Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:35][C:31]4[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=4)[C:28]([O:27][CH3:26])=[O:37])[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)c1cccc(CBr)c1
Product: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1cn(Cc2cccc(C(=O)OC)c2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of example 3 step (vii) (2. g) and 3-bromomethyl benzoic acid methyl ester (0.5 g) using the method of example 1 step (viii). Purification was by chromatography eluting with 60% ethyl acetate in toluene.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[O:14]=[C:12]1[C:11]2[C:10](=[CH:9][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)[C:17](=[O:19])[N:20]1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1ccc(Sc2ccccc2)cc1C(=O)O
Reactant: NCC(=O)O
Product: O=C(O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
5.62 g of 4-phenylsulfanyl-phthalic acid (20.5 mmol) and 1.55 g of glycine (20.5 mmol) were ground thoroughly together in a mortar. Then the mixture was heated to 210° C. to 220° C. in an oil bath. The molten mass was stirred with a spatula at this temperature for 15 min before it was allowed to cool to ambient temperature in vacuo. 6.30 g of the title compound were obtained; MS-(−)-ion: M−1=311.8.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@:22]([C@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH2:18]1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@@]2(C)COC(=O)N2)C3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@](C)(N)CO)C3)CC1

Procedure:
The mixture of (S)-4-((S)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (46.6 mg, 0.000121 mol) (isomer 2) and lithium hydroxide (31.8 mg, 0.00133 mol) in ethanol (0.77 mL, 0.013 mol) and water (0.26 mL, 0.014 mol) was heated to reflux for overnight. LCMS showed starting material was consumed and peak Rf=1.66 min left. The solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The aqueous was extensively extracted with dichloromethane. And the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into dichloromethane and subjected to chromatography purification with dichloromethane/MeOH (10:90 to 80:20) to give the product (29.0 mg, 66% yield). LCMS360.42 ([M+1], 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.89 (s, 9H), 1.06 (s, 3H), 1.04-1.40 (m, 6H), 1.77-1.88 (m, 3H), 1.97 (m, 1H), 2.15 (m, 2H), 2.56 (dd, J=15.8, 12.1 Hz, 1H), 2.71-2.84 (m, 3H), 3.47 (d, J=10.9 Hz, 1H), 3.51 (d, J=10.9 Hz, 1H), 4.07 (m, 1H), 6.58 (d, J=2.5 Hz, 1H), 6.63 (dd, J=8.2, 2.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H).
Reaction SMILES: C[O:2]C1C=CC(C(OCC(CO)(C(OCC)=O)C(OCC)=O)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=CC=1.[O:41]1[C:46](=[O:47])[CH2:45][O:44][CH2:43][C:42]1=[O:48]>O1CCOCC1>[C:42]([OH:48])(=[O:2])[CH2:43][O:44][CH2:45][C:46]([OH:41])=[O:47]
Reactant: CCOC(=O)C(CO)(COC(c1ccc(OC)cc1)(c1ccc(OC)cc1)c1ccc(OC)cc1)C(=O)OCC
Reactant: O=C1COCC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)COCC(=O)O
Reaction time: 8 h
Yield: 574.3 %

Procedure:
Referring to scheme 2, a mixture of 1 (1.11 g, 2.0 mmol), 1,4-dioxane-2,6-dione (0.70 g, 6.0 mmol), Py (5 mL), and dioxane (5 mL) was kept overnight at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with 2 M aqueous triethylammonium acetate (5×10 mL) and water (5×10 mL), dried over Na2SO4. The extract was evaporated to give crude monoester of 2 with diglycolic acid (1.54 g; triethylammonium salt) as a solid foam in a quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:12]2[NH:16][C:15](=[O:17])[O:14][N:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CC#N.CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:12]2[N:16]([CH3:24])[C:15](=[O:17])[O:14][N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(CO/N=C(/c2ccccc2)c2noc(=O)[nH]2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(/C(=N\OCc2cccc(N)n2)c2ccccc2)noc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of 3-[(Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-1,2,4-oxadiazol-5(4H)-one (1 g, 3.21 mmol, 1 eq.) in MeCN (50 ml) and DMF (10 ml) was added potassium carbonate (532 mg, 3.85 mmol, 1.2 eq.) followed by iodomethane (547 mg, 3.85 mmol, 1.2 eq.). The reaction was stirred at room temperature overnight. The reaction was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (906 mg, 85% yield) has a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc2c(c1)CCCN2
Product: Clc1nccc(N2CCCc3ccccc32)n1

Procedure:
Using an analogous method to that described in Method 3, but starting from 2,4-dichloropyrimidine and 1,2,3,4-tetrahydroquinoline, the product was obtained. MS (MH+): 246, 248.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[N:1]1([C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CCCN2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of 1,2,3,4-tetrahydroquinoline, 10.46 ml of triethylamine, 270 ml of tetrahydrofuran and then 15.13 g of para-nitrophenyl chloroformate are introduced into a 1 l round-bottomed flask. The reaction medium is stirred at ambient temperature for two hours and then filtered. The solvent is evaporated under reduced pressure and the residue is taken up in dichloromethane and washed with a 2N aqueous hydrochloric acid solution and then twice with water. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to result in 21.5 g of 4-nitrophenyl 3,4-dihydroquinoline-1(2H)-carboxylate.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]([I:15])=[CH:7]1)[CH3:5].[BH4-].[Li+].C1COCC1>CCO>[I:15][C:8]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[N:6]([CH:4]([CH3:5])[CH2:3][OH:2])[CH:7]=1
Reactant: COC(=O)C(C)n1cc(I)c2cnccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(CO)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of 2-(3-iodo-pyrrolo[3,2-c]pyridine-1-yl)-propionic acid methyl ester (Preparation 57, 18.1 g, 54.8 mmol) in EtOH (300 mL) was added 2M lithium borohydride solution in THF (63.1 mL, 126 mol) at 0° C. The reaction was stirred at this temperature for 30 minutes before warming to room temperature for 18 hours. The reaction was quenched by the addition of water (300 mL) at 0° C. with stirring for 1 hour. The EtOH was removed in vacuo and the resulting residue diluted further with water (600 mL) followed by extraction into 5% MeOH in DCM (250 mL). The organic layer was collected, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-5% MeOH in DCM to afford the title compound (12 g, 73%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])#N>CCOCC>[CH3:2][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C#N
Reactant: Cn1cccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)Cc1cccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
A 28 ml solution of ethereal hydrogen chloride (0.049 mole of HCl) is added dropwise over a 3 hr period to a solution of 2.1 g of N-methylpyrrole and 2.9 g of ethyl cyanoformate in 3 ml ether. The ether supernatant is decanted off, and the precipitate taken up in 11 mls of dry pyridine and the mixture transferred to a pressure bottle. Hydrogen sulfide (13 g) is added to the mixture at -78° C., the bottle sealed, and the mixture is stirred at ambient temperature overnight (about 16 hours). Gas chromatographic analysis with internal standards shows 57% yield of ethyl N-methylpyrrole-2-acetate.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(=O)(O)[O-].[Na+]>O>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: COCCNc1nonc1C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
N-Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride (46.0 g, 0.208 mol) was mixed with water (300 mL). The mixture was heated to 60° C. 3-Bromo-4-fluoroaniline [Oakwood products, product #013091] (43.6 g, 0.229 mol) was added and stirred for 10 min. A warm sodium bicarbonate (26.3 g, 0.313 mol) solution (300 mL water) was added over 15 min. The reaction was stirred at 60° C. for 20 min. LCMS indicated reaction completion. The reaction solution was cooled to room temperature and extracted with ethyl acetate (2×300 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (76.7 g, 98%) as a crude brown solid. LCMS for C12H14BrFN5O3 (M+H)+: m/z=374.0, 376.0. 1H NMR (400 MHz, DMSO-d6): δ 11.55 (s, 1 H), 8.85 (s, 1 H), 7.16 (t, J=8.8 Hz, 1 H), 7.08 (dd, J=6.1, 2.7 Hz, 1 H), 6.75 (m, 1 H), 6.14 (t, J=5.8 Hz, 1 H), 3.48 (t, J=5.2 Hz, 2 H), 3.35 (dd, J=10.8, 5.6 Hz, 2 H), 3.22 (s, 3 H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][N:17]3[CH2:20][C@H:21]([O:23][C:24]4[CH:29]=[N:28][C:27]([C:30]([CH3:32])=[CH2:31])=[CH:26][N:25]=4)[CH2:22][C@H:16]3[CH2:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][N:17]3[CH2:20][C@H:21]([O:23][C:24]4[CH:29]=[N:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][N:25]=4)[CH2:22][C@H:16]3[CH2:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(C)(C)C)c4)CCN3C2)cn1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)c1cnc(O[C@@H]2C[C@H]3CN(S(=O)(=O)c4cccc(C(C)(C)C)c4)CCN3C2)cn1
Yield: 56 %

Procedure:
(7R,8aS)-2-[(3-tert-Butylphenyl)sulfonyl]-7-{[5-(prop-1-en-2-yl)pyrazin-2-yl]oxy}octahydropyrrolo[1,2-a]pyrazine (164.3 mg, 0.360 mmol, Example 113) in ethanol (5 mL) was added to Raney® nickel 2800 water slurry (202.9 mg, 1.556 mmol) in a 20 mL pressure bottle. The mixture was stirred under 30 psi of hydrogen at ambient temperature for 15 hours. The mixture was filtered through a polypropylene membrane, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluted with ethyl acetate/hexane (3:7) to give the title compound (56% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (m, 6H), 1.33 (s, 9H), 1.62 (m, 1H), 1.94 (m, 2H), 2.26 (m, 4H), 2.99 (m, 2H), 3.54 (m, 1H), 3.62 (m, 1H), 3.79 (m, 1H), 5.20 (m, 1H), 7.59 (m, 2H), 7.67 (m, 1H), 7.78 (s, 1H), 8.06 (m, 1H), 8.20 (m, 1H); MS (ESI) m/z 459 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[S:55][C:45]=2[C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N:47][CH:48]=1
Reactant: O=C(O)C1CCCCC1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
From cyclohexanecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 80 %

Procedure:
The mixture of 4-piperidone hydrochloride (0.851 mol), triethylamine (1.70 mol), 4-fluoronitrobenzene (0.851 mol) in 800 ml chloroform was heated under reflux for 16 hours. The solvent was removed under vacuum and to the residue water (1 liter) was added and the precipitate was filtered to afford 4-[4-oxo-piperidin-1-yl]-nitrobenzene in 80% yield.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13])=O.C1(C)C=CC(S(Cl)(=O)=[O:21])=CC=1.[OH-].[Na+]>C1COCC1.O>[C:3]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:6]=[CH:5]\[C:4]([OH:13])=[O:21])#[N:1]
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1/C=C\C(=O)O
Temperature: 20 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 1-nitrosonaphthalen-2-ol (5 g) dissolved in THF (30 mL) was treated with p-toluenesulfonyl chloride (6.61 g) under nitrogen. The resulting mixture was stirred at 20° C. for 1 h. The mixture was treated with a solution of sodium hydroxide (4.04 g) in water (30 mL) dropwise over 30 min to keep temperature below 25° C. The reaction mixture was diluted with water (200 mL), and extracted with diethyl ether (200 mL) (discarded). The aqueous layer was acidified with 2M HCl, extracted with ethyl acetate (200 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with 50% diethyl ether in isohexane to give the subtitle compound as a solid (4.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH:4]=1.[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]12[CH2:8][CH2:7][CH:6]([CH:5]=[CH:4]1)[CH:11]1[CH:10]2[C:9](=[O:15])[NH:13][C:12]1=[O:14]
Reactant: O=C1C=CC(=O)N1
Reactant: COC1=CCC=CC1
Solvent: ClC(Cl)Cl
Product: COC12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
11 g (0.1 mol) of 1-methoxycyclohexa-1,4-diene are heated under reflux with 0.1 g of tris(triphenylphosphine)-ruthenium dichloride and 8.8 g (0.09 mol) of maleimide in 100 ml of absolute chloroform overnight. The mixture is concentrated and the residue is recrystallized from 100 ml of toluene.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[C:13]([CH3:14])=[CH:12][S:11][CH:10]=2)[O:3]1.O>CC(C)=O>[CH3:14][C:13]1[C:9]([B:4]([OH:5])[OH:3])=[CH:10][S:11][CH:12]=1
Reactant: Cc1cscc1B1OC(C)(C)C(C)(C)O1
Solvent: CC(C)=O
Solvent: O
Product: Cc1cscc1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A solution of 4,4,5,5-tetramethyl-2-(4-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane (3.69 g, 16.47 mmol) in acetone (30 mL) is treated with H2O (30 mL), followed by NaIO4 (7.05 g, 32.95 mmol). The resulting mixture is stirred at rt overnight. The organic solvent is removed in vacuo. The residue is diluted with H2O (50 mL), extracted with EtOAc ((2×100 mL). The organic extracts are combined, dried with Na2SO4, filtered and concentrated. Purification of the crude material by chromatography gives the title compound (0.82 g, 5.78 mmol, 35%). 1H NMR (CDCl3): δ 1.33 (s, 3H), 2.64-2.66 (m, 2H), 7.00-7.02 (m, 1H), 8.27 (d, J=3.0 Hz, 1H). ES-MS (m/z): calcd for C5H7BO2S (M−H)−: 141.0; found: 141.1.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C:29]([CH3:31])=O>>[CH2:31]([O:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1)[CH:29]=[CH2:28]
Reactant: CC(C)=O
Reactant: COc1ccc(Cc2oc3c(Cl)ccc(O)c3c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c12
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran (164) (Example 44) (1.5 g, 5 mmol) in 30 mL acetone was added potassium carbonate (690 mg, 5 mmol) amd allyl bromide (605 mg, 5 mmol). The mixture was refluxed for 20 h, then filtered through celite after cooling to room temperature. Concentration of the filtrate gave 1.94 g of the 4-allyloxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran as a light brown oil. The crude material was refluxed in 8 mL o-dichlorobenzene for 6 h. Evaporation of the solvent followed by chromatography gave the title compound as a white solid, mp 90°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([F:35])([F:34])[F:33])[CH2:28][CH2:27]3)=[O:25])=[CH:20][CH:19]=2)[CH:5]=[C:6]([Cl:17])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][C@@H:12](CO)[O:11][C:10]1=[O:16].[OH-].[Na+].CC[O:40]C(C)=O.CCCCCCC.I(O)(=O)(=O)=O>C1COCC1.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]([F:34])([F:35])[F:33])[CH2:30][CH2:31]3)=[O:25])=[CH:22][CH:23]=2)[CH:5]=[C:6]([Cl:17])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH:12]([OH:40])[O:11][C:10]1=[O:16]
Reactant: O=C1O[C@H](CO)C[C@H]1Cc1c(Cl)cc(-c2ccc(C(=O)N3CCC(C(F)(F)F)CC3)cc2)cc1Cl
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(O)C[C@H]1Cc1c(Cl)cc(-c2ccc(C(=O)N3CCC(C(F)(F)F)CC3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Dissolve (3R,5S)-3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-5-hydroxymethyl-dihydro-furan-2-one (1.5 g, 1 eq.) in THF (10 mL) and then add 2 N NaOH (3 mL). Allow the reaction to stir at room temperature for 1 hour with vigorous stirring. TLC (50% EtOAc/Heptane) shows the complete consumption of starting material. Add dropwise a solution of periodic acid (1.5 g, 2.3 eq.) in water (5 mL). The reaction becomes a white slurry with a small exotherm. After ˜1 hour, TLC (50% EtOAc/Heptane) shows that the reaction is finished. Dilute the slurry with 1 N HCl (10 mL) and extract 3 times with EtOAc (150 mL total). Dry the organic layer and concentrate to give the titled compound as a white foamy solid (1 g, 68% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=O.[CH2:17]([NH2:20])[CH2:18][NH2:19]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]12[NH:20][CH2:17][CH2:18][N:19]1[C:10](=[O:12])[C:9]1[C:8]2=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCN
Reactant: O=C(O)c1ccccc1C(=O)c1cccs1
Product: O=C1c2ccccc2C2(c3cccs3)NCCN12

Procedure:
Condense o-(2-thienoyl)benzoic acid with ethylenediamine by the procedure of Example 1 to obtain 9b-(2-thienyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one and reduce with lithium aluminum hydride as described in Example 1 to obtain 1,2,3,4,5,6-hexahydro-1-(2-thienyl)-2,5-benzodiazocine, m.p. 148° C. The dihydrochloride melts at 241° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1([C:20](O)=[O:21])[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1>CCOC(C)=O>[NH2:7][C:8]1([CH2:20][OH:21])[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc2c(c1)CCCC2(N)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCCC2(N)CO
Yield: 83.3 %

Procedure:
To a suspension of 172 mg (0.00452 mol) of lithium aluminum hydride in 6 mL of THY at 0° C. was added portion-wise 500 mg (0.00226 mol) of the product of Step B. The mixture was refluxed overnight. EtOAc was carefully added to quench excess hydride and 50% aqueous NaOH added. The mixture was extracted with EtOAc and the EtOAc extract washed with brine. It was dried (MgSO4) and concentrated to give an oil which solidified on standing to give 390 mg of a tan solid: mp 89°-95.6° C. 1H NMR (DMSO-d6) d 7.422 (d, 1H), 6.70 (d, 1H), 6.95 (s, 1H), 3.690 (s, 3H), 3.20-3.40 (m, 3H), 2.70 (t, 2H), 2.0-2.20 (m. 2H), 1.70 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5](C(O)=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-:3])=[O:2].C1(P([N:32]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.CC(O)(C)C>O1CCOCC1.C(OCC)(=O)C>[NH2:32][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=C(O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: Nc1nn(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 4-nitro-1-phenyl-1H-pyrazole-3-carboxylic acid (1.00 g, 4.29 mmol) in 1,4-dioxane (15 mL) were added diphenylphosphoryl azide (1.44 mL, 6.65 mmol), triethylamine (1.79 mL, 12.9 mmol) and 2-methyl-2-propanol (7.2 mL, 75.3 mmol), and the mixture was heated under reflux for 2 hours under a nitrogen atmosphere. The reaction solution was cooled down to room temperature, and ethyl acetate was added thereto. The mixture was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in chloroform (10 mL), and then trifluoroacetic acid (5 mL) was added thereto. The solution was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction solution was concentrated, ethyl acetate was added to the resulting residue. The solutionwas washedwith saturatedaqueous sodiumbicarbonate solution and saturated aqueous brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Diisopropyl ether was added to the resulting residue, and the precipitates were collected by filtration and dried to obtain the title compound (827 mg, 94%).