Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[C:21](/[CH3:25])=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>>[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[CH:17][C:18](/[C:21](/[CH3:25])=[CH:22]/[CH2:23][O:24][C:39]3[CH:38]=[CH:37][C:36]([CH2:35][C@H:29]([O:28][CH2:26][CH3:27])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:41][CH:40]=3)=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)OCC
Yield: 74.1 %

Procedure:
The title compound (429 mg, 74%) was prepared as a colourless gum from (E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol (350 mg, 1.04 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (260 mg, 1.09 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].[N:30]#[C:31]Br>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:11][CH2:12][N:13]([C:31]#[N:30])[CH2:14][CH2:15]1
Reactant: N#CBr
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-((1R,2S)-2-{2-{2-fluoro-4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidine (Step C, Example 111; 150 mg, 0.428 mmol) and potassium carbonate (244 mg, 1.77 mmol) were stirred in chloroform (7 mL). Cyanogen bromide (61 mg, 0.58 mmol) was added. The mixture was stirred at RT for 15 min and refluxed overnight. The mixture was cooled to RT, mixed with silica gel (5 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (97.5:2.5, 1 L to provide the title compound as an white solid. MS (Multimode) m/z 367 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[CH:28](OCC)(OCC)OCC>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:19]([C:20]4[O:21][CH:28]=[N:23][N:22]=4)[CH:18]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Reactant: CCOC(OCC)OCC
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnco3)c1)C2=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (200 mg, 0.52 mmol) obtained in Step 2 was suspended in triethyl orthoformate (10 mL), and the mixture was stirred at 100° C. for 24 hours. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(1,3,4-oxadiazol-2-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (165 mg, 80%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]O)#[N:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:31]([C:33]1[CH:34]=[C:35]([CH2:36][O:13][C:14]2[CH:15]=[C:16]([O:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:38]=[CH:39][CH:40]=1)#[N:32]
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Reactant: N#Cc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
Diethyl azodicarboxylate (174 mg, 1.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285 mg, 1.0 mmol), as prepared in the preceding step, 3-cyanobenzyl alcohol (133 mg, 1.0 mmol)(Yoon et al, J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofuran (10 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated NaHCO3 (2×30 mL), brine (2×30 mL) and dried over Na2SO4. The solvent was removed in vacuo the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a pale yellow oil (375 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 5.02 (s, 2 H), 6.78 (m, 2 H), 6.85 (dd, 1 H, J=4.2, 1.3 Hz), 7.20 (t, 1 H, J=8.2 Hz), 7.38 (t, 1 H, J=5.8 Hz), 7.51 (t, 1 H, J=7.7 Hz), 7.59-7.68 (m, 5 H) and 7.93 (dd, 1 H, J=4.0, 0.7 Hz).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CO>[C@@H:6]1([NH:24][C:25]([N:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN1CCNCC1
Solvent: CO
Product: CN1CCN(C(=S)N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine(1.102 g., 0.002 mole) was added to a solution of N-methylpiperazine(2.40 g., 0.024 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered and the filtrate was evaporated to a brownish heavy syrup below 30° in vacuo. The residual syrup was dissolved in the minimum amount of acetone, and anhydrous ether was added to the solution to give a sticky precipitate. The supernatant was decanted, and the residual solid was dissolved in the minimum amount of methanol. Anhydrous ether was added to the solution to give a yellow precipitate. The solid was filtered, partially dissolved in ethyl acetate, and then chromatographed on a column of silica gel(1×20 cm) using ethyl acetate as the first solvent(50 ml.) and methanol as the second solvent(200 ml.). The 200 ml. of methanol effluent was reduced to ca. 20 ml. and was set aside at 5° for 24 hours. The white precipitate was filtered, washed with methanol, and dried at room temperature in vacuo, yielding 0.325 g.(50.6%); m.p. 175°-177°(dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:17]([NH:25][C@@H:26]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:27]([OH:31])[C:28](O)=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:28](=[O:29])[C@H:27]([OH:31])[C@@H:26]([NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:3][CH:4]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: O=C(N[C@@H](c1ccccc1)[C@@H](O)C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)[C@H](O)[C@@H](NC(=O)c2ccccc2)c2ccccc2)cc1

Procedure:
Analogously to Example 1, Process step 1, 33 mg (0.15 mmol) of tert-butyl (4-aminobenzyl)carbamate and 43 mg (0.15 mmol) of (2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionic acid were dissolved in 1 ml of DCM and 1 ml of DMF and treated successively with 78 μl of DIPEA (0.45 mmol), 22.5 mg of HOAt (0.165 mmol) and 76.9 mg (0.165 mmol) of PyBrop. Without further work-up, the batch obtained was filtered and then purified using HPLC. The product-containing fractions were lyophilized.
Reaction SMILES: C(OCCN(C1C=CC(C([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)=O)=CC=1)C(=O)CCl)(C)C.Cl.N.N[C@H](C(NCC(O)=O)=O)CS>C(Cl)Cl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]2)=[CH:27][CH:28]=1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Agent: N
Agent: N[C@@H](CS)C(=O)NCC(=O)O
Solvent: ClCCl
Product: Clc1ccc(CCN2CCNCC2)cc1

Procedure:
Analogously to Example 1, 1.6 g of 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetyl-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine--freed from the corresponding hydrochloride by treatment with a mixture of aqueous ammonia solution/methylene chloride--are reacted with 0.55 g of L-cysteinyl-glycine, yielding 1-{{4-{N-2-isopropoxyethyl)-N-[[[2R]-2-[N'-(carboxymethyl)carbamoyl]-2-amino-ethylmercapto-acetyl]]-amino}-benzoyl}}-4-[2-(4-chlorophenyl)-ethyl]-piperazine. The hemihydrate thereof has a melting point of 85°-87° and an αD25 =-1.5° (c=0.545%, methanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24](OC)[N:23]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[N:7][C:2]([NH:28][C:27]2[C:22]([O:21][CH3:20])=[N:23][C:24]([P:15]([CH3:17])([CH3:12])=[O:16])=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)ncc2Cl)cc1
Reactant: COc1ccc(N)c(OC)n1
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccc(P(C)(C)=O)cc2)n1

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with 2,6-Dimethoxypyridin-3-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].S(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:3]([C:9]([F:10])([F:11])[F:12])=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=S(Cl)Cl
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Product: Oc1ccc(F)c(C(F)(F)F)c1Cl

Procedure:
4-Fluoro-3-(trifluoromethyl)phenol was chlorinated with thionyl chloride to afford 2-chloro-4-fluoro-3-(trifluoromethyl)phenol.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[NH:5][C:4](=[O:10])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C@H:40]2[CH2:42][C@@H:41]2[CH2:43]O)=[N:32]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[N:5]=[C:4]([O:10][CH2:43][C@H:41]2[CH2:42][C@@H:40]2[C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]([CH3:30])[N:32]=2)[CH:3]=1
Reactant: Cn1[nH]c(=O)cc(Br)c1=O
Reactant: Cn1nc([C@H]2C[C@@H]2CO)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nc(OC[C@H]2C[C@@H]2c2nn(C)c3ccccc23)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-1-methyl-1,2-dihydropyridazine-3,6-dione (300 mg, 1.485 mmol) in THF (20 mL) at 0° C. was added PPh3 (781 mg, 2.97 mmol) and ((1S,2S)-2-(1-methyl-1H-indazol-3-yl)cyclopropyl)methanol (300 mg, 1.485 mmol) followed by dropwise addition of DIAD (0.6 mL, 2.97 mmol). The reaction mixture was warmed to ambient temperature. After stirred for 2 h, the mixture was concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EA (2/1) to give the title compound as oil.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: Cc1cccc(-c2nc(C)c(C)cc2O)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3cccc(C)n3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,6′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (157 mg), cesium carbonate (229 mg), and 4-(N,N-dimethylamino)-pyridine (86 mg), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (17 mg, yield 18%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH:8]([S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11])=[CH2:9].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCOCC1>[CH:8]([S:10]([CH2:13][CH2:14][N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])(=[O:12])=[O:11])=[CH2:9]
Reactant: C=CS(=O)(=O)C=C
Reactant: O=C1C=CC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CS(=O)(=O)CCN1C(=O)C=CC1=O
Temperature: 45 °C
Yield: 84.8 %

Procedure:
In a 50 mL round bottom flask, a mixture of 0.5 g of maleimide, 0.61 g of divinylsulfone and 10 g of 1,4-dioxane was heated to 40-50° C. and stirred. To the reaction solution was added 0.67 g of 40% aqueous tetrabutylammonium hydroxide solution. Subsequently, the mixture was stirred at 40-50° C. for 3 more hours. After stopping stirring, the reaction solution was cooled to room temperature and precipitated and dispersed in 100 mL of methanol. The resultant precipitate was filtered, redispersed in a large volume of clean water, filtered again and washed to remove salt. Then, the product was redispersed in 50 mL of methanol, filtered and dried to obtain 0.94 g of N-vinylsulfonylethylmaleimide (yield=61%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[C:11]([CH3:16])=[CH:10]2)[CH3:2]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Product: CCOC(=O)C(Cc1ccc2c(c1)cc(C)n2Cc1nc(-c2ccc(C(C)C)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole to give rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.[C:28]1([CH2:34][C:35](Cl)=[S:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:35](=[S:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:5]2[S:4]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: S=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Temperature: -15 °C
Yield: 90.2 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.0 g) was suspended in dried dichloromethane (50 ml) and then dissolved by adding triethylamine (0.72 g) and dimethylamiline (1.9 g) under cooling at -15° C. To a mixture was dropwise added a solution of phenylthioacetyl chloride (2.2 g) in dried dichloromethane (10 ml) under stirring, and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, ether was added to the residue, after which the precipitated crystals were collected by filtration and dried to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (3.4 g), mp 140° to 142° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[N:18][O:19][CH3:20])[C:14]([NH:16][CH3:17])=[O:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:3][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[C:13](=[N:18]\[O:19][CH3:20])/[C:14]([NH:16][CH3:17])=[O:15]
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: O=S(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CNC(=O)/C(=N/OC)c1ccccc1CCl
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Thionyl chloride (3.0 ml) was added to a mixture of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (3.0 g), tetrabutylammonium chloride (380 mg) and toluene (30 ml) at room temperature. The mixture was stirred for 10 minutes, and then stirred at 60° C. for 1.5 hours. After the mixture was cooled by allowing it to stand, the solvent was evaporated under reduced pressure. The residue was dissolved in diethyl ether, and washed successively with water and saturated brine. The ether layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in a small amount of diethyl ether. Hexane was added to the solution to obtain the title compound as crystals (2.6 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:37][C:38]([F:53])([F:52])[C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=1B(O)O>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([C:40]3[CH:41]=[CH:42][C:43]([C:45]([F:48])([F:46])[F:47])=[CH:44][C:39]=3[C:38]([F:37])([F:52])[F:53])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(Cc1c[nH]c2c(OS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1c[nH]c2c(-c3ccc(C(F)(F)F)cc3C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 89.2 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (262 mg, 0.600 mmol) in dimethylformamide (3.5 mL) is added triethylamine (0.11 mL, 0.780 mmol), tetrakis(triphenylphosphine)-palladium (28 mg, 0.0240 mmol) and 2,4-bistrifluoromethylbenzeneboronic acid (201 mg, 0.780 mmol). The mixture is heated to 100° C. for 20 hours, then cooled, diluted with brine and ethyl acetate. The organics are washed seven times with brine then dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue is purified using silica gel chromatography (hexane/20% ethyl acetate, hexane gradient elution) to give 268 mg of {2-[7-(2,4-Bis-trifluoromethyl-phenyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (89%). FDMS m/e=501 (M++1).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:27]1([O:26][C:20]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([NH:17][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][C:11]([F:15])=[C:10]([F:16])[CH:9]=3)[CH2:14]2)=[O:31])[CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2cc(F)c(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3cc(F)c(F)cc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
The mixture 2-(2-cyclobutoxy-3-methyl-benzoylamino)-5,6-difluoro-indan-2-carboxylic acid ethyl ester (104) (367 mg, 0.85 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate formed. After the filtration, the solid is purified by HPLC to give a pure product (105) as white solid (300 mg, 88%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:12][CH3:13])=[S:11])[CH3:2].[CH:14]([CH:16]=[O:17])=[O:15].NC(N)=S>C(COC)OC.C(N(CC)CC)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:14]([OH:15])[CH:16]([OH:17])[N:12]([CH3:13])[C:10]1=[S:11])[CH3:2]
Reactant: CCc1ccccc1NC(=S)NC
Reactant: O=CC=O
Agent: NC(N)=S
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCc1ccccc1N1C(=S)N(C)C(O)C1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
30.0 g of N-(2-ethyl-phenyl)-N'-methyl-thiourea were stirred in 200 ml of dimethoxyethane and 10 ml of triethylamine, and 36.0 g of a 30% strength aqueous glyoxal solution were added. The mixture was stirred for 1 hour at 20° C. and for 1 hour at 50° C., the thiourea dissolving completely. The solvent was distilled off in vacuo, the residue was stirred with water and a little dilute acetic acid and the oily reaction product was taken up in methylene chloride. The methylene chloride solution was washed with water, dried over potassium carbonate, concentrated and completely freed from the solvent at 60°/1.0 mm Hg. This gave 26.0 g of the reaction product as a viscous oil which slowly solidified. The elementary analysis and the NMR spectra were in agreement with the supposed structure.