Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH:4]1[NH:7][C:6](=[O:8])[CH:5]1[CH2:9][CH2:10][O:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:2].C([O:27][CH:28](O)[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])C.C1C=CC=CC=1>O>[CH2:1]([S:3][CH:4]1[N:7]([CH:28]([OH:27])[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C:6](=[O:8])[CH:5]1[CH2:9][CH2:10][O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:2]
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCSC1NC(=O)C1CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccccc1
Product: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
4-Ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-azetidine (9.0 g), p-nitrobenzyl glyoxylate ethyl hemiacetal (8.15 g) and benzene (350 ml) were heated at reflux for 20 hours under a nitrogen atmosphere using a Dean-Stark water separator. The solution was then concentrated in vacuo and the residue was dissolved in 700 ml of dichloromethane. The dichloromethane solution was washed two times with water, dried over anhydrous sodium sulfate and concentrated in vacuo to a yellowish semi-solid (15.0 g) of the title compound. The NMR spectrum in deuterochloroform showed peaks at 1.02-1.52 (c, 8H); 2.6 (m, 2H); 3.3 (m, 1H); 4.1 (b, 1H); 4.78-5.56 (c, 5H); 7.48 (d, 4H); and 8.18 (d, 4H) ppm. The IR spectrum in dichloromethane showed absorptions at 5.62 and 5.7 microns.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[C:12](=[O:13])[CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1.[SH:22][CH2:23][CH2:24][OH:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][CH:15]([S:22][CH2:23][CH2:24][OH:25])[C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: CC1(c2ccc(F)cc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccc(F)cc2)OC(CC(SCCO)c2ccsc2)=CC1=O

Procedure:
Following the procedure of Method C, Example 1, (E)-2-(4-fluorophenyl)-2-methyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 2-mercapto-1-ethanol to provide 2-(4-fluorophenyl)-5-[2-[(2-hydroxyethyl)thio]-2-(3-thienyl)ethyl]-2-methylfuran-3(2H)-one: 1H NMR (DMSO-d6) δ1.53 and 1.56 (singlets, 3H), 4.39 (m, 1H), 5.56 (overlapped singlets, 1H), 7.08-7.35 (m, 5H), 7.43-7.60 (m, 2H); MS (HR-Cl) m/z 379.0832 (M+H calcd. for C19H20FO3S2 379.0837)
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:19]=2)=[O:15])[NH:5]1.[O:30]=[C:31]1[NH:35][CH:34]([CH2:36][C:37](O)=[O:38])[C:33](=[O:40])[NH:32]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:30]=[C:31]1[NH:35][CH:34]([CH2:36][C:37]([N:27]2[CH2:26][CH2:25][N:24]([C:20]3[CH:19]=[C:18]([CH2:17][NH:16][C:14]([C:6]4[NH:5][C:4](=[O:3])[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]=4)=[O:15])[CH:23]=[CH:22][CH:21]=3)[CH2:29][CH2:28]2)=[O:38])[C:33](=[O:40])[NH:32]1
Reactant: O=C(O)CC1NC(=O)NC1=O
Reactant: O=C(NCc1cccc(N2CCNCC2)c1)c1nc2ccccc2c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(CC(=O)N2CCN(c3cccc(CNC(=O)c4nc5ccccc5c(=O)[nH]4)c3)CC2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A suspension of 4-oxo-N-[(3-piperazin-1-ylphenyl)methyl]-3,4-dihydroquinazoline-2-carboxamide dihydrochloride obtained in Reference Example 116 (0.109 g, 0.250 mmol), (2,5-dioxoimidazolidin-4-yl)acetic acid (0.047 g, 0.300 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (0.096 g, 0.500 mmol) and 1-hydroxybenzotriazole (0.068 g, 0.500 mmol) in DMF (5 mL) was stirred at room temperature for 1 hr. Triethylamine (0.139 mL, 1.00 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from methanol-diethyl ether to give the title compound as a pale-yellow powder (0.078 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[NH:9][N:8]=1)=[O:5].FC(F)(F)C(O)=O.[O:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[H-]>ClCCl>[C:19]1([S:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[NH:6][C:4](=[O:5])[C:3]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[CH:28][C:2]=2[NH:1][CH:46]2[CH2:47][CH2:48][O:43][CH2:44][CH2:45]2)(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCOCC1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
2-Amino-N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide (245 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.77 mL, 10 mmol), treated first with tetrahydro-pyran-4-one (0.055 mL, 0.6 mmol) and then with tetramethylammonium triacetoxyborohydride (197 mg, 0.75 mmol). The reaction was stirred at room temperature overnight then additional ketone (0.055 mL, 0.6 mmol) and hydride (2 portions: 197 mg first and 50 mg after a couple of hours) were added. After additional stirring overnight the volatiles were removed under reduced pressure. Dichloromethane was added and the organic phase was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography over silica gel (eluent: dichloromethane/methanol/33% NH4OH in 95:5:1 ratio) affording 186 mg of product still containing some impurities. Further purification by preparative HPLC (basic method) gave 80 mg of title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[N:3]=1.CO[C:13](OC)(OC)[CH2:14][CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>COCCO>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([NH:9][C:13]([CH2:14][CH2:15][CH3:16])=[N:8]2)=[C:4]([CH3:10])[N:3]=1
Reactant: CCCC(OC)(OC)OC
Reactant: Cc1nc(Cl)nc(N)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Temperature: 140 °C
Yield: 47.1 %

Procedure:
A mixture of 2-Chloro-4,5-diamino-6-methylpyrimidine (0.80 g, 5.04 mmol), trimethylorthobutyrate (1.2 ml, 7.6 mmol) and p-TsOH (0.0 8 g) in 2-methoxyethanol (24 ml) was heated in an oil bath at 140° C. for 24 hours. The product was isolated as described in Step 2 of Example 12 and purified by flash chromatography using EtOAc-hexane (1:1) to give the crystalline titled compound (0.5 g, 47%). NMR(CDCl3): δ 1.03 (t, J=8 Hz,3H), 1.9 (q,2H), 2.82 (s, 3H), 3.0 (t, J=8 Hz, 2H), FAB-MS: m/e 211 and 213 (M+H). Analysis calculated for C9H11N4Cl: C, 51.31; H, 5.26; N,26.60. Found: C, 51.43; H, 5.50, N, 26.81.
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.[CH3:18][NH:19][NH2:20]>C(O)(=O)C>[CH3:18][N:19]1[C:5]2[C:4](=[O:3])[CH2:9][CH2:8][CH2:7][C:6]=2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:20]1
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reactant: CNN
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(C)c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
30 g (0.125 mol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 150 mL of glacial acetic acid and 6.5 mL of methylhydrazine were added. The mixture was stirred at room temperature for 6 hours. The solvent was then evaporated and the crude redissolved with water, the solution made basic with 30% NH4OH and extracted with chlorform. The organic layer was then dried over Na2SO4 and concentrated. The residue was chromatographed on a silica gel column (eluant: chloroform) and crystallized from a mixture n-hexane/diethyl ether (TLC chloroform; 63% yield as a white solid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH2:10])[NH:7][C:6]=2[CH:11]=1.N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:18](=[O:20])[CH3:19])[NH:7][C:6]=2[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccc(Br)cc2[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
To a 250 mL round-bottomed flask was added 6-bromo-1H-benzo[d]imidazol-2-amine (2.00 g, 9.43 mmol, Carbocore, The Woodlands, Tex.), DCM (100 mL), pyridine (1.0 mL, 12.3 mmol) and acetic anhydride (0.979 mL, 10.4 mmol). The mixture was stirred at 25° C. for 18 h. The solution was concentrated and then diluted with 10% MeOH (2M in NH3)/CH2Cl2 until homogeneous and then the solution was concentrated onto silica. Purification by silica gel chromatography (0.5 to 5.0% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid (0.676 g, 28%). MS (ESI, positive ion) m/z: 254 (M(79Br)+1).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].O.C(=O)([O-])O.[Na+:40]>C1COCC1.[Pd]>[Na+:40].[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH3:34])=[O:32])=[CH:29][CH:30]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3]
Reactant: CNC(=O)c1ccc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reaction time: 0.5 h

Procedure:
4-Nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (60 mg) obained in the above Step b) was dissolved in THF (6 ml) and ion-exchange water (4.7 ml), and thereto was added 0.1 N aqueous sodium hydrogen carbonate solution (1.3 ml). To the mixture was added 10% palladium on carbon (120 mg), and the mixture was subjected to hydrogenolysis for 30 minutes under atmospheric pressure at room temperature. The catalyst was removed by filtration, and washed with water, and chloroform was added to the filtrate, and extracted and separated (three times). The organic solvent in the aqueous layer was removed under reduced pressure, and the resultant was purified by polymer chromatography (CHP-20P). The fractions eluted with 0–2% aqueous THF solution were combined and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]-phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt (18 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][C:4](=[CH:8][CH3:9])[C:5]([OH:7])=O.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][C:26](=[O:38])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[NH2:28]>ClCCl>[CH3:24][NH:25][C:26](=[O:38])[C@H:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[NH:28][C:5](=[O:7])[C:4]([CH2:3][CH:2]([CH3:1])[CH3:10])=[CH:8][CH3:9]
Reactant: CC=C(CC(C)C)C(=O)O
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC=C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Temperature: 25 °C
Yield: 99.5 %

Procedure:
2-(2-methylpropyl)-but-2-enoic acid (37 g, 0.261M) prepared as described in Example 1 in dry dichloromethane (200 ml) and N-methyl morpholine (65 ml) was treated at -5° C. with oxalyl chloride (33.2 g, 0.261M) over 30 minutes. The mixture was heated under reflux for 10 minutes, then re-cooled to ca -60° C. and O-methyl-L-tyrosine N-methylamide (51 g, 0.245M) in dry dichloromethane (100 ml) added over 30 minutes. The mixture was left to warm up to room temperature over ca 1 hour, diluted with more dichloromethane then washed with aqueous sodium hydroxide (0.1N), aqueous saturated sodium hydrogen carbonate solution and saturated brine. The organic extract was dried, then evaporated in vacuo to afford N-[2-(2-methylpropyl)-but-2-enoyl]-O-methyl-L-tyrosine-N-methylamide as a yellow gum (81 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26].O>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([CH:13]=[C:25]([C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:26][O:17]2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)C1=Cc2ccc(OCc3ccccc3)cc2OC1
Temperature: 155 °C
Yield: 76.8 %

Procedure:
To a stirred solution of 4-benzyloxy-2-hydroxy benzaldehyde (11.41 g, 50 mmol) in NMP (30 ml) was added K2CO3 (13.0 g, 100 mmol) and heated to 155° C. under N2 atmosphere. t-Butyl acrylate (36.5 ml, 250 mmol) was divided into 4 portions (10, 10, 10 & 6.5 ml). First 10 ml was added to the reaction mixture and heated at 155° C. The rest were added after 2 hr intervals and the reaction mixture was heated for total of 8 hrs. The reaction mixture was cooled to room temperature and water (150 ml) was added. The product was extracted with 150 ml of ether. The ether layer was washed with water twice and dried. Ether layer was diluted with 50% hexanes and passed through a pad of silica (3 inch length and 4 inch diameter). The silica was washed with 50% ether/hexane mixture and the solvent was evaporated to give the product as pale yellow solid (13 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:44][CH2:43][C:40]1[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=1)=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1ccncc1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccncc2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 4-picolylamine.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]3)[CH:34]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([N:33]2[CH:34]=[C:30]([C:2]3[C:3]([O:17][CH:18]4[CH2:21][CH2:20][CH2:19]4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]4)[CH:31]=[N:32]2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)N1c2ccc(Br)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 104.6 %

Procedure:
A mixture of methyl (S)-6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.096 g, 0.254 mmol), tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.113 g, 0.325 mmol), and cesium carbonate (0.264 g, 0.811 mmol) in dioxane (2.0 mL) and water (0.40 mL) was purged with nitrogen to remove any oxygen. XPhos Precatalyst 2nd Generation (0.020 g, 0.027 mmol) was added and the reaction was purged with nitrogen and then heated at 100° C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic phases were concentrated to afford an oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 25-50% ethyl acetate-hexane) to afford methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.132 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 497 [M+H]+.
Reaction SMILES: [C:1]([Li])#[C:2][CH3:3].[F:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]>O=[Mn]=O>[F:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:7]=1[C:8](=[O:9])[C:1]#[C:2][CH3:3]
Reactant: O=Cc1cccc(F)c1F
Reactant: [Li]C#CC
Agent: O=[Mn]=O
Product: CC#CC(=O)c1cccc(F)c1F

Procedure:
Intermediate 40 was prepared (as described above for intermediate 36) from 1-propynyllithium, 500 mg of 2,3-difluorobenzaldehyde, and 1.5 g of MnO2 to yield 440 mg of the title compound homogeneous by TLC (Rf=0.5, 2/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ7.82-7.86 (m, 1H), 7.43-7.35 (m 1H), 7.22-7.15 (m, 1H), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:22]
Reactant: Cc1ccnc(N)c1
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Product: Cc1ccnc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)c1
Yield: 91 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-pyridyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 6 from methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-pyridine with a yield of 91% of theory; M.p.: 250°-251° C. (decomposition).
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[C:6]([CH2:8][C:9]1[C:17]2[O:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)#[N:7]>C(OC(=O)C)(=O)C.[Ni]>[C:1]([NH:7][CH2:6][CH2:8][C:9]1[C:17]2[O:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc2cccc(CC#N)c2o1
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2cccc(CCNC(C)=O)c2o1

Procedure:
A suspension of 1.07 g of sodium acetate, 2.00 g of methyl 7-cyanomethylbenzofuran-2-carboxylate in 10.4 ml of acetic anhydride is hydrogenated in the presence of 0.22 g of Raney nickel at 50° C. over 5 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (6:1 EtOAc-heptane); Rt=3.23.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CO>[C:1]1([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CC1
Yield: 147.5 %

Procedure:
To a solution of 1-phenylcyclopropanecarboxylic acid (25 g, 0.15 mol) in CH3OH (200 mL) was added TsOH (3 g, 0.1 mol) at room temperature. The mixture was refluxed overnight. The solvent was evaporated under reduced pressure to give crude product, which was dissolved into EtOAc. The EtOAc layer was washed with aq. sat, NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 1-phenylcyclopropanecarboxylate (26 g, 96%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 3.63 (s, 3H), 1.63-1.60 (m, 2H), 1.22-1.19 (m, 2H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:8]3=[C:7]([CH3:19])[C:6]=2[CH:5]=1.[Br:20]Br>>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:8]3=[C:7]([CH3:19])[C:6]=2[C:5]=1[Br:20]
Reactant: Cc1c2c(nc3ccc(N)cc13)CCCNC2
Reactant: BrBr
Agent: Cl
Product: Cc1c2c(nc3ccc(N)c(Br)c13)CCCNC2
Yield: 60 %

Procedure:
9-Amino-10-bromo-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline dihydrochloride was prepared from 9-amino-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline dihydrochloride by bromination with an equimolar quantity of bromine analogous to Example 148.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]#[N:17])=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:18].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:18])=[C:2]([CH3:19])[CH:10]=3)[C:6]([C:16]#[N:17])=[CH:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1cn(C2CCCC2)c2cc(Br)c(F)cc12
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc2c(cc1F)c(C#N)cn2C1CCCC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Into a solution of 6-bromo-1-cyclopentyl-5-fluoro-1H-indole-3-carbonitrile (6.6 g, 21.5 mmol) and PdCl2dppf (0.31 g, 0.43 mmol) in dioxane (45 mL) was added a solution of dimethylzinc in toluene (1.2 M, 35.8 mL, 43 mmol). The atmosphere was replaced with nitrogen. The mixture was stirred at 90° C. for 90 min and then cooled to room temperature. The reaction was quenched by careful addition of methanol. Ethyl acetate (200 mL) was added and the mixture washed with aq. 2 N HCl, water and brine, dried over Na2SO4 and concentrated. The residue was purified on silica gel eluting with a gradient of 5 to 35% ethyl acetate in hexane to provide 1-cyclopentyl-5-fluoro-6-methyl-1H-indole-3-carbonitrile (4.4 g, 85%)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl/[C:6](=[N:11]\[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH:21]1[CH2:23][CH2:22]1)/[C:7]([F:10])([F:9])[F:8]>C(#N)C>[CH:21]1([C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[N:11]2[C:6]([C:7]([F:10])([F:9])[F:8])=[N:3][N:2]=[N:1]2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)c(/N=C(\Cl)C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C2CC2)c(-n2nnnc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of NaN3 (0.56 g, 8.57 mmol, 2.5 eq) and (Z)—N-(1-chloro-2,2,2-trifluoroethylidene)-2-cyclopropyl-5-nitrobenzenamine intermediate (1.0 g, 3.43 mmol, 1.0 eq) in 15 mL dry acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold aqueous Na2CO3 solution, extracted with ethyl acetate. The organic layer washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude mixture was purified by column chromatography, eluting with n-hexane:ethyl acetate (10-50% EtOAc in increments of 10% EtOAc)), giving the desired product in 37% overall yield (1.55 g).