Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:8].[NH2:15][CH:16]1[C:30](=[O:31])[N:18]2[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH2:23][S:24][CH2:25][CH3:26])[CH2:21][S:22][C@H:17]12>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][C:12]([NH:15][CH:16]1[C:30](=[O:31])[N:18]2[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH2:23][S:24][CH2:25][CH3:26])[CH2:21][S:22][C@H:17]12)=[O:14])=[O:8]
Reactant: CCSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CCCS(=O)c1ccccn1
Product: CCSCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCS(=O)c3ccccn3)[C@H]2SC1

Procedure:
426 mg. of 4-(2-pyridylsulfinyl)butyric acid and 7-amino-3-ethylthiomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 366 mg. of 7-[4-(2-pyridylsulfinyl)butyramido]-3-ethylthiomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [N+](C1C=CC(C(O[CH:11]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH:15]([CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:14]([CH2:34][O:35][C:36](=[O:46])[C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)[CH2:13][O:12]2)=O)=CC=1)([O-])=O.[F:49][C:50]([F:65])([F:64])[C:51]1[CH:52]=[C:53]([C@H:61]([OH:63])[CH3:62])[CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[N+:43]([C:40]1[CH:41]=[CH:42][C:37]([C:36]([O:35][CH2:34][C@@H:14]2[C@@H:15]([CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[C@@H:11]([O:63][C@@H:61]([C:53]3[CH:52]=[C:51]([C:50]([F:64])([F:65])[F:49])[CH:56]=[C:55]([C:57]([F:58])([F:59])[F:60])[CH:54]=3)[CH3:62])[O:12][CH2:13]2)=[O:46])=[CH:38][CH:39]=1)([O-:45])=[O:44]
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(F)ccc1C1C(OC(=O)c2ccc([N+](=O)[O-])cc2)OCC(COC(=O)c2ccc([N+](=O)[O-])cc2)C1COCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@H](COC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1COCc1ccccc1
Temperature: -25 °C

Procedure:
The intermediate from step F (6.17 g, 9.36 mmol) was combined with (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (2.53 g, 9.83 mmol) and dissolved in 100 mL DCM. The vessel was cooled to −25° C. followed by the addition boron trifluoride etherate (0.23 mL, 1.87 mmol). The reaction vessel was maintained at −25° C. for 1 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3 and the mixture was allowed to warm to ambient temperature. The aqueous mixture was extracted several times with EtOAc and washed with brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted with tBuOMe/hexanes=10 to 14%. The first component collected off the column was the desired diastereomer. (M+Na)+772
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Product: O=C(Cl)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl

Procedure:
106.6 g of 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are heated at the boiling point under reflux with 250 ml of thionyl chloride for 2 hours. The excess thionyl chloride is then distilled off under normal pressure and the residue is fractionated under a fine vacuum. 104.7 g of 2,4-dichloro-5-fluoro-3-nitro-benzoyl chloride pass over at 110°-115° C./0.08-0.09 mbar. When left to stand, crystals of melting point 35°-37° C. form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:15][O:16][C:17](=[O:23])[C@H:18]([CH2:20][CH2:21][CH3:22])[NH2:19]>>[CH3:15][O:16][C:17](=[O:23])[C@@H:18]([NH:19][C:11](=[O:13])[CH2:10][NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)CNc1ccc(Cl)c(Cl)c1
Reactant: CCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCC[C@H](NC(=O)CNc1ccc(Cl)c(Cl)c1)C(=O)OC

Procedure:
Following General Procedure D and using N-(3,4-dichlorophenyl)glycine (from Example I above) and L-norvaline methyl ester hydrochloride (Sennchem), the title compound was prepared. The reaction was monitored by tlc (Rf=0.32 in 50% ethyl acetate/hexanes) and purification was by silica gel chromatography using ethyl acetate/hexanes as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][CH:14]([OH:16])[CH3:15])[C:6]2=[O:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14](=[O:16])[CH3:15])[C:6]2=[O:11]
Reactant: CCOc1cc(C(CC(C)O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
A mixture of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]isoindoline-1,3-dione (0.7 g, 1.82 mmol), pyridinium chlorochromate (0.79 g, 3.64 mmol) and Celite (0.6 g) in methylene chloride (40 mL) was stirred at room temperature for 4 hours. The mixture was filtered through celite and the filtrate was washed with water, brine, dried and concentrated. The residue was purified by chromatography (silica gel, methylene chloride:ethyl acetate 95:5) to give 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]isoindoline-1,3-dione as a white solid (0.49 g, 71%); 1H NMR (CDCl3) δ7.38-7.31 (t, J=7.3 Hz, 1H), 7.08-7.05 (m, 3H), 6.81-6.77 (m, 2H), 5.74-5.67 (dd, J=5.9 and 9.4 Hz, 1H), 5.20 (s, 2H), 4.11 (q, J=7.0 Hz, 2H), 3.98-3.87 (dd, J=9.5 and 17.8 Hz, 1H), 3.83 (s, 3H), 3.33-3.23 (dd, J=5.6 and 17.7 Hz, 1H), 2.18-(s, 3H), 1.44 (t, J-6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[N+:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[C:20]2Cl)([O-:14])=[O:13].Cl.C(=O)([O-])O.[Na+]>CN1C(=O)CCC1.O1CCOCC1>[N+:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:21]=[CH:20]2)([O-:14])=[O:13]
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc([N+](=O)[O-])c4n3)c2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
2,5-Dimethylindole (300 mg) and 8-nitro-4-chloroquinoline (430 mg) were suspended in NMP (10 ml) containing 4M HCl in dioxane (2 drops) and maintained under a nitrogen atmosphere. The reaction was heated to 120° C. with stirring for 8 hours. When cooled, the mixture was basified with saturated sodium hydrogen carbonate solution and extracted into ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was purified by flash column chromatography using 2:1 isohexane/ethyl acetate as eluent to give the sub-title compound (560 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:26][O:27][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)=[O:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[C:28]([O:27][CH3:26])=[O:29])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: COC(=O)C1CCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(methyloxycarbonyl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.30 minutes; C23H22C12N4O4 (489.36); mass spectrum: (M−H)−=488/490/492 (chlorine isotope).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc2c(c1)CCCN2
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)CCCN2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Based on R. Nagata et al., J. Med. Chem., 1994, 37, 3956-3968, 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol) was dissolved in DMF (15 mL) under N2 and cooled to 0° C. N-Chlorosuccinimide (1.35 g, 10 mmol) was dissolved in DMF (10 mL) under N2 and was added to the tetrahydroquinoline solution dropwise, via pressure equalizing dropping funnel, over 45 min. The reaction was stirred at 0° C. for 3 h, then quenched by pouring it into water (100 mL). This mixture was extracted with a 5:1 mixture of EtOAc:toluene, then two times with EtOAc. All of the organic extracts were washed with brine, combined, dried over Na2SO4, filtered, and concentrated, then eluted through a 17×2.5 cm column of silica gel (5%, 10% and 15% EtOAc/Hexane step gradient) giving 6-chloro-1,2,3,4-tetrahydroquinoline as a green oil.
Reaction SMILES: [C:1]1([Si:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]1=[O:30]>N1C=CC=CC=1>[C:1]1([Si:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1ccn(CCCCCCO)c(=O)[nH]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccn(CCCCCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 0.75 h

Procedure:
A solution of triphenylsilyl chloride (0.337 g, 1.14 mmol) in dry pyridine (3 mL) was added drop-wise to a solution of 1-(6′-hydroxyhexyl)uracil (0.200 g, 0.94 mmol) in dry pyridine (4 mL) cooled in an ice-salt bath. The reaction mixture was kept at 0° C. under nitrogen for 3 h30. As TLC monitoring evidenced the presence of unreacted starting material, triphenylsilyl chloride (0.325 g, 1.10 mmol) in dry pyridine (1 mL) was added. After a further 45 min at 0° C., the reaction had reached completion and was quenched with CH3OH (0.1 mL). Removal of the solvent in vacuo afforded a crude yellow oil which was purified by silica gel chromatography using a Jones Chromatography Isolute SI column with a gradient elution of 0→5% CH3OH in CHCl3. The title compound was obtained as a white solid (0.140 g, 32%) from the fractions with Rf=0.52 (10% CH3OH/CHCl3). Some starting material (0.130 g, 65%) was also recovered, possibly resulting from hydrolysis during the work up.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>Cl>[CH:21]1([CH2:27][CH2:28][CH2:29][N:30]2[CH2:2][CH:3]3[CH:5]([C:4]3([CH3:20])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:6]2=[O:8])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Reactant: NCCCC1CCCCC1
Agent: Cl
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCC3CCCCC3)C(=O)C21
Yield: 72.7 %

Procedure:
A solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 1 g, 3.36 rmnol) in 3-cyclohexylpropylamine ([Preparation—Eur. J. Med. Chem. (1992), 27, 321-330], 2.9 g, 20.5 mmol) was heated to 160° C. for 16 h. The mixture was cooled, 2N hydrochloric acid solution (20 ml) was added and the mixture was extracted with dichloromethane (3×20 ml). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with dichloromethane then diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as an amber oil (870 mg, 73%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20]>CCO.O>[N+:8]([C:7]1[C:2]([NH:17][C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@@H](Nc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Yield: 69.2 %

Procedure:
2-Chloro-3-nitropyridine (500 mg, 3.15 mmol) was dissolved in EtOH (12.5 ml), added potassium carbonate (435 mg, 3.15 mmol) and to this mixture (S)-2-aminopropanoic acid (561 mg, 6.3 mmol) in 2.5 ml water was added and refluxed for overnight. Reaction mixture cooled to 0° C. to obtain the solid. Then EtOH was removed on rotavapour and acidified with 2N HCl and solid filtered and dried on vacuum to obtain the title compound (460 mg) as an yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:22]12([N:32]=[C:33]=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:33](=[O:34])[NH:32][C:22]34[CH2:23][CH:24]5[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]5)[CH2:31]3)[CH2:29]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Product: CCOC(=O)CC1CC2(CCN(C(=O)NC34CC5CC(CC(C5)C3)C4)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared from (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and 1-adamantyl isocyanate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR=2.32 min, m/z=531; 1H NMR (CDCl3) δ=7.38 (d, 1H), 7.12-7.04 (m, 2H), 4.19 (q, 2H), 3.87 (m, 2H), 3.57 (m, 1H), 3.13-2.83 (m, 4H), 2.63 (dd, 1H), 2.44 (m, 2H), 1.42 (d, 2H), 1.29 (t, 3H).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[C:11]([C:17]([F:20])([F:19])[F:18])=[N:12][C:13](Cl)=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=1[NH2:24]>O1CCOCC1>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[C:11]([C:17]([F:20])([F:19])[F:18])=[N:12][C:13]([NH:24][C:23]3[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:22]=3[Cl:21])=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Nc1cc(F)ccc1Cl
Solvent: C1COCCO1
Product: O=C(NCC1CCCC1)c1cnc(Nc2cc(F)ccc2Cl)nc1C(F)(F)F
Yield: 25.8 %

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-amide (100 mg Example 183a), 2-chloro-5-fluoroaniline (ex-Fluorochem, 237 mg), and 1,4-dioxan (1 ml) were stirred at 100° C. under nitrogen for 18 h. The cooled reaction mixture was evaporated in vacuo, treated with ethyl acetate (5 ml), washed with aqueous 2M hydrochloric acid (2×3 ml), followed by water (2×3 ml), and dried (Na2SO4). The solution was evaporated in vacuo and the residue purified by mass directed auto-preparative purification to give the title compound (35 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1
Reactant: COC(=O)c1c[nH]cn1
Reactant: OB(O)c1ccccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2ccccc2Cl)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg (1.59 mmol) of methyl 1H-imidazole-4-carboxylate, 496 mg (3.17 mmol) of 2-chloro-phenylboronic acid, 100 mg of 3 Å molecular sieve and 432 mg (2.28 mmol) of copper(II) acetate were initially charged in 2 ml of dichloromethane, and 256 μl (3.17 mmol) of pyridine were added. The mixture was stirred at RT for 20 h. For work-up, the mixture was filtered through a little kieselguhr, the filter residue was rinsed with about 15 ml of ethyl acetate and the combined filtrates were washed with 5 ml of water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1→1:1→1:3). This gave 55 mg (13% of theory) of the target compound.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:36])[CH2:34][CH3:35]>>[CH2:34]([C:33]1[N:36]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:30][N:32]=1)[CH3:35]
Reactant: CCC(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: CCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 27 mg (0.306 mmol) of N′-hydroxypropanimidamide were reacted according to the General Method 2. Yield: 7 mg (10% of theory)
Reaction SMILES: [N:1]([CH2:4][C@H:5]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+]=[N-].[H][H]>CCO.CC(O)=O.[Pd]>[NH2:1][CH2:4][C@H:5]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CN=[N+]=[N-])COCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)[C@@H](CN)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-yl(methyl)carbamate (4 g, 11.66 mmol) in EtOH (100 mL) and AcOH (10 mL) was added Pd/C (10%, 1.0 g). The resulting mixture was transferred to an autoclave and charged with hydrogen (45 psi). The reaction mixture was stirred at RT for 1 h and filtered. The filtrate was concentrated to give (S)-tert-butyl 1-amino-3-(benzyloxy)propan-2-yl(methyl)carbamate, which was used without further purification. LRMS (M+Na+) m/z 317.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2.[CH3:21][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([OH:12])[CH3:21])[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(C=O)c21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carbaldehyde (600 mg, 1.689 mmol) in tetrahydrofuran (10 mL) at −78° C. was added methylmagnesiumbromide (3M in diethyl ether, 1.13 mL, 3.38 mmol). After 5 min, the ice bath was removed and stirring continued for 30 min. The reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The mixture was poured into diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 575 mg (92%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.76 (s, 1H), 7.61 (s, 1H), 5.92 (d, J=11.6, 1H), 5.80 (d, J=11.6, 1H), 5.56 (m, 1H), 3.46 (m, 2H), 3.26 (s, 1H), 1.64 (d, J=6.4, 3H), 0.80 (m, 2H), −0.11 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 136.2, 133.5, 130.8, 128.1, 126.9, 122.9, 114.8, 80.3, 66.5, 64.6, 23.0, 17.8, −1.4.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=Cc1ccccn1
Reactant: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2NCc1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.2 %

Procedure:
To a solution of 0.090 g (0.35 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one in 3.5 ml of dichloromethane was added 0.030 mL (0.36 mmol) of 2-pyridine carboxaldehyde, 0.184 g (0.87 mmol) of sodium triacetoxyborohydride and few drops of glacial acetic acid. The reaction mixture was stirred at room temperature for 15 hours. The residue was dissolved in dichloromethane and a saturated aqueous solution of sodium carbonate, extracted with dichloromethane and washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. A recrystallization in isopropanol gives 0.042 g (35%) of pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15].N([O-])=O.[Na+].[N-:20]=[N+:21]=[N-].[Na+]>Cl>[N:1]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15])=[N+:20]=[N-:21]
Reactant: CCNC(=O)c1ccc(N)c(OCC)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CCNC(=O)c1ccc(N=[N+]=[N-])c(OCC)c1
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of 4-amino-3-ethoxy-N-ethylbenzamide (0.53 g) obtained in Example 131c) in 0.2N hydrochloric acid (12.5 ml) was added 1M aqueous sodium nitrite solution (2.5 ml) under ice-cooling, and the mixture was stirred for 2 hr. To the obtained reaction mixture was added an aqueous solution (5 ml) of sodium azide (0.17 g) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (0.50 g, 85%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=3[CH3:22])[C:6]=2[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:4]1)[CH3:2].S(Cl)([Cl:31])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:31])=[O:18])=[CH:15][C:14]=3[CH3:22])[C:6]=2[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)O)cc1C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)Cl)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a mixture of 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoic acid (2.0 g, 5.07 mmol, Preparation #V.1) and thionyl chloride (1.8 mL, 25.3 mmol) in DCM (20 mL) was added DMF (0.04 mL, 0.51 mmol) and stirred at about 50° C. for about 2 h. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure to give 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoyl chloride (2.1 g, 5.09 mmol, 100%) as a brown solid. LC-MS (Table 1, Method k) Rt=1.97 min, m/z 409 (M+H)+ for MeOH quench.