Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH2:49][OH:50])=[CH:43]2)=[NH:39]>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:39]=[C:38]([C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH2:49][OH:50])=[CH:43]4)[N:37]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc2[nH]c(CO)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CO)cc4c3)no2)cc1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (150 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 10 min. N-Hydroxy-2-(hydroxymethyl)-1H-indole-5-carboximidamide (D25) (144 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 7 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was recrystallized from EtOAc/ether to afford [5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]methanol (E11) (95 mg) as a light brown solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 4.65 (2H, d), 4.89 (1H, m), 5.36 (1H, t), 6.46 (1H, s), 7.47 (2H, m), 7.78 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d), 8.27 (1H, s), 11.43 (1H, s). MS (ES): C20H18ClN3O3 requires 383; found 384.0 (M+H+).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])[C:8]=1[O:23][CH3:24])(=O)=O.[C-:25]#[N:26].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][O:13][C:9]1[C:8]([O:23][CH3:24])=[C:7]([CH2:6][C:25]#[N:26])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1c(COS(C)(=O)=O)cccc1OCc1c(C)cccc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(CC#N)cccc1OCc1c(C)cccc1C

Procedure:
The solution of 3-(2,6-dimethylbenzyloxy)-2-methoxybenzyl methanesulfonate (Step C, 8.8 g, 30.26 mmol) and NaCN (1.60 g, 32.6 mmol) in dry DMF (40 ml) was heated at 85° C. for 18 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), concentrated, and passed through short silica gel column using methylene chloride to give the title compound as a yellow solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[C:20]([C:22]1[C:23]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1)#[N:21]>>[O:19]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[N:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[C:20]#[N:21])[CH2:30][CH2:31]2)=[O:16])=[CH:17][CH:18]=1)([CH3:8])[CH3:9]
Reactant: Cc1cnc(N2CCNCC2)c(C#N)c1
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(C(C)(C)N4CCCS4(=O)=O)cc3)CC2)c(C#N)c1
Yield: 79.7 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (100 mg) described in Preparation Example 39 and 4-(3-cyano-5-methylpyridin-2-yl)piperazine (51 mg) described in Preparation Example 107 and by the reaction and treatment in the same manner as in Example 87, the title compound (94 mg) was obtained.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.Cl[C:17]1[N:22]=[C:21]([NH2:23])[C:20]([F:24])=[CH:19][N:18]=1>O>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][O:15][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([F:24])=[CH:19][N:18]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: OCc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Nc1nc(OCc2cccc(Br)c2)ncc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
To a magnetically stirred mixture of KOtBu (1.0 M in tBuOH, 1.36 ml, 1.36 mmol) was added (3-bromophenyl)methanol (0.25 g, 1.36 mmol). To the resulting solution was added 2-chloro-5-fluoropyrimidine-4-ylamine (0.10 g, 0.68 mmol) and the mixture was capped and stirred at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water, and the resulting precipitate was collected by filtration. The solid was washed with water, washed with cyclohexane, and dried in the vacuum oven. A CH2Cl2 solution of the compound was loaded onto Biotage SCX column and eluted with CH2Cl2 followed by 2.0 M NH3 in MeOH. The solvent was evaporated under reduced pressure to give the title compound (0.100 g, 49%) as an off-white solid: mp 143-145° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=2.5 Hz, 1H), 7.61 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 5.28 (s, 2H), 5.20 (br s, 2H); GCMS (EI) m/z 297, 299 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH:27]=[CH:26][C:25]([O:29][CH3:30])=[O:28])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C(F)(F)F)CC1
Reactant: C=CC(=O)OC
Product: COC(=O)C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1

Procedure:
4-(5-Bromo-3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (a) above (3.7 g, 9.0 mmol) reacted with methyl acrylate under the conditions of Example 183d to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 316 (M−Bu+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1(OCC(C)C)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:23]([CH3:25])[CH3:24]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)COC1(OCC(C)C)CCCCCC1
Product: CC(C)COC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCC1
Yield: 45.6 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-diisobutoxycycloheptane (2.42 g, 10 mmol) in the same manner as the example 20 to give the compound 28 (234 mg, 46%). Rf 0.31 (Al2O3 type E, hexane-EtOAc (10:1)) PMR (CDCl3 -0.1% d5 -Py): δH0.87 (6 H, d, J 6.6 Hz, CH3) 1.24 (6 H, d, J 6.6 Hz, (CH3)2C), 1.30-1.75 (13 H, m, --CH2 --), 3.00 (2 H, t, J 6.2 Hz, CH2 -Im), 3.10 (1 H, sep, J 6.6 Hz, (CH3)2CH), 3.17 (2 H, t, J 6.6 Hz), 3.51 (3 H, s, NCH3), 3.70 (2 H, t, J 6.2 Hz, OCH2), 6.81 (2 H, d, J 1.6 Hz, arom-H), 7.12 (1 H, t, J 1.6 Hz, arom-H) Elementary analysis (for C26H38N2O2Cl2S) Cacld.: C, 60.81% H, 7.46% N, 5.45% S, 6.24% Cl, 13.81% Found: C, 61.34% H, 7.69% N, 5.33% S, 6.10% Cl, 13.42%
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[N:5]=1>C(Cl)Cl.C(O)C.[Pd]>[F:15][CH:2]([F:1])[O:3][C:4]1[N:5]=[C:6]([CH3:14])[C:7]([NH2:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)nc1OC(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N)c(C)nc1OC(F)F
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 2-(difluoromethoxy)-3,6-dimethyl-5-nitropyridine (33.4 g, 153 mmol) in methylene chloride (100 mL) and ethanol (600 mL) was added 10% palladium on charcoal (3.3 g). The resulting suspension was hydrogenated on a Parr device at 40 psi H2 for 1 h. TLC was used to monitor the reaction. Additional 3.3 g of palladium on charcoal were added hourly until no starting material remained. A total of 13.2 g of Pd/C was added. The reaction mixture was kept under an H2 atmosphere for 2 h after the last addition of catalyst. The reaction mixture was filtered through Celite and sand and the collected solids were washed with ethyl acetate (2×100 mL). The filtrate was concentrated in vacuo to give a grey oil, which was purified by column chromatography on silica gel (35%→50% ethyl acetate in hexanes) to furnish 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (25.7 g, 89% yield) as a pale yellow oil which solidified upon cooling in a refrigerator. The product was recrystallized from hexanes below 0° C. to afford white needles: mp 40-42° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (1, J=74.0 Hz, 1H), 6.84 (s, 1H), 2.27 (s, 3H), 2.15 (s, 3H); LRMS (ESI) m/e 189.2 [(M+H)+, calcd for Ca8H11N2OF2 189.1]. Anal calcd. for C8H10N2OF2: C, 51.12; H, 5.38; N, 14.86. Found: C, 51.17; H, 5.29; N, 14.87.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22]>CCO>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:22][CH2:21][C:20]#[N:23])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To a solution of diphenyl-4-piperidylmethane (810 mg, 3.22 mmol, 1.00 equiv) in EtOH (5 mL) was added acrylonitrile (0.53 mL, 8.06 mmol, 2.50 equiv) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 hours and then concentrated. The residue was purified by flash chromatography (SiO2, EtOAc-hexane 9:1 to 2:1) to give 480 mg (49%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C=O)C>[Si:12]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)ccc1F
Reaction time: 0.5 h
Yield: 94020.3 %

Procedure:
To a stirred solution of 2,5-difluorophenol (15.1 g, 116 mmol) in DMF (100 ml) was added sodium hydride (60% W/W dispersion in mineral oil; 5.13 g, 139 mmol) with ice-cooling. After stirring for 30 min, tert-butyldimethylsilyl chloride (17.5 g, 0.116 mmol) was added and stirring was continued for an additional 1 hr. The mixture was poured into water (200 ml) and extracted with ether (300 ml). The extract was washed with brine (200 ml), dried (sodium sulfate) and solvent removed by evaporation to give 26.65 g (94%) of the titled compound as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.C(Cl)CCl.[Cl:10][C:11]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][N:15]=[CH:16]2>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][C:3]([NH:21][C:20]1[C:11]([Cl:10])=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[N:15][CH:14]=[CH:13]2)=[O:5]
Reactant: O=C(O)CCl
Reactant: Nc1ccc2cnccc2c1Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CCl)Nc1ccc2cnccc2c1Cl
Reaction time: 4 h

Procedure:
To chloroacetic acid in DMF is added EDC, DMAP and 5-chloro-6-aminoisoquinoline. This mixture is stirred for 4 hours. The reaction is washed with NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gives 2-chloro-N-(5-chloro-isoquinolin-6-yl)acetamide.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[C:33]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CCCC4)C3)sc12
Yield: 75 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), cyclopentanone (33.5 μL, 0.038 mmol) and sodium (triacetoxy)borohydride (175 mg, 0.83 mmol), to obtain 25.6 mg of the title compound as a white solid (75%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>CS(C)=O>[C:11]([NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)N
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1
Yield: 72.5 %

Procedure:
A solution of 1-fluoro-4-nitro-benzene (1 g, 7.1 mmol) and tert-butylamine (1.5 g, 21 mmol) in DMSO (5 mL) was stirred at 75° C. overnight. The mixture was poured into water (10 L) and extracted with EtOAc (7 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford N-tert-butyl-4-nitroaniline (1 g, 73%). 1H NMR (CDCl3, 400 MHz) δ 8.03-8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([NH2:17])[C:9]1=[O:18])[CH3:7])=[O:5])[CH3:2].O=[C:20]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[CH2:1]([O:3][C:4]([CH:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([NH:17][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]1=[O:18])[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)N1CCCCCCC(N)C1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCCCCN(C(C)C(=O)OCC)C1=O

Procedure:
Hydrogenate 2.42 g 1-(1-ethoxycarbonylethyl)-3-aminoperhydroazonin-2-one and 3.09 g ethyl 2-oxo-4-phenylbutyrate in 100 ml ethanol containing 0.60 g acetic acid as described in Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].Cl[C:13]([C:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O>>[CH2:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][CH2:19][C:15]1([C:30]1[O:1][C:2]2[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=2)[N:11]=1)[CH3:13])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Product: CC1(c2nc3c(C(=O)O)cccc3o2)CCCN1C(=O)OCc1ccccc1

Procedure:
2-(1-(Benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)benzo[d]oxazole-4-carboxylic acid is prepared from 3-hydroxyanthranilic acid and benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate using the conditions described in Example 3A. MS (ESI) m/e 381 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[OH-].[Na+]>>[CH2:2]([OH:1])[CH:3]1[O:4][CH:11]([OH:12])[CH:9]([OH:10])[CH:7]([OH:8])[CH:5]1[OH:6]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: OCC1OC(O)C(O)C(O)C1O
Temperature: 100 °C

Procedure:
A 40-% D-fructose solution was adjusted to pH 11 for heating at 100° C. for 90 minutes by a batch-wise process. So as to maintain the pH, an appropriate volume of 4N NaOH was added every 30 minutes.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>CO.O.[Pd]>[NH:12]1[C@H:13]([C:15]([OH:17])=[O:16])[CH2:14][C@@H:11]1[C:9]([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H](C(=O)O)N1

Procedure:
208 mg (0.5 mmol) of stereochemically pure transor cis-N-benzylazetidine-2,4-dicarboxylic acid dibenzyl ester and 20 mg of 10% Pd/C in 15 ml of methanol are hydrogenated as above. The reaction mixture is diluted with 50 ml of warm water, filtered, and evaporated to dryness to afford as off-white solids the trans- or cis azetidine-2,4-dicarboxylic acid in virtually quantitative yield.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:19][OH:20]>CCO.CCOCC>[OH:20][NH:19][C:1]([C:3]1[CH:11]=[CH:10][C:6]2[NH:7][CH:8]=[N:9][C:5]=2[CH:4]=1)=[NH:2]
Reactant: N#Cc1ccc2nc[nH]c2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: N=C(NO)c1ccc2[nH]cnc2c1
Temperature: 25 °C

Procedure:
A solution of 5-cyanobenzimidazole (1.43 g; 10 mmol; 1 eq.) in EtOH (30 ml) was treated with K2CO3 (2.76 g; 20 mmol; 2 eq.) and hydroxylaminehydrochloride (765 mg; 11 mmol; 1.1 eq.) and heated to reflux over night. After cooling to room temperature, the mixture was diluted with Et2O. The resulting solid was collected by filtration, washed with Et2O and water and used without further purification. Yield: 1.28 g (72.7%); MS m/z: 177.3 [M+H]+
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)CCCN1CCN(C(=O)CCNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCCN1CCN(C(=O)CCN)CC1
Yield: 42.3 %

Procedure:
To methyl 4-{4-[N-(tert-butoxycarbonyl)-beta-alanyl]piperazin-1-yl}-butanoate (290 mg, 0.8 mmoles) in 2 mL dichloromethane was added 2 mL trifluoroacetic acid. After 1 hour the solvents were evaporated. The residue was dissolved in 10% DMF/DCM and MP-carbonate (0.8 g) was added. After 16 h the solution was filtered and evaporated to afford methyl 4-(4-beta-alanylpiperazin-1-yl)butanoate (87 mg, 41%) as an oil. MS (ESI+) for m/z 272 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:32]=[CH:31]2>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2[NH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:32]=[CH:31]2)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.60 g, 4.23 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (1.0 g, 4.28 mmol) were refluxed in anhydrous iso-propanol (60 mL) for 5 h. The mixture was allowed to cool to RT, upon which the solid was collected via filtration and was washed with Et2O to give tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (2.2 g, 4.23 mmol, 100%). HPLC retention time=7.75 mins.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Fc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(F)cccc5s4)cc3CC[C@@H]12
Yield: 58 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-fluoro benzothiazole (86 mg, 0.46 mmol and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 91 mg (58%) of the title compound as an amorphous solid. mp 140°-145°. FDMS: m/e=412. α[D]589 =+70.06 (c=0.52, chloroform).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]([OH:21])=O)[N:15]=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][O:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH2:59])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:46][O:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH:59][C:19]([C:14]3[N:15]=[CH:16][C:17]4[C:12]([CH:13]=3)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:18]=4)=[O:21])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccc(OCc3ccccc3)cc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cc4ccc(OCc5ccccc5)cc4cn3)nc12
Yield: 88.4 %

Procedure:
0.70 g (2.5 mmol) of 7-benzyloxy-isoquinoline-3-carboxylic acid synthesized above, 1.0 g (2.7 mmol) of HBTU in a mixture of 7.5 ml of DMF and 1.7 mL of DIEA was reacted with 0.48 g (2.5 mmol) of 2-Amino-3H-benzoimidazole-4-carboxylic acid methyl ester (Intermediate A) as described in general procedure A. 2-[(7-Benzyloxy-isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester (1.0 g, 88%) was isolated after column chromatography using 1:1 ethyl acetate and hexane as an eluents. LCMS: 453 (M+1)+.