30.3 mmol) was heated to 150-155° C. as a melt for 18 hours. The mixture was cooled to room temperature, and the resulting orange coloured wax dissolved in a mixture of water (50 ml), hot ethanol (20 ml) and dichloromethane (100 ml). The aqueous layer was basified to pH 14 by adding 10M sodium hydroxide, then 1M hydrochloric acid was added until pH 8-9. The organic layer was collected and the aqueous layer further extracted with dichloromethane (2×75 ml). The combined organics were washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to a dark coloured gum, which was purified by column chromatography on silica gel, with 6% methanol in dichloromethane as eluent, giving the product as a colourless solid.
Reaction SMILES: [C:1]([O:15]CCO)(=[O:14])[C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8]CCO)=[O:7])=[CH:4][CH:3]=1.CC(C1OCC2(COC(C(C)(C)CO)OC2)CO1)(C)CO.C(C1(CC)COC(C(C)(C)CO)OC1)O>C(O)CO>[C:1]([OH:15])(=[O:14])[C:2]1[CH:13]=[CH:12][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(OCCO)c1ccc(C(=O)OCCO)cc1
Agent: *CC*
Agent: CC(C)(CO)C1OCC2(CO1)COC(C(C)(C)CO)OC2
Agent: CCC1(CO)COC(C(C)(C)CO)OC1
Solvent: OCCO
Product: O=C(O)c1ccc(C(=O)O)cc1

Procedure:
PTA; polyethylene terephthalate: PET; bis(β-hydroxyethyl) terephthalate: BHET; ethylene glycol: EG; 3,9-bis(1,1-dimethyl-2-hydroxyethyl)-2,4,8,10-tetraoxaspiro[5.5]undecane: SPG; 5-methylol-5-ethyl-2-(1,1-dimethyl-2-hydroxyethyl)-1,3-dioxane: DOG
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[S:5][C:6]=1[CH:7]=[O:8].[OH:15]OS([O-])=O.[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:9])[S:5][C:6]=1[C:7]([OH:15])=[O:8]
Reactant: CCOC(=O)c1c(C)sc(C=O)c1Cl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)sc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 4-chloro-5-formyl-2-methylthiophene-3-carboxylate (F-4) (9.72 g, 41.77 mmol, 1.0 eq) in DMF (150 mL), oxone (77.1 g, 125.3 mmol, 3.0 eq) is added in portions and the resulting mixture is stirred at RT overnight. The mixture is poured into H2O (800 mL) and stirred for 30 min. The precipitate is collected by filtration, rinsed with H2O (100 mL) and then slurried in H7O (80 mL) for 30 min. The solid is collected by filtration, rinsed with H2O (3×60 mL) and petroether (3×60 mL), and dried in vacuo to afford the product, 3-chloro-4-(ethoxycarbonyl)-5-methylthiophene-2-carboxylic acid (F-5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(Cl)cc1Nc1cccnc1

Procedure:
Method B was applied to a mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (105 mg, 0.34 mmol), 3-aminopyridine (34 mg, 0.36 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), xantphos (20 mg, 0.035 mmol) and cesium carbonate (225 mg, 0.69 mmol) in dioxane (4.5 ml).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:50]([O:57][C:58]([NH:60][C@H:61]([C:73](=[O:79])[NH:74][CH2:75][CH2:76][CH:77]=O)[CH2:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[CH2:66]([O:65][C:63](=[O:64])[CH2:62][C@@H:61]([C:73](=[O:79])[NH:74][CH2:75][CH2:76][CH2:77][NH:1][C@@H:2]([C@H:10]([CH:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:60][C:58](=[O:59])[O:57][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: O=CCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 70.1 %

Procedure:
By using an analogous procedure to that described in Example 1, a solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (100 mg, 0.139 mmol, obtained from Reference Example 6), benzyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-oxo-4-[(3-oxopropyl)amino]butanoate (71 mg, 0.173 mmol, obtained from Reference example 24), acetic acid (1 drop), and sodium triacetoxyborohydride (59 mg, 0.277 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred under nitrogen at room temperature for 5 hours. The product was purified by chromatography (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-5-[2-(benzyloxy)-2-oxoethyl]-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (109 mg, 70%) as a white amorphous solid.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([S:77]([CH3:80])(=[O:79])=[O:78])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:72][CH2:73][N:74]([S:77]([CH3:80])(=[O:79])=[O:78])[CH2:75][CH2:76]5)=[CH:67][CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(S(C)(=O)=O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 86.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.087 mmol) was hydrolyzed with lithium hydroxide (19 mg, 0.438 mmol) in THF/methanol/water (5/1/1 mL) to yield 40 mg (70.17% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.63-8.62 (d, 1H), 8.54 (s, 1H), 8.29 (s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.69-7.67 (d, 2H), 7.40-7.38 (q, 1H), 7.18-7.02 (m, 5H), 5.46 (s, 2H), 3.40-3.37 (m, 8H), 2.91 (s, 3H). MS: m/z=531.0 (M+1), HPLC: 99.35% in method B.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1/[CH:14]=[C:15](\[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)/[C:16]([OH:18])=[O:17].[OH-].[Na+].N([O-])=O.[Na+].S(=O)(=O)(O)N>O.CC(C)=O.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[Br:25][C:22]1[CH:21]=[C:20]2[C:19](=[CH:24][CH:23]=1)[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]2=1
Reactant: Nc1cc(Cl)ccc1/C=C(/C(=O)O)c1ccc(Br)cc1
Agent: [Fe+2]
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc2ccc(Cl)cc2c2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
This quinone can be obtained by following the procedure describe in Example 36, Step 1 to 3, or by the using the following procedure: to a 0° C. solution of 118 mL of concentrated sulphuric acid in 1.0 L of water was added drop wise a solution prepared as follows: 65 g of (2E)-3-(2-amino-4-chlorophenyl)-2-(4-bromophenyl)acrylic acid from Step 2 in 1 L of water followed by the addition of 11 g of NaOH, stirring for 10 minutes at 0° C., addition of NaNO2 (15 g) and stirring of the resulting solution at 0° C. for 20 minutes. After 30 minutes, sulfamic acid (12.5 g) was added to this mixture and after the gaz evolution seized, 1.3 L of acetone was added and the solution was stirred at 0° C. for 10 minutes. This mixture was then added to a solution of ferrocene (6.9 g) in 480 mL of acetone resulting in the formation of a green precipitate. After stirring for 20 minutes, water (2.0 L) was added, the solid was filtered and the 6-bromo-3-chlorophenanthrene-9-carboxylic acid was obtained and allowed to air dry. This crude phenanthrene was placed in 2.0 L of acetic acid followed by the addition of 54 g of CrO3. The reaction was placed at 110° C. and after stirring for 1 hr, 18 g of CrO3 were added. The reaction was monitored by TLC and 18 g of CrO3 were added every hour for 3 hours where 100% conversion was observed by 1H NMR. The mixture was cooled to room temperature, diluted in water (2.0 L), filtered and washed with water (1.0 L) to afford, after drying, 37 g of 3-Bromo-6-chlorophenanthrene-9,10-dione as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O>[O:22]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCCCc2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCCc2ccncc2)cc1
Yield: 99.3 %

Procedure:
A mixture of alpha-oxo-4-[4-(4-pyridinyl)butoxy]benzeneacetic acid methyl ester (0.58 g) in hot methanol (10 mL) was treated with 1N sodium hydroxide (3.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue in water was washed with diethyl ether. The aqueous layer was concentrated to about 25 mL and chilled in ice. Cold 2N hydrochloric acid (1.5 mL) was added dropwise and the product was allowed to crystallize and was filtered and air dried. Recrystallization from water provided 0.55 g of alpha-oxo-4-[4-(4-pyridinyl)butoxy]benzeneacetic acid as a colorless solid, mp 198°-199° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C)C=O>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:15]1[CH2:16][CH2:17][N:13]([S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH2:14]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Yield: 100.1 %

Procedure:
1-(2-Nitro-benzenesulfonyl)-pyrrolidin-3-ol (12.25 g, 0.04499 mol) in N,N-dimethylformamide (40 mL) was treated with tert-butyldimethylsilyl chloride (8.137 g, 0.05399 mol) and 1H-imidazole (4.594 g, 0.06748 mol) at room temperature for 3 h. The reaction mixture was partitioned between water and ethyl ether, and the layers were separated. The aqueous layer was extracted twice with ethyl ether, and then the organic extracts were washed extensively with water, then once with brine, dried (MgSO4), filtered and concentrated to give 3-(tert-butyl-dimethyl-silanyloxy)-1-(2-nitro-benzenesulfonyl)-pyrrolidine as an off-white solid (17.4 g, 92%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>C(#N)C>[Cl:42][CH2:41][CH2:40][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:32])[CH:14]=3)[C:19]2=[O:23])=[CH:30][CH:29]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(O)cc3)ccc2c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1

Procedure:
A mixture of the product of step i) (0.33 g), potassium carbonate (1.07 g) and 1-bromo-2-chloroethane (1.12 g) in acetonitrile (10 mL) was heated at reflux for 38 hours. The reaction mixture was concentrated to dryness and the residue partitioned between dichloromethane and water. The organics were collected and purified (SiO2, 9:1 dichloromethane:methanol) to give the sub-title compound (0.31 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]2[O:15][C@@H:11]([CH2:12][CH2:13]2)[C@@H:10]1[C:16]([O:18]C)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]2[O:15][CH:11]([CH2:12][CH2:13]2)[CH:10]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@H]2CC[C@@H]1O2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1C2CCC(O2)C1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
(1S,2R,3S,4R)-methyl 3-(tert-butoxycarbonylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxylate (12) (600 mg, 2.2 mmol) was taken in MeOH/H2O (3:1) and LiOH (265 mg, 11 mmol) was added at 0° C. The reaction mixture was allowed to come to rt and then stirred at rt for 16 h. MeOH was removed and saturated ammonium chloride solution was added. This was followed by extraction with DCM. The aqueous extract was acidified to pH 3 using 1N HCl and extracted with DCM again. The combined organic extracts was dried and concentrated to afford the desired product (450 mg, 87%) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][N:11](C(OCC)=O)[CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>C(O)CCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][NH:11][CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CCC=C(c2cccc(OC)c2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: COc1cccc(C2=CCCNC2)c1
Yield: 100.4 %

Procedure:
A solution of 11 g of the product of Step C in 110 ml of n-butanol and 11 g of potassium hydroxide was heated for 6 hours at 120° C. and the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 6-3-1 chloroform-acetone-triethylamine mixture. The distilled fraction residue was taken up in methylene chloride and the solution was filtered and evaporated to dryness under reduced pressure to obtain 8 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:20](=[O:21])[C@H:19]([CH2:22][C:23](OC)=[O:24])[CH2:18][C:17]2[CH:16]=[C:15]([Cl:27])[C:14]3[NH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH2:8]1.O.[OH-].[Li+].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.Cl.[O:54]=[C:55]1[N:64]([CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH2:63][C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[NH:56]1>O.O1CCCC1.CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:20](=[O:21])[C@H:19]([CH2:22][C:23](=[O:24])[N:68]2[CH2:67][CH2:66][CH:65]([N:64]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]3=[O:54])[CH2:70][CH2:69]2)[CH2:18][C:17]2[CH:16]=[C:15]([Cl:27])[C:14]3[NH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH2:8]1
Reactant: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ncc[nH]2)C1=O
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ncc[nH]2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
(S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (58 mg, 0.15 mmol) was dissolved in a mixture containing methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added to the mixture. Reaction stirred at room temperature for 15 hours. Reaction was quenched with 1N hydrochloric acid (0.5 mL). Mixture was concentrated in vacuo. Residue was dissolved in DMF (2 mL). N,N-Diisopropylethylamine was added to the mixture followed by o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium Tetrafluoroborate (60 mg, 0.19 mmol). Mixture stirred at room temperature for 30 minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine hydrochloride (50 mg, 0.19 mmol) was added to the mixture. Reaction stirred at room temperature for 3 hours. Reaction mixture was purified by preparatory HPLC. Desired fractions were identified. Acetonitrile was removed from the fractions in vacuo. Remaining aqueous was made basic with sodium bicarbonate. Mixture was extracted twice with ethyl acetate. Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 28% yield. MS m/e (M+H)+=587.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 11.75 (s, 1H), 9.20 (s, 1H), 8.14 (s, 1H), 7.19 (s, 1H), 7.12 (m, 2H), 6.84 (m, 2H), 6.77 (d, J=7.93, 1H), 5.23 (d, J=15.16, 1H), 4.76 (m, 1H), 4.69 (dd, J1=15.26, J2=5.19, 1H), 4.53 (d, J=13.43, 1H), 4.47 (d, J=15.26, 1H), 4.40 (m, 1H), 4.29 (d, J=3.97, 2H), 4.08 (m, 1H), 3.89 (d, J=9.77, 1H), 3.15 (m, 2H), 3.00 (m, 1H), 2.91 (m, 3H), 2.60 (m, 1H) 2.44 (m, 2H), 1.80 (m, 1H), 1.60 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])[C:4](=O)[CH2:5][CH2:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].O>C1COCC1>[CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])[CH2:4][CH2:5][CH2:6][CH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][CH:9]=1)[OH:19])[CH3:2]
Reactant: CCN(CCCCCC(C)O)C(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CCCCCC(C)O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 54.8 %

Procedure:
A solution of the product from Step IV (1.34 g, 3.28 mmol) in THF (25 ml) was added during 45 minutes under nitrogen, to an ice cold, stirred suspension of LiAlH4 (0.31 g, 8.2 mmol) in THF (10 ml). The mixture was kept in the ice bath for 90 minutes and then treated cautiously with a solution of saturated aqueous sodium potassium tartrate (6.5 ml) and water (6.5 ml). The mixture was stirred for 90 minutes in the ice bath and then extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and concentrated; the residue was chromatographed over silica gel with 1% NH4OH-10% MeOH--CHCl3 to give 0.72 g of the titled product which is a compound of Formula I'. The high resolution FAB mass spectrum had (M+H)+ at m/z 401. Theory for C20H37N2O4S: 401.24; measured: 401.2480.