Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12](O)=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.O1CCCC1.B.O.Cl>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)CCc1ccc2c(c1)CCO2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc2c(c1)CCO2
Reaction time: 16 h
Yield: 103 %

Procedure:
3-(2,3-Dihydrobenzofuran-5-yl)propionic acid (2.00 g) was dissolved in tetrahydrofuran (20 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 11.5 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 16 hr. Water was added to the reaction mixture, and 1M aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (1.91 g) as a colorless oil.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)[CH2:15][C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1>>[N:2]1([CH2:7][C:8]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][CH:40]=[C:12]([F:11])[CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)CN1C(=O)Cn1cncn1
Yield: 31 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 51, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (59 mg, 31%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.58-7.52 (m, 2H), 7.40-7.31 (m, 1H), 7.25-6.92 (m, 10H), 5.24 (q, 2H), 4.55-4.48 (m, 1H), 3.89-3.76 (m, 1H), 2.84-2.66 (m, 3H), 2.03-1.90 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:3]=1[CH2:4][S:5][CH:6]1[CH2:12][CH2:11][CH2:10][NH:9][C:8](=O)[CH2:7]1.[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:3]=1[CH2:4][S:5][CH:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: Cc1cc(C)c(CSC2CCCNC(=O)C2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(CSC2CCCNCC2)c(C)c1

Procedure:
3.3 g of 4-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-azepan-2-one are added to a mixture of 15 ml of a 1M-solution of LiAlH3 and 50 ml THF are added. The mixture obtained is heated for 1 hour at 80°, poured into 200 ml of a 20% aqueous NH4Cl-solution and the mixture obtained is extracted with EtAc. The organic phase obtained is dried and solvent is evaporated. 4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepane is obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH3:9])[CH2:3][C:4](OC)=[O:5].C[Si](C)(C)[O-].[K+].C(N(CC)C(C)C)(C)C.Cl.Cl.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][C@H:44]4[CH2:49][CH2:48][C@H:47]([NH2:50])[CH2:46][CH2:45]4)[CH2:38][CH2:37]3)[C:30]=2[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>O1CCOCC1>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][C@H:44]4[CH2:45][CH2:46][C@H:47]([NH:50][C:4](=[O:5])[CH2:3][C@H:2]([OH:1])[CH2:8][CH3:9])[CH2:48][CH2:49]4)[CH2:38][CH2:37]3)[C:30]=2[CH2:29][CH2:28]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC[C@@H](O)CC(=O)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reaction time: 23 h

Procedure:
To a stirred solution of (R)-methyl 3-hydroxypentanoate (49.4 mg, 48 μl, 0.374 mmol) in dioxane (3 ml) was added at room temperature potassium trimethylsilanolate (63.9 mg, 0.5 mmol) and the mixture was allowed to stir for additional 23 h. Afterwards N,N-diisopropylethyl-amine (177 mg, 1.37 mmol), trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and TBTU (120 mg, 0.374 mmol) were added, and the mixture was allowed to stir for 3 h at room temperature. The reaction mixture was poured into saturated NaHCO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1) to yield the title compound as white solid (58 mg, 54%), MS (ISP) m/z=429.4 [(M+H)+], mp 201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21](O)=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH2:36]1[CH2:42][O:41][CH2:40][CH2:39][NH:38][CH2:37]1.Cl>>[CH:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:38]4[CH2:37][CH2:36][CH2:42][O:41][CH2:40][CH2:39]4)=[O:22])[C:15]=3[N:14]=2)=[O:35])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: C1CNCCOC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Agent: Cl
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCCOCC4)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-([1,4]oxazepane-4-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 423 mg (0.85 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 128.3 mg (0.94 mmol) homomorpholine-hydrochloride. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: [C:1]([CH:3]=[CH:4][NH:5][NH:6][C:7]([NH2:9])=[O:8])#[N:2].C(N(CC)CC)C>C(O)C>[NH2:2][C:1]1[N:6]([C:7]([NH2:9])=[O:8])[N:5]=[CH:4][CH:3]=1
Reactant: N#CC=CNNC(N)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)n1nccc1N
Yield: 80 %

Procedure:
A solution of 5.0 g of the product of Example 13 in 50 ml of ethyl alcohol containing 3.0 ml of triethylamine is heated at reflux for 4 hours then concentrated in vacuo to a residue which is stirred with cold water. The resulting solid is filtered, washed with additional cold water and dried to give 4.0 g of the desired product as a yellow crystalline solid. M+H=127.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CC(C)Oc1cc(Cl)ccc1CO
Product: CC(C)Oc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-propan-2-yloxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, DMSO-d6): δ 1.34 (6H, d, J=6.0 Hz), 4.56-4.62 (1H, m), 5.21 (2H, s), 5.77 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=1.2 Hz), 6.93 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.57 (1H, d, J=1.6 Hz), 8.04 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H17ClN4O2, 369; Found, 369.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]1[O:14][CH2:13]1>CS(C)=O>[OH:14][CH:12]([CH2:11][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: NCCc1ccc(O)cc1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CS(C)=O
Product: Oc1ccc(CCNCC(O)COc2ccccc2)cc1
Yield: 50.1 %

Procedure:
A mixture of 4.0 g of tyramine and 5.25 g of phenyl glycidyl ether in 100 ml of dimethylsulfoxide was heated to 100°60 for 17 hours. The solvent was evaporated in vacuo and the residue was chromatographed on 400 g of silica gel. 4.3 g of p-[2-[bis[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol was firstly eluted with chloroform/n-propanol/concentrated ammonia (1000:10:1) as an amorphous substance, ε218 =20710. The further fractions yielded 4.2 g of pure (RS)-p-[2-[(2-hydroxy-3-phenoxypropyl) amino]ethyl]phenol of m.p. 122°-124°, ε221 =15310.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:13]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@H]2CCCO2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (168 mg, 0.51 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylfomamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 291 μL, 0.58 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 30 min at 25° C. After this time, the reaction was concentrated in vacuo to ⅓ of the original volume. In a separate flask a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 86 mg, 0.56 mmol), 2,6-lutidine (84 μL, 0.76 mmol) and methylene chloride (10 mL) was cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and the aqueous layers were than extracted with methylene chloride (2×10 mL). The combined organic layers were then washed with a 1 N aqueous hydrochloric acid solution (1×20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 70% ethyl acetate/hexanes to 90% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-furan-2(R)-yl)-propionamide (155 mg, 65%) as a mixture of roughly 1:1 mixture of diastereomers as a white foam: ES-HRMS m/e calcd for C21H28N3O5SCl (M+H)+ 470.1511, observed 470.1504; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02, 1.03 (2×s, 6H, 2×CH3), 1.37-1.52 (m, 1H, CH of CH2), 1.64-1.99 (m, 4H, 4×CH of CH2), 2.08-2.40 (m, 1H, CH of CH2), 3.34, 3.35 (2×s, 3H, SO2CH3), 3.43-3.77 (m, 3H, OCH2 and OCH), 3.86 (brs, 2H, NCH2), 3.97-4.12 (m, 1H, ArCH), 4.62, 4.63 (2×s, 1H, OH), 6.43 (m, 1H, Ar), 7.49 (m, 1H, Ar), 7.59 (2×dd, Jo=8.2 Hz, Jm=1.7 Hz, 1H, Ar), 7.69 (2×d, Jm=1.7 Hz, 1H, Ar), 7.99 (2×d, Jo=8.2 Hz, 1H, Ar), 10.75, 10.81 (2×s, 1 H, NH).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:18])[C:12]([I:19])=[CH:11][CH:10]=1.[CH3:20]O>C1C=CC=CC=1>[F:8][C:9]1[C:14]([C:15]([O:17][CH3:20])=[O:16])=[C:13]([CH3:18])[C:12]([I:19])=[CH:11][CH:10]=1
Reactant: Cc1c(I)ccc(F)c1C(=O)O
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)c1c(F)ccc(I)c1C

Procedure:
Trimethylsilyldiazomethane solution (2 M in Hexane) (18 mL, 35 mmol) was added dropwise to a stirred solution of the product of Step A (7.3 g, 33.2 mmol) in benzene containing 20% of methanol (total: 100 mL) at room temperature until solution retained a yellow color. The mixture was concentrated to remove the organic solvent. The remaining oil was poured over a silica gel plug in a 60-mL filter frit funnel and eluting with 200 mL of hexane containing 10% ethyl acetate. The filtrate was then concentrated to dryness to give the title compound as a bright yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)=S)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:6]([OH:31])[N:5]=[CH:4][N:3]=1.[S]>[Hg]=O.C(O)C>[NH2:1][C:2]1[C:7]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:17](=[N:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[O:31][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)N1CCC(NC(=S)N(Cc2ccc(F)cc2)c2c(N)ncnc2O)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: CCO
Product: CCOC(=O)N1CCC(N=c2oc3ncnc(N)c3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A mixture of 88.8 parts of ethyl 4-[[[(4-amino-6-hydroxy-5-pyrimidinyl)[(4-fluorophenyl)methyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate, 88 parts of mercury(II) oxide, 0.1 parts of sulfur and 1200 parts of ethanol was stirred overnight at reflux temperature. The reaction mixture was filtered over diatomaceous earth while hot and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethyl acetate. The product was filtered off and dried, yielding 50.7 parts (66.1%) of ethyl 4-[[7-amino-1-[(4-fluorophenyl)methyl]oxazolo[5,4-d]-pyrimidin-2(1H)-yliden]amino]-1-piperidinecarboxylate; mp. 174.6° C. (compound 24).
Reaction SMILES: ClCCl.[CH3:4][CH:5]([O:12][CH2:13][CH2:14][OH:15])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[Br-].[K+].Cl[O-].[Na+]>O>[CH3:4][CH:5]([O:12][CH2:13][CH:14]=[O:15])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)CCCC(C)OCCO
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)CCCC(C)OCC=O
Reaction time: 15 h
Yield: 78.1 %

Procedure:
Dichloromethane (25 mL), 2-[(1,5-dimethylhexyl)oxy]ethanol (5 g, 29 mmol), a solution of potassium bromide (0.34 g, 2.9 mmol) in water (4.72 g) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 0.053 g, 0.34 mmol) was charged to 100 mL flask fitted with addition funnel, condenser, nitrogen, thermocouple and mechanical stirrer. A 2.8 wt % aqueous solution of sodium hypochlorite (173.5 g, 65 mmol) was added and the reaction stirred for a total of 15 hrs. The product was extracted with hexane (200 ml) and washed with water (2×200 ml). The organic phase was dried over sodium sulphate, filtered and the solvent removed by evaporation to yield a colourless oil (3.9 g). This oil (2 g) was chromatographed over silica gel (methyltert-butyl ether/hexane) to yield the product as a colourless oil (1.18 g, equating to a total chemical yield of 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.[NH3:23].CO>O1CCCC1>[NH2:23][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 14 g of 5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester, A. D. Rudzik & B. V. Kamdar, J. Med. Chem., 1971, 14, 1078-1081) in 700 ml of tetrahydrofuran were added firstly 260 ml of 25% aqueous ammonia solution and then 50 ml of methanol. The solution was stirred at room temperature for 20 h. and then concentrated to about 25 ml in a vacuum. The crystalline precipitate was filtered off and recrystallized from dioxan. There were obtained 13.2 g of 2-amino-5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine of m.p. 222-224° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1.[Cu](C#N)[C:16]#[N:17].CN(C)C=O.[C-]#N.[Na+]>O>[C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1)#[N:17]
Reactant: COc1nsnc1-c1ccc(Br)cc1
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nsnc1-c1ccc(C#N)cc1
Yield: 62.1 %

Procedure:
In a manner similar to L. Friedman and H. Shechter, J. O. C., 26, 2522 (1961), incorporated herein by reference, 1.15 g (0.0043 mole) of 4-(4-bromophenyl)-3-methoxy-1,2,5-thiadiazole, 0.46 g (0.0051 mole) of copper cyanide, 15 ml of N,N-dimethylformamide, and a solution of 66.5 g of sodium cyanide in 200 ml of water were reacted to produce 0.58 g of 4-(4-cyanophenyl)-3-methoxy-1,2,5-thiadiazole, Compound 30 of Table I. Compounds 8 and 44 were also prepared by this method.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:12][CH:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[K+]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(N)CNC(=O)OC(C)(C)C
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Product: CC(CNC(=O)OC(C)(C)C)Nc1ccc([N+](=O)[O-])c(N)n1

Procedure:
tert-Butyl {2-[(6-amino-5-nitropyridin-2-yl)amino]propyl}carbamate (Example 39A) is prepared in analogy to Example 38A from 2-amino-6-chloro-3-nitropyridine (637 mg, 3.7 mmol), tert-butyl (2-aminopropyl)carbamate (320 mg, 1.8 mmol) and potassium bicarbonate (368 mg, 3.7 mmol). 561 mg (98% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=1[C:6](N(OC)C)=[O:7])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCCCCC.C(OC(=O)C)C>C1COCC1>[CH2:1]([NH:3][C:4]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:5]=1[CH:6]=[O:7])[CH3:2]
Reactant: CCNc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCNc1cc(C(F)(F)F)ccc1C=O
Yield: 29.5 %

Procedure:
2-Ethylamino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (95 mg, 0.343 mmol) was reacted with LAH in THF at −40° C. for 1.5 hrs as described above to yield title compound (22 mg, 29%) after column chromatography (hexane/ethylacetate=20/1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1C[CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=[O:44])C=CC=2)N=1.Cl.COC(=O)[C@H]1CCCN1>>[S:24]([CH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:4]3[C:3]([O:2][CH3:1])=[O:44])[N:11]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])(=[O:25])[NH2:27]
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: COC(=O)[C@H]1CCCN1
Agent: Cl
Product: COC(=O)[C@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B21 was obtained as a white crystalline solid by following the procedure reported for B4 using A1 and (R)-proline methyl ester hydrochloride; yield: 158 mg (45%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.88-2.08 (m, 3H), 2.22-2.42 (m, 1H), 3.50-3.77 (m, 2H), 3.55 and 3.60 (2 s, 3H), 4.22 (2 s, 2H), 4.50-4.67 (m, 1H), 6.88 (bs, 2H), 6.97-7.05 (m, 1H), 7.20-7.32 (m, 1H), 7.60-7.72 (m, 1H), 7.68 and 7.89 (2bs, 1H), 8.19 and 8.26 (2 s, 1H), 9.73 and 9.78 (2 s, 1H). MS (ES) C16H20N6O4S requires: 392. found: 393 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C@H:6]([OH:19])[CH2:7][NH:8]C(=O)OCC1C=CC=CC=1.CC1C=CC(S(O[C@H]([C@@H]2C=CCO2)CO)(=O)=O)=CC=1>[OH-].[NH4+]>[NH2:8][CH2:7][C@H:6]([C@@H:2]1[CH:3]=[CH:4][CH2:5][O:1]1)[OH:19]
Reactant: O=C(NC[C@@H](O)[C@@H]1C=CCO1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O[C@@H](CO)[C@@H]2C=CCO2)cc1
Agent: [NH4+]
Agent: [OH-]
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C

Procedure:
Alternative preparation of Benzyl (R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (18); ‘One-pot’ procedure 3; Aqueous Conditions. (S)-1-((S)-2,5-Dihydrofuran-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate (14) (0.95 g, 3.35 mmol) was suspended in ammonium hydroxide (4 mL) then stirred and heated at 75° C. in a sealed tube for 6 hours during which time the two liquid phases became a single phase solution. The mixture was stirred at ambient temperature for 20 hours then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][NH2:31]>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][NH:31][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCc1nc2ccccc2[nH]1
Product: CCc1cc(-c2cncc(C(=O)NCCc3nc4ccccc4[nH]3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(1H-benzoimidazol-2-yl)-ethyl-amine to afford the title compound. MS: m/e=402 (M+H).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[O:5][CH3:6].[H-].[Na+].[CH3:10][C:11]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.O>CN(C)C=O>[CH3:1][O:2][N:3]([CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH3:10])[C:4](=[O:7])[O:5][CH3:6]
Reactant: Cc1c(CBr)cccc1-c1ccccc1
Reactant: CONC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cccc(-c2ccccc2)c1C)OC
Reaction time: 3 h
Yield: 50.6 %

Procedure:
0.40 g of methyl N-methoxycarbamate in N,N-dimethylformamide (20 ml) was stirred together with 0.18 g of 60% sodium hydride at room temperature for 30 minutes. 1.00 g of 2-methyl-3-phenylbenzyl bromide was added dropwise at room temperature, and the resulting solution was stirred for 3 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.55 g of methyl N-methoxy-N-(2-methyl-3-phenylbenzyl)carbamate as a transparent viscous liquid.