Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:22][C:21]([C:23](OCC)=[O:24])=[N:20][N:19]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>O1CCCC1.CO.CCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:28][C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:22][C:21]([CH2:23][OH:24])=[N:20][N:19]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nnc(-c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(-c4nnc(CO)s4)cc3c2)cc1
Reaction time: 0.67 h
Yield: 103.6 %

Procedure:
Ethyl 5-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-1,3,4-thiadiazole-2-carboxylate (230 mg) was dissolved in a mixed solvent of tetrahydrofuran (8 mL)-methanol (2 mL), sodium borohydride (32 mg) was added under ice-cooling, and the mixture was stirred for 40 min. Water and 1M hydrochloric acid were added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90 to 90:10, volume ratio) to give the title compound (220 mg, yield 100%) as a pale-yellow solid. The obtained pale-yellow solid was recrystallized from ethyl acetate-diethyl ether to give pale-yellow crystals. melting point 159-160° C. MS 508 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[OH:1][CH2:2][C:3]1([CH2:6][O:7][N:9]2[C:13](=[O:14])[C:12]3[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: OCC1(CO)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1(CO)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56.9 %

Procedure:
(1-Hydroxymethyl-cyclopropyl)-methanol (4.08 g, 0.04 mol), N-hydroxyphthalimide (6.53 g, 0.04 mol) and triphenylphosphine (10.50 g, 0.04 mol) were combined in anhydrous tetrahydrofuran (100 mL) and stirred at 0° C. for 1.5 hours. Diethyl azodicarboxylate (6.97 g, 0.04 mol) was added at 0° C. and the reaction mixture was stirred at room temperature overnight. Repeated concentration of the reaction mixture from chloroform and filtration of the resulting precipitate (triphenylphosphine oxide) afforded the crude product which was further purified by silica gel chromatography. Elution with hexane/ethyl acetate (3:2) provided 2-(1-Hydroxymethyl-cyclopropylmethoxy)-isoindole-1,3-dione (5.63 g, 57% yield) as a white solid: 1H NMR (400 MHz; CDCl3) δ 7.82-7.85 (2H, m), 7.74-7.78 (2H, m), 4.19 (2H, s), 3.72 (2H, s), 0.63 (4H, s)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([S:13][C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([S:13][C:14]2[CH:15]=[C:16]([NH:20][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(OC)c1cc(Sc2cccc(N)c2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(OC)c1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenylsulfanyl)-phenylamine (0.0384 mol) and TEA (0.0576 mol) in THF (q.s.) was stirred at 5° C., and benzenesulfonyl chloride (0.0384 mol) was added dropwise at 5° C., then the reaction mixture was reacted at room temperature and purified by column chromatography over silica gel (eluent: CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue. (The product was used in subsequent steps without further purification.)
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:25][CH2:26][CH2:27][C:28]1[C:32]2[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:31]=2[O:30][N:29]=1>CN(C)C=O.[I-].[K+]>[CH3:40][O:39][C:34]1[C:35]([O:37][CH3:38])=[CH:36][C:31]2[O:30][N:29]=[C:28]([CH2:27][CH2:26][CH2:25][N:13]3[CH2:14][CH2:15][CH:10]([O:9][C:8]4[C:16]([F:23])=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:7]=4[F:6])[CH2:11][CH2:12]3)[C:32]=2[CH:33]=1
Reactant: COc1cc2onc(CCCCl)c2cc1OC
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2onc(CCCN3CCC(Oc4c(F)c(F)c(F)c(F)c4F)CC3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 60.4 %

Procedure:
A mixture of 10 g of sodium bicarbonate, 0.12 g of potassium iodide, 5.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 75 ml of dimethylformamide was treated with a solution of 5.37 g of 3-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisoxazole in 25 ml dimethylformamide and stirred for five hours at 70° C. The reaction mixture was filtered and the filtrate poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, evaporation under reduced pressure afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 5.5 g of 1-[(5,6-dimethoxy-1,2-benzisoxazol-3-yl)propyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as a waxy solid. This material was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate the corresponding hydrochloride salt. Recrystallization from isopropanol afforded 3.3 g (36%) of 1-[(5,6-dimethoxy- 1,2-benzisoxazol-3-yl)propyl]-4-(2,3,4,5, 6-pentafluorophenoxy)piperidine hydrochloride, m.p. 210°-212° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([CH:17]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18]3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([CH:17]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18]3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(C3CCCOC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 11.9 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (29 mg, 0.197 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. Then the reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-(tetrahydro-2H-pyran-3-yl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.51 mg, 10%). 1H-NMR (MeOD): 1.69 (t, 2H), 1.91 (m, 2H), 2.18 (t, 1H), 2.41 (d, 1H), 3.08 (t, 2H), 3.24 (s, 3H), 3.49 (m, 2H), 3.88 (dd, 2H), 4.40 (m, 1H), 7.05 (d, 1H), 7.50 (m, 1H), 7.61 (m, 3H), 7.86 (t, 1H), 7.94 (d, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[N:16][O:17][C:18]=3[CH3:19])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.C([S-])C.[Na+].O.Cl>CN(C=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[N:16][O:17][C:18]=3[CH3:19])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3noc(C)c23)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc2c(=O)[nH]nc(-c3ccc(O)cc3)c12
Temperature: 100 °C
Yield: 53.7 %

Procedure:
To 1.05 g of 4-(4-methoxyphenyl)-3-methyl-6h-isoxazolo[3,4-d]pyridazin-7-one (4.08 mmol) in 15 mL dry DMF was added 1.03 g of sodium ethanethiolate in 15 mL dry DMF at room temperature. The reaction was then heated at 100° C. for 2.5 h. Added water and 1M HCl until acidic. Extracted the product with diethyl ether and dried the extracts with Na2SO4, filtered, and concentrated in vacuo. The product was purified via silica gel chromatography eluting with 95:5 dichloromethane:methanol to give 533 mg of 4-(4-hydroxyphenyl)-3-methyl-6h-isoxazolo[3,4-d]pyridazin-7-one; Mp 268-276° C.; MS m/z 216 (M−N2+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[CH:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=[C:31]([CH:40]=O)[CH:30]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=[C:31]([CH2:40][NH:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[CH2:13][CH2:12]4)[CH:30]=3)=[CH:25][CH:24]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Product: Fc1ccccc1N1CCN(CCNCc2cc(-c3ccc(C4CCCCC4)cc3)n(-c3ccccc3)n2)CC1
Yield: 64.8 %

Procedure:
Compound 71 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-(4-cyclohexylphenyl)-1-phenyl pyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)=[N:5][N:6]([CH3:12])[C:7]=1N=COC)#[N:2].CNN.[CH3:25][NH:26][NH:27][CH:28]=[N:29]C1N(C)N=C(C2N(C)C([N+]([O-])=O)=CN=2)C=1C#N>C(O)C>[CH3:25][NH:26][NH:27][C:28]([C:7]1[N:6]([CH3:12])[N:5]=[C:4]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[C:3]=1[C:1]#[N:2])=[NH:29]
Reactant: CNNC=Nc1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C
Reactant: COC=Nc1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C
Agent: CNN
Solvent: CCO
Product: CNNC(=N)c1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C

Procedure:
A mixture of 1.0 g. of methyl N-[4-cyano-1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)pyrazol-5-yl]formimidate, 1 ml. of methyl hydrazine, and 10 ml. of ethanol was stirred at ambient room temperature for about 1 hour. The reaction product mixture was filtered. The solid which was recovered was recrystallized from ethanol to yield product in the form of yellow needles having a melting point of about 232°-234° C. The product was identified by NMR spectrum and elemental analyses as N-[4-cyano-1-methyl-3-(1-methyl-5-nitroimidazol-2-yl)pyrazol-5-yl]formimidic acid, 2-methyl hydrazide.
Reaction SMILES: B.O1CCCC1.[C:7]1([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:7]1([NH:13][CH2:14][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
Borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 57 mL, 57 mmol) was added to a stirred, cooled (0° C.) solution N-phenyl-1-t-butoxycarbonylpiperidine-4-carboxamide (5.78 g, 19 mmol) in tetrahydrofuran (95 mL) and the mixture was stirred at room temperature for 18 h. Methanol (10 mL) was added and the solvent was evaporated under reduced pressure. Potassium carbonate (13.13 g, 95 mmol) and methanol (150 mL) were added and the mixture was heated under reflux for 1 h. The mixture was cooled and the solvent was evaporated under reduced pressure. Water (100 mL) was added and the mixture was extracted with dichloromethane (3×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (20:80) to give the title compound as a colorless solid (5.08 g, 92%), δH (250 MHz, CDCl3) 7.18 (2H, t, J 7.6 Hz), 6.69 (1H, t, J 7.6 Hz), 6.59 (2H, d, J 7.6 Hz), 4.14 (2H, m), 3.73 (1H, br s), 3.03 (2H, d, J 6.2 Hz), 2.69 (2H, m), 1.79-1.55 (3H, m), 1.46 (9H, s), and 1.20 (2H, m).
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([C:35]4[CH:40]=[CH:39][C:38]([I:41])=[CH:37][CH:36]=4)([C:28]4[N:32]([CH3:33])[C:31](S)=[N:30][N:29]=4)[OH:27])[CH:24]=3)[N:19]3[N:42]=[N:43][N:44]=[C:18]3[N:17]=2)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCOC(C)=O.O>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([C:35]4[CH:40]=[CH:39][C:38]([I:41])=[CH:37][CH:36]=4)([C:28]4[N:32]([CH3:33])[CH:31]=[N:30][N:29]=4)[OH:27])[CH:24]=3)[N:19]3[N:42]=[N:43][N:44]=[C:18]3[N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cn1c(S)nnc1C(O)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cnnc1C(O)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Sodium nitrite (0.0094 mol) was added at 5° C. to a mixture of nitric acid (12 ml) and water (12 ml). A solution of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanol (0.0094 mol), obtained in Example B27a, in THF (10 ml) was added. The mixture was stirred at 5° C. for 15 minutes and poured out into ice water. EtOAc was added. The mixture was basified with potassium carbonate 10%. The precipitate was filtered, washed with EtOAc and dried under a vacuum, yielding 3.5 g of fraction F1 (63%) of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanol. The filtrate was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 1.5 g F2 (27%). This fraction was taken up in water. The mixture was stirred. The precipitate was filtered off and dried, yielding 1.2 g (21%) of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanol, mp. 228° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc(C3(CN)CCOCC3)cc2)CC1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(Oc2ccc(C3(CNc4ccccn4)CCOCC3)cc2)CC1
Yield: 26.4 %

Procedure:
(4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (300 mg, 0.9 mmol), 2-bromopyridine (50 μL, 0.75 mmol), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.018 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.036 mmol) and sodium tert-butoxide (100 mg, 1 mmol) were heated at 70° C. in toluene (6 ml) for 24 hours under nitrogen. The reaction was partitioned between aqueous sodium bicarbonate (302 ml) and dichloromethane (2×75 ml). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4, to 94:6:0.6 by volume) to provide the title compound (81 mg, 22%) as a white solid after trituration in diethyl ether. 1H NMR (400 MHz, CDCl3) δ 1.11 (d, 6H), 1.86-1.95 (m, 4H), 2.07-2.16 (m, 4H), 2.46-2.51 (m, 2H), 2.82-2.86 (m, 3H), 3.49 (d, 2H), 3.56-3.61 (m, 2H), 3.80-3.85 (m, 2H), 4.03 (m, 1H), 4.33 (m, 1H), 6.22 (d, 1H), 6.51 (t, 1H), 6.91 (d, 2H), 7.24 (d, 2H), 7.32 (t, 1H), 8.01 (d, 1H). HRMS ESI+ m/z 410.2793 [MH]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:8]3[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:7]=3[N:6]2[CH:26]=1.C(=O)([O-])[OH:28].[Na+]>O1CCOCC1.O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:8]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:7]=2[N:6]2[CH:26]=[C:3]([CH2:2][OH:28])[N:4]=[C:5]2[CH2:11][N:10]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nc(CCl)cn1-2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nc(CO)cn1-2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A solution of 2.7 g of 2-chloromethyl-6-(2-chlorophenyl)-8-nitro-4H-imidazo [1,2-a][1,4]benzodiazepine in 30 ml of dioxan was treated with a solution of 0.74 g of sodium hydrogen carbonate in 10 ml of water and the mixture was stirred at 80° C. for 2.5 h. The mixture was filtered and the filtrate was made neutral with aqueous 3N hydrochloric acid. The filtrate was evaporated in a vacuum and the residue was taken up in chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and evaporated in a vacuum. The residue was crystallized in 30 ml of ethyl acetate and diethyl ether and filtered. The crystals were dissolved in dichloromethane and chromatographed over 75 g of silica gel. With dichloromethane/ ethanol 99:1, 98:2 and 97:3 there were eluted small amounts of different impurities, with dichloromethane/ethanol 95:5 there was eluted 6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. After recrystallization from ethyl acetate there were obtained 1.4 g of pure 6-(2-chlorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 173-174° C. which was converted into the methane-sulphonate (m.p. 211-212° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:32])=[CH:5][C:6]([F:31])=[C:7]([C@:9]23[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH3:21])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:22]C(=O)C2C=CC=CC=2)=[N:10]3)[CH:8]=1)#[N:2].NC1SC[C@@H]2C[C@H](COCC3C=CC=CC=3)OC[C@]2(C2C(F)=CC(F)=C(C=2)C#N)N=1>>[NH2:22][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:15][C@H:16]([CH2:19][O:20][CH3:21])[O:17][CH2:18][C@:9]2([C:7]2[C:6]([F:31])=[CH:5][C:4]([F:32])=[C:3]([CH:8]=2)[C:1]#[N:2])[N:10]=1
Reactant: COC[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(C#N)c(F)cc2F)CO1
Agent: N#Cc1cc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CSC(N)=N3)c(F)cc1F
Product: COC[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2cc(C#N)c(F)cc2F)CO1

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Cyano-2,4-difluorophenyl)-6-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C16) was converted to the product using the method described for the synthesis of 5-[(4aR,6R,8aS)-2-amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile (2) in Example 2. Yield: 13.2 mg, 38.0 μmol, 19%. LCMS m/z 354.2 [M+H+]. 1H NMR (400 MHz, CD3OD), δ 7.64 (t, J=7.8 Hz, 1H), 7.3 (dd, J=12, 9.1 Hz, 1H), 4.01 (dd, J=11.1, 2.5 Hz, 1H), 3.76-3.82 (m, 1H), 3.66 (d, J=11.1 Hz, 1H), 3.45 (dd, J=10.3, 6.4 Hz, 1H), 3.39 (dd, J=10.3, 3.9 Hz, 1H), 3.36 (s, 3H), 2.84-2.92 (m, 2H), 2.67-2.71 (m, 1H), 1.70-1.80 (m, 1H), 1.50-1.55 (m, 1H).
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[Cl:38]CCl>[Ti](Cl)(Cl)(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:5]1[Cl:38])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCl
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=C(OC[C@H]1OC(Cl)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (3.02 g, 5.98 mmol) in dry dichloromethane (100 ml) was added via cannula a dichloromethane solution of titanium tetrachloride (1.13 g, 5.98 mmol, 5.98 ml of a 1M solution). The solution was stirred at room temperature for 1.5 hours under argon, then washed with water (3×100 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compounds as a colourless oil (2.9 g, 100%). 1H nmr indicated it to be an approximately 1:1 mixture of α:β-anomers.
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[C:14]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:19]=[CH:18][C:17]([CH2:20][C@@H:21]([NH:30]C(OC(C)(C)C)=O)[CH2:22][C@:23]([CH2:28][OH:29])([CH3:27])[C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1.CCN(CC)CC.Cl.O1CCOCC1>CC(C)=O.CC#N>[CH:7]1([O:6][C:1]([O:2][CH:3]([O:26][C:24](=[O:25])[C@@:23]([CH2:28][OH:29])([CH3:27])[CH2:22][C@H:21]([NH2:30])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:15][CH:16]=2)[CH3:4])=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(OC(=O)OC1CCCCC1)OC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
1-Chloroethyl cyclohexyl carbonate (240 mg, 1.2 mmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (300 mg, 726 μmol) and Et3N (106 μL, 762 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. The individual isomers were separated (˜1:1) and purified (Interchim reverse phase chromatography column) the solvent was removed under vacuum. MeCN (2 mL) and 4 M HCl in 1,4-dioxane (3 mL, 10 mmol) was added and the resulting mixture was stirred for 30 minutes. The solvent was evaporated under vacuum and the product was azeotroped with toluene (1×) to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester.