Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH:9]=[C:8]([CH2:10][S:11]C(=O)C2C=CC=CC=2)[CH:7]=[N:6]1.[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34](OS(C)(=O)=O)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1>C1COCC1.CN(C=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:43])=[C:34]([S:11][CH2:10][C:8]4[CH:7]=[N:6][N:5]([CH3:4])[CH:9]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: Cn1cc(CSC(=O)c2ccccc2)cn1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(CSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(N)n4)[C@H]3SC2)cn1
Temperature: -65 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Under nitrogen atmosphere, 1.35 ml of sodium methoxide (6.5 m mol) was added slowly to a solution of 1.50 g of 1-methyl-4-benzoylthiomethylpyrazole (6.5 m mol) in THF (6 ml) and DMF (18 ml) at 0° C. Stirring was continued for 1 hour. The mixture was cooled to −65° C. with dry ice/ethanol bath, and added to a solution of 4.36 g of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylate (5 m mol) in a mixture of THF (15 ml) and DMF (25 ml) at the same temperature. After stirring for 1 hour, the reaction was quenched with 10% hydrochloric acid, and the mixture was poured into water-ethyl acetate. The organic layer was separated washed with brine, dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified on silica gel (eluent: dichloromethane-acetone) to afford a diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(1-methylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (2.15 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]5[O:34][C:33]([CH3:36])([CH3:35])[O:32][CH:31]5[C:37]([O:39]CC)=[O:38])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]5[O:34][C:33]([CH3:36])([CH3:35])[O:32][CH:31]5[C:37]([OH:39])=[O:38])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1OC(C)(C)OC1c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OC(C(=O)O)C(c2ccc(-c3cccc(-n4cc(C(=O)NC5CC5)c(=O)c5cccnc54)c3)cc2)O1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of ester from step 3 in THF-MeOH (1:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 15 min. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The combined organic extract was washed with brine, dried and solvent evaporated, the residue triturated in hexane/ether then isolated by filtration to afford the title acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[Si:10]([O:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][C:30]1=[O:35])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([N:31]2[CH2:32][CH2:33][CH2:34][CH:29]([CH2:28][O:27][Si:10]([C:23]([CH3:25])([CH3:24])[CH3:26])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:30]2=[O:35])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)(C)[Si](OCC1CCCNC1=O)(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(I)c(Cl)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OCC1CCCN(c2ccc(N)cc2Cl)C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
2.75 g (10.8 mmol) of 3-chloro-4-iodoaniline are dissolved in 20 ml of anhydrous dioxane and admixed successively with 4.98 g (13.5 mmol) of the compound from example 92A, 103 mg (0542 mmol) of copper(I) iodide, 4.61 g (21.7 mmol) of potassium phosphate and 116 μl (1.085 mmol) of N,N′-dimethylethylenediamine. The reflux apparatus is inertized by repeated application of a gentle vacuum and flushing with argon. The reaction mixture is heated to reflux for 15 hours. After this time, it is allowed to cool to RT. It is admixed with water and extracted with ethyl acetate. The organic extract is washed successively with water and saturated sodium chloride solution. Then it is dried over anhydrous magnesium sulfate and filtered, and the filtrate is freed of the solvent under reduced pressure. The crude product thus obtained is first purified by suction filtration through silica gel with 20:1→1:4 cyclohexane/ethyl acetate as the eluent. This affords 3.12 g of a still-contaminated product which is purified further by means of preparative HPLC with an acetonitrile/water mixture. This affords 0.71 g (13% of theory) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[CH3:20][O:21][NH2:22]>>[CH3:20][O:21][N:22]=[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[CH:11][CH:12]=1)[CH3:17]
Reactant: CON
Reactant: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1
Agent: Cl
Product: CON=C(C)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
1.2 mmol of (4-(3-(1H-imidazol-4-yl)propyloxy)phenyl)ethanone (Example 78) and 2.4 mmol of O-methylhydroxylamine hydrochloride are treated as described in Example 92.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2>>[F:22][C:11]([F:10])([F:21])[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:16][CH2:15]2
Reactant: FC(F)(F)c1ccc2c(c1)CCN2
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)N1CCc2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 5-trifluoromethylindoline (D43) to give (E22) (0.12 g, 38%) m.p. 188°-189° C.
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:43])[N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]3)[CH3:31])[CH:23]=2)=[C:19]([F:46])[CH:18]=1.[F:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][C:55]([N:57]=[C:58]=[S:59])=[O:56])=[CH:50][CH:49]=1>C(O)C>[CH3:41][N:40]([CH3:42])[CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]([CH3:31])[C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:20]3[CH:44]=[CH:45][C:17]([NH:16][C:58]([NH:57][C:55](=[O:56])[CH2:54][C:51]4[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=4)=[S:59])=[CH:18][C:19]=3[F:46])[N:27]=[CH:26][N:25]=2)=[O:43])[CH2:33][CH2:34]1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.6 %

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (101 mg) to a solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (110 mg) in ethanol (2.0 ml), the mixture was stirred for 15 minutes at room temperature. After adding 2-(4-fluorophenyl)acetyl isothiocyanate (3.06 ml, 0.25 M solution in toluene) thereto, the mixture was further stirred at room temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate (10 ml) and ethyl acetate (30 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated. Diethyl ether:hexane=1:1 was added to the obtained solid to produce a suspension. The precipitate was filtered and then washed with diethyl ether to provide the title compound (50.5 mg, 31.6%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:33][CH2:32][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4NN=[N:29][N:28]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:33][CH2:32][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]4[O:36][C:34]([CH3:35])=[N:29][N:28]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C1N(c2ccc(Cc3nnn[nH]3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1nnc(Cc2ccc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)cc2)o1

Procedure:
This material was obtained essentially following a procedure described in the literature (Jurisic et al, Synth. Comm. 1994, p 1575) from above 8-(2-chloro-benzenesulfonyl)-2-[4-(1H-tetrazol-5-ylmethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (135 mg) on treatment with acetic anhydride (2 ml), in CH2Cl2 (2 ml), heating at reflux for 30 minutes and subsequent usual aqueous work-up to give the desired 8-(2-chloro-benzenesulfonyl)-2-[4-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (133 mg) as a light brown crystalline solid. MS (ESI): 501.1 (MH+).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])(O)(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:16]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:31])=[O:24])=[CH:5][NH:6]2
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(OCCCO)cc3)c(F)c12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(OCCCO)cc3)c(F)c12
Temperature: 0 °C
Reaction time: 10 h
Yield: 43.2 %

Procedure:
To a mixture of 4,6-difluoro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carbaldehyde (30 mg, 0.1 mmol) in ACN/t-butanol=1/1 (2 mL) was added 2-methyl-2-butene (0.5 mL) and cooled to 0° C. and added the aqueous solution of sodium chlorite (180 mg, 0.5 mL) and sodium dihydrogen phosphate (270 mg, 2 mmol) in water (0.5 mL) dropwise via additional funnel. The reaction was stirred at room temperature for 10 h. The reaction was quenched with sodium sulfite. The mixture was partioned between dichloromethane and water. The combined organics were concentrated to give a residue, which was purified by reverse phase HPLC to give the title compound (15 mg, 43%) as a white solid. MS (AP+) 348.1 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.74 (s, 1 H), 7.36 (d, 2 H), 7.03-6.98 (m, 3 H), 4.14 (t, 2 H), 3.77 (t, 2 H), 2.04-2.01 (m, 2 H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17]1)=[O:37]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Br)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 40.2 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 63c (0.51 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.2 g, 40%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[C@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=4)[C:32](O)=[O:33])[C:20]3=[O:38])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][C:29]4[CH:37]=[CH:36][CH:35]=[C:31]([C:32]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[O:33])[CH:30]=4)[C:20]3=[O:38])[CH2:18]2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2cccc(CN3C(=O)[C@@]4(C[C@H]4c4ccc(Cl)cc4)c4ccccc43)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 1-isopropylpiperazine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C31H32ClN3O2: 513, observed (M+H)+: 514.2 1H NMR (400 MHz, CDCl3) δppm 1.37 (d, J=6.32 Hz, 6 H) 2.04 (dd, J=7.71, 4.67 Hz, 1 H) 2.28 (dd, J=9.22, 4.67 Hz, 1 H) 2.86 (br. s., 2 H) 3.35 (t, J=8.46 Hz, 1 H) 3.61 (br. s., 6 H) 4.96 (d, J=15.92 Hz, 1H) 5.18 (d, J=16.17 Hz, 1 H) 6.02 (d, J=7.33 Hz, 1 H) 6.71-6.82 (m, 2 H) 7.06-7.19 (m, 3 H) 7.31 (s, 1 H) 7.33-7.39 (m, 1 H) 7.39-7.51 (m, 3 H).
Reaction SMILES: C[N+]1([O-])CCOCC1.[CH2:9]([O:11][C:12]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][C:15]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:13]=1[C:24]1[N:28]2[CH:29]=[C:30]([CH2:33][OH:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1)[CH3:10]>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:9]([O:11][C:12]1[C:17]([CH:18]([CH3:19])[CH3:20])=[CH:16][C:15]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:13]=1[C:24]1[N:28]2[CH:29]=[C:30]([CH:33]=[O:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1)[CH3:10]
Reactant: CCOc1c(-c2cnc3ccc(CO)cn23)cc(C(C)C)cc1C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOc1c(-c2cnc3ccc(C=O)cn23)cc(C(C)C)cc1C(C)C
Reaction time: 3 h

Procedure:
Tetrapropylammonium perruthenate (24 mg, 0.07 mmol) and 4-methylmorpholine N-oxide (239.3 mg, 2.04 mmol) were added to a solution of [3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-methanol (480 mg, 1.36 mmol) in dichloromethane under an atmosphere of nitrogen. After 3 h, the reaction was filtered through celite and evaporated. The residue used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([CH2:13][C:14]([O-:16])=O)=O)=[CH:9][CH:8]=2)[C:5]([CH3:19])=[N:4][C:3]=1[CH:20]1[O:24]CCO1.[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]([NH2:33])=[C:28]([NH2:34])[CH:27]=1.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]2[NH:33][C:14](=[O:16])[CH2:13][C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:6]4[C:2]([Cl:1])=[C:3]([CH:20]=[O:24])[N:4]=[C:5]4[CH3:19])=[CH:18][CH:17]=3)=[N:34][C:28]=2[CH:27]=1
Reactant: Cc1nc(C2OCCO2)c(Cl)n1-c1ccc(C(=O)CC(=O)[O-])cc1
Reactant: Cc1cc(N)c(N)cc1C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)NC(=O)CC(c1ccc(-n3c(C)nc(C=O)c3Cl)cc1)=N2
Temperature: 70 °C

Procedure:
A solution of 4-[5-chloro-4-(1,3-dioxolan-2-yl)-2-methylimidazol-1-yl]benzoylacetate from Preparation 5 (155 mg, 0.38 mmol), and 4,5-dimethyl-1,2-diaminobenzene (55 mg, 0.4 mmol) in toluene (4 ml) was heated at reflux for 4.5 hours, then evaporated to dryness and purified by flash chromatography (eluting with ethyl acetate) to afford a pale yellow gum. 1M HCl (2 ml) was added to a solution of the residue in THF (2 ml) and the mixture was heated to 70° C. for 1 hour. The THF was evaporated and the residue was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was dried over magnesium sulphate and evaporated.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:15][CH:12]1[CH2:13][CH2:14][N:9]([C:4]2[C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: NC1CCN(c2ncccc2C(F)(F)F)CC1
Product: O=S(=O)(NC1CCN(c2ncccc2C(F)(F)F)CC1)c1ccccc1Cl
Yield: 41.4 %

Procedure:
1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (100 mg, 0.42 mmol) was reacted with 2-chlorobenzenesulfonyl chloride (106 mg, 0.50 mmol) to afford the title compound (73 mg), a white solid, in 41% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:12]([NH:14][CH:15]([C:17]1[N:21]2[CH2:22][C@H:23]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=3[F:42])[CH2:24][CH2:25][C@@H:26]([NH:27]C(=O)OC(C)(C)C)[C:20]2=[N:19][CH:18]=1)[CH3:16])=[O:13])([CH3:11])([CH3:10])[CH3:9].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:27][C@@H:26]1[CH2:25][CH2:24][C@@H:23]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[F:42])[CH2:22][N:21]2[C:17]([CH:15]([NH:14][S:12]([C:8]([CH3:9])([CH3:11])[CH3:10])=[O:13])[CH3:16])=[CH:18][N:19]=[C:20]12
Reactant: CC(NS(=O)C(C)(C)C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (1 mL, 13.5 mmol) was added to a solution of tert-butyl [(6S,9R)-3-{1-[(tert-butylsulfinyl)amino]ethyl}-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (144 mg, 0.28 mmol) in dichloromethane (5 mL). After 1.5 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 411.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH2:19]([NH2:22])[C:20]#[CH:21]>>[CH2:19]([NH:22][C:13]([C:11]1[S:12][C:8]([C:5]2[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:9][CH:10]=1)=[O:15])[C:20]#[CH:21]
Reactant: C#CCN
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: C#CCNC(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and propargylamine by the method described in Example 2 Method B. Pale yellow solid (122 mg, 97%). 1H NMR (DMSO-d6) 2.41 (d, J=1.3, 3H), 3.25 (t, J=2.6, 1H), 4.13 (dd, J=5.7, 2.6, 2H), 7.79 (d, J=4.0, 1H), 7.97 (d, J=4.0, 1H), 9.29 (t, J=5.7, 1H). 19F NMR −62.30. LC/MS 6.07 min, [M+1]+ 315.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24]SCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5].[C:28](OCC)(=O)C.C(O)C>>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[CH:19]=[N:20][CH:25]=[CH:24][CH:28]=2)=[C:12]([NH2:26])[CH:11]=1)=[O:5]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: CCO
Product: COC(=O)CCNC(=O)c1ccc(NCc2cccnc2)c(N)c1

Procedure:
The same procedure is used as in (2). Rf value: 0.07 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].O[C@@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C1C=CC=CC=1>[Br:38][C:16]1[CH:17]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:19]=[C:14]([Br:13])[C:15]=1[O:39][C@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Yield: 90.4 %

Procedure:
Diethylazodicarboxylate (0.437 mL, 2.74 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (1.00 g, 1.83 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.494 g, 2.74 mmol), triphenylphosphine (0.72 g, 2.74 mmol) and benzene (12 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 3.5 h. Upon cooling to room temperature, the reaction mixture was diluted with dichloromethane and silica gel (30 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (96:4 petroleum ether:ethyl acetate) to provide the title compound as a white solid (1.20 g, 90%): mp 138-139.5° C.: NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.83 (ddd., J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J =8, 7, 1 Hz, 1 H), 7.60 (dd, J=5, 2 Hz, 2 H), 7.60-7.48 (m, 2 H), 7.46-7.28 (m, 6 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.74 (ddd, J=8, 1, 1 Hz, 1 H), 5.26 (t, J=8 Hz, 1 H), 3.76 (s, 3 H), 3.59 (dd, J=8, 5 Hz, 2 H); MS (FAB+): [M+], 3 bromine isotope pattern, 722 (30%), 724 (70%) 726 (100%) 728 (35%); Anal. Calc. for C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00. Found: C, 52.60, H, 2.68, N, 0.07.