Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH3:32][S:29]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCO)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 2-[3-(3-hydroxypropyl)phenoxy]-2-methylpropionate (10.1 g, 34.3 mmol) was dissolved in methylene chloride (50 mL). Subsequently, triethylamine (6.94 g, 68.6 mmol) was added thereto. Mesyl chloride (4.71 g, 41.2 mmol) was added dropwise under ice-cooling, and the mixture was stirred for five hours at room temperature. Diluted hydrochloric acid was added thereto, the resultant mixture was extracted with chloroform. The reaction mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=4/1), whereby the target compound was obtained (7.8 g, 61%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCBr
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 1-1 (510 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (506 mg) and n-heptyl bromide (0.235 ml) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (640 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
In a flask were placed 2-amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (40 mg, 0.13 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid (31 mg, 0.26 mmol), pyridine (21 μL, 0.26 mmol) and N,N-dimethylformamide (2 mL), followed by stirring at room temperature for 24 hour. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (16 mg). MS m/e (ESI) 389 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (112 mg, 0.459 mmol, Compound C of Example 22) in methylene chloride (4 mL) at 0° C. was added 96 μL (0.55 mmol) of diisopropylethylamine followed by 61 μL (0.48 mmol) of ethyl 3-chloro-3-oxopropanoate. The reaction was stirred at 0° C. for 1 h and was then quenched with 10 mL of saturate NaHCO3 solution. The aqueous layer was extracted with chloroform (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil that solidified on standing (180 mg). 1H NMR (CDCl3) δ 9.45 (br s, 1H), 7.89 (s, 1H), 7.71 (dd, 1H, J=2.5, 1.5 Hz), 7.68 (dd, 1H, J=11.8, 2.2 Hz), 7.18 (m, 2H), 6.93 (dd, 1H, J=4.4, 1.4 Hz), 6.78 (dd, 1H, J=4.4, 2.6 Hz), 4.19 (q, 2H, J=7.2 Hz), 3.41 (s, 2H), 1.25 (t, 3H, J=7.2 Hz); MS(ESI+) m/z 359.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]C)=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12>CO.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([OH:33])=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:19])=[O:20])=[C:13]([F:29])[CH:12]=3)[C:3]=12
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Solvent: O
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c1)nn2CC(=O)O
Temperature: 90 °C
Reaction time: 48 h
Yield: 52.6 %

Procedure:
In a resealable Schlenk flask, methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.030 g, 0.057 mmol) was dissolved in methanol/water (1:1, 1 mL). The flask was sealed with a teflon screwcap and heated at 90° C. After 2 days, the reaction was cooled to ambient temperature. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.3-6.7 min) afforded 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid as a white solid (0.006 g, 0.030 mmol): RP-HP (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 6.42 min. 1H NMR (DMSO-d6, 400 MHz) δ 8.13 (s, 1H), 7.97 (d, 1H), 7.62 (d, 1H), 7.36 (t, 1H), 7.19 (m, 3H), 7.15 (d, 1H), 4.59 (s, 2H); MS: (M−H)− 509.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:38])[N:8]([C:15]1([CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OCC3C=CC=CC=3)[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14])(=[O:3])[CH3:2].[H][H].[ClH:41]>C(O)C.[Pd]>[ClH:41].[NH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:15]1([N:8]2[C:7](=[O:38])[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH3:2])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22]
Reactant: [H][H]
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1cccc2c1C(=O)N(C1(CCCCN)CCC(=O)NC1=O)C2=O
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of 15 (0.02 g, 0.038 mmol) in 2% HCl in ethanol (2.0 mL) was added palladium on activated charcoal (0.004 g) under an atmosphere of argon. The mixture was subsequently saturated with hydrogen using a hydrogen balloon. After 2 h, the mixture was flushed with argon, filtered and concentrated. Preparative HPLC afforded 16 (0.002 g, 12%). 1H NMR (400 MHz, D2O) δ 8.37 (s, 2H), 8.16 (d, J=8.5 Hz, 1H), 7.76 (dd, J=12.9, 5.5 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H), 2.95 (t, J=7.6 Hz, 2H), 2.73 (m, 3H), 2.61-2.47 (m, 1H), 2.41-2.10 (m, 4H), 1.80-1.59 (m, 2H), 1.43 (d, J=39.6 Hz, 3H). MS (ESI) m/z calcd for C19H23N4O5 [M-Cl]+387.4, found 387.7.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:38]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][C:28]4[O:30][CH2:31][O:32][C:27]=4[CH:26]=3)[N:20]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cccc(C=O)c1
Reactant: NC(=O)c1cc2c(cc1N)OCO2
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3cc4c(cc3c(=O)[nH]2)OCO4)c1
Yield: 6.1 %

Procedure:
According to the preparation of 42, 16 (1.0 g, 5.5 mmol) and 3-methoxybenzaldehyde (34) (0.7 g, 5.5 mmol) were used to afford 54 (0.1 g, 8.8%) as pale yellow needles.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH2:19])(C)(C)C.[C:21](O)([C:23]([F:26])([F:25])[F:24])=[O:22]>>[NH2:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:21](=[O:22])[C:23]([F:26])([F:25])[F:24]
Reactant: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)C(F)(F)F
Product: Nc1cc([N+](=O)[O-])ccc1CN(CC(=O)O)C(=O)C(F)(F)F

Procedure:
A solution of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (0.28 g, 1.0 mmol) was heated at 120° C. for 16 hours in TFA (5 mL). Concentration and chromatography on silica gel with methylene chloride and methanol (20:1) gave 0.3 g of [(2-amino-4-nitro-benzyl)-(2,2,2-trifluoro-acetyl)-amino]-acetic acid. Following a procedure analogous to Example 1848d, [(2-amino-4-nitro-benzyl)-(2,2,2-trifluoro-acetyl)-amino]-acetic acid was converted to 8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one: 1H NMR (300 MHz, CD3OD) δ 8.0 (m, 2H), 7.6 (dd, 1H), 4.98 (s, 1H), 4.57 (s, 2H), 4.53 (s, 1H).
Reaction SMILES: O.[OH-].[K+].[C:4]1([CH:10]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH:24]=[C:25]([C:33]([O:35]C)=[O:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH:10]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH:24]=[C:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1=CC2=CC[C@H]3[C@@H]4CC[C@H](C(=O)NC(c5ccccc5)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1

Procedure:
10 ml of water and 1 g of potassium hydroxide were added to a solution of 25 ml of methanol containing 214 mg of methyl 17β-(N-diphenylmethylcarbamoyl)-androsta-3,5-diene-3-carboxylate (prepared as described in Example 27). The reaction mixture was then heated under reflux for 4 hours. At the end of this time, methanol from the reaction mixture was removed by distillation under reduced pressure. The mixture was then made acidic by the addition of 1N aqueous hydrochloric acid and extracted with methylene chloride three times. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 20 g of silica gel and using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 2:98 to 50:50 by volume as the eluent, to give 110 mg of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[N:29][CH:28]=3)[CH:22]=2)[CH:6]=[C:7]([O:11]CC2C=CC(OC)=CC=2)[C:8](=[O:10])[CH:9]=1)[CH3:3].FC(F)(F)C(O)=O>ClCCl>[OH:11][C:7]1[C:8](=[O:10])[CH:9]=[C:4]([CH:2]([OH:1])[CH3:3])[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[N:29][CH:28]=3)[CH:22]=2)[CH:6]=1
Reactant: COc1ccc(COc2cn(-c3cccc(-c4cncc5ccccc45)c3)c(C(C)O)cc2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1cc(=O)c(O)cn1-c1cccc(-c2cncc3ccccc23)c1

Procedure:
To a 25 mL round bottom flask containing 2-(1-hydroxyethyl)-1-[3-(isoquinolin-4-yl)phenyl]-5˜[(4-methoxybenzyl)oxy]pyridin-4(1H)-one was added 5 mL 1:1 (v/v) dichloromethane:trifluoroacetic acid and the solution was stirred at room temperature for 30 minutes and turned deep red. Concentration under nitrogen stream, purification by reversed phase HPLC (2 cm×5 cm CI 8, acetonitrile-water gradient, 0.05% TFA added), and elution from an SCX column (50 g, sulfonic acid, rinsed with MeOH, eluted with 1 N N¾ in MeOH) afforded 5-hydroxy-2-(1-hydroxyethyl)-1-[3-(isoquinolin-4-yl)phenyl]pyridin-4(1H)-one. ′H NMR (599 MHz, DMSO, 75° C.): 6 9.35 (s, 1H); 8.51 (s, 1H); 8.22 (d, J−8.2 Hz, 1H); 7.90 (d, J=8.5 Hz, 1H); 7.81 (t, J=7.7 Hz, 1H); 7.77-7.69 (m, 3H); 7.61 (s, 1H); 7.58 (d, J−7.8 Hz, 1H); 7.39 (s, 1H); 6.48 (s, 1H); 4.44 (q, J=6.4 Hz, 1H); 1.24 (d, J−6.4 Hz, 3H). HRMS (FT/ICR) calc 359.1390 (M+H)+ 359.1395 found.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[N:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[N:2]1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: c1cnc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ncc2cccnc21
Temperature: 70 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 7-aza indazole (250 mg, 2.1 mmol) and ethyl bromoacetate (0.47 mL, 4.2 mmol) in DMF (8 mL) was added K2CO3 (1.16 gm, 8.4 mmol) and the resulting mixture stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic layer was washed with water (2×5 mL), brine (5 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified using silica gel column chromatography eluting with EtOAc:hexane 10:90 to afford the title compound as an off-white solid in 49% yield, 210 mg.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1>O1CCCC1>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.67 h

Procedure:
12.20 ml of triethylamine and 6.81 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 12.41 g of trans-4-hydroxy-1-(4-nitro-benzyloxycarbonyl)-L-proline in 100 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 40 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with 350 ml of ethyl acetate and 50 ml of 1N aqueous hydrochloric acid. The mixture was then stirred at room temperature for 2.5 hours, after which the organic layer was separated and washed three times with an aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 12.57 g of the title compound, as a powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[N+:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([NH:20][NH2:21])=[O:19])([O-:15])=[O:14]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:21][NH:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[N+:13]([O-:15])=[O:14]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: O=C(NN=Cc1ccc2ccccc2n1)c1ccccc1[N+](=O)[O-]
Yield: 32.4 %

Procedure:
A mixture of 2.99 gm (0.019 mole) of 2-quinolinecarboxaldehyde, 3.44 gm (0.019 mole) of o-nitrobenzhydrazide and 150 ml of absolute ethanol is refluxed 9 hrs. The solvent is evaporated in vacuo. The solid is crystallized from methanol to give 1.97 gm (32%) of title compound, having a melting point of 195°-196° C.
Reaction SMILES: Cl[CH:2]([O:4][C:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[O:6])[CH3:3].[I-:15].[Na+]>C(#N)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:5]([O:4][CH2:2][CH2:3][I:15])=[O:6])=[CH:9][CH:10]=1
Reactant: [I-]
Reactant: Cc1ccc(SC(=O)OC(C)Cl)cc1
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(SC(=O)OCCI)cc1
Temperature: 50 °C

Procedure:
A 50 mL, three-neck, round-bottomed flask equipped with a magnetic stir bar, a reflux condenser, an internal thermometer, and a nitrogen inlet was charged with chloro-ester D1 (2 g, 8 mmol) and sodium iodide (1.8 g, 12 mmol) in acetonitrile (10 mL). The resulting slurry was warmed to 50° C. for 36 hours. The reaction mixture was cooled to room temperature and inorganic solids were removed by filtration. The clear organic phase was concentrated to give a viscous-oil. The crude product was purified by column chromatography using ethyl acetate and hexane to give the title compound E3b as a viscous-oil (1 g, ˜30% yield). 1H NMR (CDCl3, 400 MHz): δ 2.31 (d, J=5.6 Hz, 3H), 2.47 (s, 3H), 6.80 (q, J=6 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].F[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N+:37]([O-:39])=[O:38].C(N(CC)CC)C>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])[CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2o1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3[N+](=O)[O-])CC2O)CCCCC1)c1cc2ccccc2o1

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (6.0 g) obtained in Step 2 of Example 1 in 50 ml of ethanol, were added 3.7 ml of 2-fluoronitrobenzene and 4.8 ml of triethylamine. The reaction mixture was refluxed overnight and concentrated. The resulting residue was filtered and dried to give 7.2 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14]C(=NC)SC)#[N:13]>C(#N)C>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]=[C:12]([NH2:14])[NH2:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NC#N)SC
Solvent: CC#N
Product: Cc1[nH]cnc1CSCCN=C(N)N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (17.0 g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500 ml.) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallized from acetonitrileether to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthioethyl]guanidine, m.p. 141°-142°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]=[N+:27]=[N-:28])[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]12CC(CC1)=C[CH:32]=2>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:32]=[CH:31][N:28]=[N:27]4)[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Reactant: C1=C2CCC(=C1)C2
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1

Procedure:
(5R)-3-(4-(1-Benzyl-1,2,5,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-5-azidomethyl-oxazolidin-2-one (4.55 g, 11.2 mM) and norbornadiene (5.15 g, 56 mM) were dissolved in dioxan (50 ml) and heated under reflux for 4 hours. The reaction mixture was evaporated and the product isolated by MPLC on silica, eluting with 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product as a gum which crystallised on trituration with diethyl ether (2.9 g).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CC(=O)O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(CC(=O)Cl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-methyl-3-phenylbutyric acid (0.508 g, 2.85 mmol) in dichloromethane (10 μL) at −78° C. was treated with oxalyl chloride (3.62 , 28.5 mmol) and 1 drop of dimethylformamide. The reaction mixture was stirred at −78° C. for 10 min, and dry ice/acetone bath was removed to stir at room temperature over night. Solvent was removed under reduced pressure, and dried under high vacuum. The product was used directly for subsequent reaction without analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][C@H:6]([NH:20]C(=O)OC(C)(C)C)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:20][C@@H:6]([CH2:5][C:4]1[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reaction time: 1 h

Procedure:
tert-Butyl (1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate (VII, EXAMPLE 4, 258 mg, 0.59 mmol) is dissolved in methylene chloride (1 mL) at 20-25 degrees C., and trifluoroacetic acid (1 mL) is added with stirring under nitrogen. The reaction mixture is stirred at 20-25 degrees C. for 1 hour, whereupon the reaction mixture is concentrated under reduced pressure to give the title compound. The title compound is used in the next reaction without further purification.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].[OH-:9].[K+]>O>[NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:8])=[O:9]
Reactant: [OH-]
Reactant: N#Cc1cccn1N
Agent: [K+]
Solvent: O
Product: NC(=O)c1cccn1N
Temperature: 0 °C

Procedure:
A solution of 1-amino-1H-pyrrole-2-carbonitrile (100 mg, 0.934 mmol) and potassium hydroxide (1.26 g, 22.5 mmol) in water (3 mL) was stirred at RT for 6 hours. The resulting mixture was then cooled to 0° C. and filtered. The collected solid was washed with cold water until the washings were pH neutral and purified by silica gel chromatography using 0-100% of 90/10/1 CH2Cl2/MeOH/NH4OH in CH2Cl2 to afford 1-amino-1H-pyrrole-2-carboxamide.