Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7].[C:17]([N:21]1[C:25](=[O:26])[C:24](Cl)=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:22]1(=[O:35])=[O:34])([CH3:20])([CH3:19])[CH3:18].C(OCC)C>CC#N.CN(C=O)C>[C:17]([N:21]1[C:25](=[O:26])[C:24]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:22]1(=[O:34])=[O:35])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1cccc(C)c1OC(=O)CCCN
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cccc(C)c1OC(=O)CCCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.9 %

Procedure:
2,6-Dimethylphenyl 4-aminobutanoate hydrochloride (80.4 mg, 0.33 mmol) and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (89.9 mg, 0.91 mmol) were dissolved in a mixture of MeCN/DMF (4:1, 5 ml, dry). TEA (0.134 ml) was added and the reaction mixture was stirred at rt for 15 h. Diethyl ether (30 ml) was added and the resulting mixture was extracted with water (2×10 ml). The organic layer was dried (MgSO4), evaporated and the residue was purified by column chromatography on silica, using n-heptane/EtOAc (7:3) as eluent. The obtained product was further purified by re-chromatography, using the same conditions as before, to give the title compound (17 mg, 11%) as colorless oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3): δ 1.73 (s, 9H), 1.78-1.85 (m, 2H), 2.06 (s, 6H), 2.38 (t, 2H), 2.96-3.01 (m, 2H), 5.37 (bt, 1H), 7.04 (s, 31), 7.42-7.44 (m, 3H), 7.50-7.52 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[S:21][C:20]([C:22](O)=O)=[CH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl-].[Cl-].[NH2:39][C:40]1[C:48]([NH2:49])=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43]>N1C=CC=CC=1.CN(C=O)C>[C:42]([C:41]1[C:40]2[N:39]=[C:22]([C:20]3[S:21][C:17]([CH:12]4[CH2:13][CH2:14][CH2:15][CH2:16][N:11]4[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:18][CH:19]=3)[NH:49][C:48]=2[CH:47]=[CH:46][CH:45]=1)(=[O:43])[NH2:44]
Reactant: O=C(O)c1ccc(C2CCCCN2C(=O)OCc2ccccc2)s1
Reactant: NC(=O)c1cccc(N)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCCN4C(=O)OCc4ccccc4)s3)nc12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 28D (0.35 g) in pyridine (10 mL) and DMF (10 mL) was added CDI (0.23 g), and the mixture was heated at 40° C. for 1 hour. 2,3-Diaminobenzamide dichloride (0.22 g) was added, and the mixture stirred at ambient temperature overnight and concentrated. The concentrate was stirred in acetic acid (20 mL) at 80° C. for 4 hours and concentrated. The concentrate was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The extract was washed with water and concentrated, and the concentrate was flash chromatographed on silica gel with 40-80% ethyl acetate in hexane.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9](/[CH:12]=[CH:13]/[CH:14]=[CH:24]/[CH:25]=[O:26])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C/C=C/c1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/C=C/c1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-[4-(1H-pyrazol-1-yl)phenyl]-2-propenal (prepared as described in Reference Example 30) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH2:18][CH2:19][NH2:20])([O-:16])=[O:15]>>[N+:14]([O:17][CH2:18][CH2:19][NH:20][C:7]([C@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:16])=[O:15]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1N[C@@H](C(=O)O)CS1
Solvent: O=[N+]([O-])O
Product: O=C1N[C@@H](C(=O)NCCO[N+](=O)[O-])CS1
Yield: 31.3 %

Procedure:
Following a procedure similar to that described in Example 1, but using 1.0 g of (4S)-2-oxothiazolidine-4-carboxylic acid and 1.15 g of N-(2-nitrooxyethyl)amine nitrate, 0.50 g of the title compound was obtained as pale yellow needles, melting at 129°-130° C. (with decomposition).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH3:12])=[C:15]([CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Br)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester and 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([O:15]C)=[O:14].O[Li].O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cc1cc(OC)c(C#N)cc1Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)O)c(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl (2-chloro-4-cyano-5-methoxyphenyl)acetate (30 mg, 0.125 mmol) in 15 mL of THF/MeOH/H2O (V/V/V=2:2:1) was added LiOH H2O (11 mg, 0.250 mmol). The mixture was stirred at rt. For 1 hr, and then most of the solvent was concentrated. The residue was diluted with water, adjusted pH=3 with 3 N HCl, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give (2-chloro-4-cyano-5-methoxyphenyl)acetic acid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 1H), 6.91 (s, 1H), 3.92 (s, 3H), 3.83 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[C:17]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:16]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH2:30]([O:29][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=1)[CH2:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#Cc3ccccc3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#Cc3ccccc3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
[4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 120 mg (97%). HPLC-MS: m/z: 461.7 (M+H)+; Rt: 2.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[H-].[Na+].I[CH2:37][CH3:38].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[C:14]([F:15])([F:17])[F:16])[N:8]2[CH2:37][CH3:38])=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCI
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(CC)c2cc1Cl
Yield: 64.7 %

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (1.00 g, 2.03 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (20 ml). Sodium hydride (60%; 0.079 g, 1.97 mmol) was added and the mixture was stirred while cooling with ice for 2 h. Subsequently, iodoethane (0.15 ml, 1.93 mmol) was added dropwise. The reaction mixture was thawed while stirring within 36 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (4/1) and gave 0.65 g (64% of theory) of ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate.
Reaction SMILES: [Si]([N:8]1[C@H:11]([C:12]2[CH:16]=[N:15][NH:14][N:13]=2)[CH2:10][C:9]1=[O:17])(C(C)(C)C)(C)C.[ClH:18].[CH3:19][CH2:20][OH:21]>>[ClH:18].[CH2:20]([O:21][C:9](=[O:17])[CH2:10][C@@H:11]([C:12]1[CH:16]=[N:15][NH:14][N:13]=1)[NH2:8])[CH3:19]
Reactant: CCO
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1c1cn[nH]n1
Agent: Cl
Product: CCOC(=O)C[C@H](N)c1cn[nH]n1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
1-tert-Butyldimethylsilyl-4(S)-(2H-1,2,3-triazol-4-yl)-2-azetidinone (0.3 g) was added to 6N HCl/EtOH (10 ml). The mixture was stirred for 1 hour, and then evaporated in vacuo. The crystalline solid was washed with diethyl ether to give 3(S)-(2H-1,2,3-triazol-4-yl)-β-alanine ethyl ester hydrochloride (0.25 g, 94.4%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH:9]=[C:8]([CH:10]=O)[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C=C(C=O)CC[C@H]1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1C[C@@H](C)CC[C@H]1C(=O)OC(C)(C)C
Yield: 109.7 %

Procedure:
140 mg (0.529 mmol) of the t-butyl (S)-N-acetyl-5-formyl-1,2,3,4-tetrahydropyridine-2-carboxylate obtained in Synthesis Example 14 was dissolved in 20 mL of ethanol, followed by the addition of 5% Pd/C (140 mg). It was treated in a hydrogen atmosphere of 3 kg/cm2 by the use of mediumpressure catalytic reduction equipment to conduct hydrogenation. The catalyst was removed by filtration and the filtrate was concentrated to give 140 mg of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=O)[CH:16]2[CH:14]([CH2:15]2)[C:13]1=O.O>C(OCC)C>[CH:14]12[CH2:15][CH:16]1[CH2:17][N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:13]2
Reactant: O=C1C2CC2C(=O)N1CCCO
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCN1CC2CC2C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a cold (0° C.) solution of sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (70% in mass, 2.43 mL, 4.5 eq.) was added 3-(3-hydroxy-propyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (example 5, step 1, 320 mg, 1.0 eq.) in diethyl ether (5 mL). The mixture was stirred 40 min at 0° C. and 4 h at reflux. Water was carefully added to and the white mixture was filtered on a dicalite pad. The filtrate was extracted with diethyl ether and the combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo, yielding 220 mg (78%) of the desired product as a purple liquid which was used without additional purification. MS (m/e): 143.1 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][N:14]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[C:15]1B(O)O.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:15]2[N:14]([CH3:13])[C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cn1c(C#N)ccc1-c1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
4-Bromo-3-trifluoromethylaniline (1.77 g, 7.4 mmol), 1-methyl-5-cyano-2-pyrrole-boronic acid (2.0 g, 13.3 mmol), KF (1.42 g, 24.4 mmol), and Pd2(dba)3 (179 mg, 0.185 mmol) were added to a 50 mL round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 minutes. THF (18.5 mL) was added and the mixture was purged with nitrogen for an additional 5 minutes. A solution of tri-t-butylphosphine (10% wt in hexanes) (1.1 mL, 0.37 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 16 hours. The mixture was diluted with 250 mL of EtOAc, filtered through a plug of silica gel, washed through with 200 mL of EtOAc and concentrated to give a crude brown/black semi-solid. Purification via Isco chromatography (the Redisep® column, silica, gradient 5-100% ethyl acetate in hexane) afforded 5-[4-amino-2-(trifluoromethyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile as a white solid (1.8 g, 92%).
Reaction SMILES: Cl.[Cl-].[CH3:3][NH+:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[CH3:5]>C(OCC)C>[CH3:3][N:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[CH3:5]
Reactant: C[NH+](C)CCCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CN(C)CCCCc1ccc([N+](=O)[O-])cc1

Procedure:
The solid thus formed was added portion-wise over one hour to a stirred solution of 275 ml. of a 0.94 molar solution of borane in tetrahydrofuran.Following complete addition of the solid, the reaction mixture was heated at reflux for twelve hours, and then cooled to 0° C. in an ice bath. The reaction mixture was diluted by the dropwise addition of 75 ml. of 2 N hydrochloric acid. The reaction solvent was then removed by evaporation under reduced pressure, and the residue was dissolved in 100 ml. of concentrated hydrochloric acid and heated at reflux for one hour. The acidic mixture then was cooled and made alkaline by the addition of 5 N sodium hydroxide. The alkaline solution was extracted several times withdiethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded 18.4 g. of N,N-dimethyl-4-(4-nitrophenyl)butylamine. The amine thus formed was dissolved in diethyl ether containing hydrogen chloride, whereupon a solid precipitate formed. Crystallization of the precipitate from 150 ml. isopropanol afforded 18.1 g. of N,N-dimethyl-4-(4-nitrophenyl)butylaminium chloride. M.P. 143°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3(O)[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[S:19])=[C:4]([F:20])[CH:3]=1.BrC1C=CC(N2C(Cl)C3CCCCC=3C2=O)=C(F)C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[S:19])[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:16]2=[O:17])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1N(c2ccc(Br)cc2F)C(=S)C2CCCCC12O
Agent: O=C1C2=C(CCCC2)C(Cl)N1c1ccc(Br)cc1F
Product: O=C1C2=C(CCCC2)C(=S)N1c1ccc(Br)cc1F

Procedure:
By the same procedure as described in Example 4, there was obtained the subject compound in red-purple crystals of 97° to 98° C. in melting point from 2-(4-bromo-2-fluorophenyl)-3a-hydroxy-1-thioxo-octahydroisoindol-3-one or 2-(4-bromo-2-fluorophenyl)-3-chloro-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([O:24]C)=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][C:6]([CH3:27])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-9-carboxylate; (4.50 g, 12.2 mmol) in Tetrahydrofurane; (100 mL) was added a slurry of Lithium Hydroxide (880 mg, 36.7 mmol) in water (20 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS analysis of the reaction mixture showed no more starting material. The solvent was removed and the residue was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.I[CH2:23][CH2:24][OH:25]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][CH2:24][OH:25])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: OCCI
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(CCO)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 2-iodo-ethanol as described in Example 49 and isolated as a yellow oil (0.11 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.54 (d, J=3 Hz, 1H), 7.71 (d, J=4 Hz, 1H), 7.50 (d, J=2 Hz, 1H), 7.27-7.31 (m, 1H), 6.82 (d, J=2 Hz, 1H), 6.24-6.28 (bm, 1H), 4.62 (d, J=8 Hz, 2H), 4.29 (t, J=4 Hz, 2H), 4.04 (t, J=4 Hz, 2H), 2.89-2.95 (bm, 1H), 2.74 (s, 3H); MS (M+H)+=344.1; Rt=0.85 min; HRMS (M+H)+=344.12.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCOCC3)ccc2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (200 mg, 0.48 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), morpholine (80 mg, 0.90 mmol, 1.70 equiv), and potassium carbonate (0.2 g, 3.00 equiv). The resulting solution was stirred overnight at 80° C. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 0.1 g of crude product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9](O)[CH2:8][CH2:7][CH2:6]2>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[CH:8][CH2:7][CH2:6]2)=[CH:11][CH:12]=1
Reactant: COc1ccc2c(c1)CCCC2O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC=C2
Temperature: 115 °C
Yield: 96 %

Procedure:
Crude 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (10.3 g, 0.058 mol) was dissolved in 100 ml of toluene and heated in an oil bath (115° C.). P-tolylsulphonic acid (20 mg) was added to the reaction mixture and it was refluxed for about 1 h. The reaction was monitored by GC. The reaction mixture was then cooled and washed with sat. NaHCO3 solution, water and brine and organic layer was dried over Na2SO4. Concentration gave 8.879 of light brown oil. Yield 96%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5](I)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(N(CC)CC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(C)cc(Br)c32)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C#C[Si](C)(C)C)c(C)cc(Br)c32)cc1
Temperature: 25 °C

Procedure:
To a suspension of 7-bromo-4-iodo-5-methyl-1-tosyl-1H-indole (90 mg, 0.184 mmol), CuI (5.60 mg, 0.029 mmol) and Pd(PPh3)4 (16.9 mg, 0.015 mmol) in triethylamine (3 mL) was added trimethylsilylacetylene (0.036 mL, 0.257 mmol) and the mixture was stirred at room temperature. After 3 hours the reaction was purified directly by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (d, J=3.79 Hz, 1H) 7.70 (d, J=8.34 Hz, 2H) 7.34-7.48 (m, 3H) 6.85 (d, J=3.79 Hz, 1H) 2.38 (s, 3H) 2.37 (s, 3H) 0.27-0.31 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:16])[CH2:14][CH3:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:16])[CH2:14][CH3:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH3:28])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)NC)cc1
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
To a solution of 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (Compound 1, 0.50 g, 1.19 mmol) in acetonitrile (15 ml) was added K2CO3 (0.25 g, 1.84 mmol) at room temperature and stirred for 15 minutes. To this was added methyl iodide (0.20 g, 0.08 ml, 1.42 mmol). The so obtained mixture was stirred at room temperature for 15 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The concentrated mass was diluted with water (20 ml). The mixture so obtained was extracted with ethyl acetate (3×30 ml). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude product. The crude product so obtained was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain first title compound (0.05 g, 9.38%) and second title compound (0.045 g, 8.7%).