Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:21]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCO)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 84 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (3.41 g), 3-(4-hydroxyphenyl)propanol (2.50 g), potassium carbonate (3.40 g) and N,N-dimethylformamide (25 ml) was stirred for 14 hours at 60° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propanol (4.46 g, yield 84%) was obtained from a fraction eluted with ethyl acetate-hexane (1:1, v/v) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals. m.p. 70-71° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([CH:25]=[CH2:26])[O:19]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:14][C@H:9]1[O:10][C@@H:11]([CH3:13])[CH2:12][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2](/[CH:26]=[CH:25]/[B:20]3[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:27])([CH3:17])[O:19]3)=[CH:3][CH:4]=2)[CH2:8]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(/C=C/B3OC(C)(C)C(C)(C)O3)cc2)C[C@H](C)O1
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a solution of 4-(4-bromobenzyl)-cis-2,6-dimethylmorpholine (20 g, 71 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (13 mL, 77 mmol, 1.1 eq.) in toluene (250 mL) was added triethylamine (19.7 mL, 142 mmol) and Pd(PtBu3)2 (368 mg, 0.71 mmol) and the solution was heated to 80° C. for 2 h under argon. After cooling to rt, the reaction was quenched with sat. NaHCO3 (50 mL), water (50 mL), extracted with EtOAc (3×100 mL) and dried over MgSO4. After evaporation of the solvents, the residue was purified by Biotage column system (EtOAc/hex gradient: 0-100%) to give the title compound as a white solid (16 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0 Hz, 2H), 7.40 (d, J=18.4 Hz, 1H), 7.30 (d, J=7.6 Hz, 2H), 6.16 (d, J=18.4 Hz, 1H), 3.75-3.65 (m, 2H), 3.47 (s, 2H), 2.70 (d, J=10.8 Hz, 2H), 1.75 (t, J=10.2 Hz, 2H), 1.32 (s, 12H), 1.14 (d, J=6.4 Hz, 6H); MS ESI 358.2 [M+H]+, calcd for [C21H32BNO3+H]+ 358.2.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2scc(Br)c2c1
Reactant: CSc1ccc(B(O)O)cc1
Product: COC(=O)c1ccc2scc(-c3ccc(SC)cc3)c2c1
Yield: 76 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzothiophene-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 76%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[N:4]([C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH2:5][C:6]([CH3:8])=O.Cl.[CH3:20][O:21][NH2:22].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[N:4]([CH2:5][C:6](=[N:22][O:21][CH3:20])[CH3:8])[C:9](=[O:13])[CH2:10][O:11][CH3:12]
Reactant: COCC(=O)N(CC(C)=O)c1c(C)cccc1C
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC(=O)N(CC(C)=NOC)c1c(C)cccc1C
Yield: 94.3 %

Procedure:
20 g (0.08 mol) of 2,6-dimethyl-N-methoxyacetyl-N-acetonylaniline, 7.5 g (0.09 mol) of O-methyl-hydroxylamine hydrochloride and 9.1 g (0.09 mol) of triethylamine in 100 ml of ethanol were heated under reflux for 5 hours. After distilling off the solvent in vacuo, the residue was partitioned between water/methylene chloride. The organic phase was separated off, dried over sodium sulphate and concentrated. After adding petroleum ether, the residue crystallized. 21 g (94% of theory) of 2,6-dimethyl-N-(2-methoxyimino-prop-1-yl)-N-methoxyacetylaniline of melting point 56°-57° C. were obtained.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[N:16]=[C:15]([C:17](O)([CH3:19])[CH3:18])[C:14]([F:21])=[CH:13][N:12]=1>ClCCl>[Cl:10][C:11]1[N:16]=[C:15]([C:17]([F:7])([CH3:19])[CH3:18])[C:14]([F:21])=[CH:13][N:12]=1
Reactant: CC(C)(O)c1nc(Cl)ncc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)c1nc(Cl)ncc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
Diethylaminosulfur trifluoride (6.53 g, 40.5 mmol) is added drop wise to a −78° C. solution of 2-(2-chloro-5-fluoro-pyrimidin-4-yl)propan-2-ol (4.825 g, 25.31 mmol) in dichloromethane (70 mL) under nitrogen. The reaction is stirred at −78° C. for 30 minutes under nitrogen, is then quenched with aqueous saturated sodium bicarbonate and is warmed to room temperature. The reaction mixture is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated under vacuum. The resulting crude product is purified over silica gel with a 40 minute, 5% to 100% ethyl acetate in hexanes gradient to give the title compound (4.23 g, 87%). ES/MS (m/e): (35Cl/37Cl) 193/195 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[NH2:28][CH2:29][CH2:30][OH:31]>CCN(C(C)C)C(C)C.O>[OH:31][CH2:30][CH2:29][NH:28][C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1
Reactant: NCCO
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(O)c1cc(NCCO)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1

Procedure:
A mixture of Example 9 (0.1 g, 0.25 mmol) and 2-amino ethanol (24 mg, 0.38 mmol) in DIEA (1 mL) and water (0.5 mL) was stirred at 170° C. for 2 hours. The two phases were separated and the aqueous layer concentrated in vacuo. Purification by column chromatography (increasing amount of MeOH in DCM) followed by washing with Et2O afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[CH:18]1>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:19]2[CH2:18][C:17](=[O:23])[O:22][C:20]2=[O:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)OC2=O)cc(C(C)(C)C)c1O
Yield: 56.5 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 9.8 grams of maleic anhydride, and 0.51 grams of triethylamine. The residue is recrystallized once from hexane-toluene mixture and once from cyclohexane to give 19.0 grams of a light yellow solid, m.p. 92°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BrH:18]>C(OCC)(=O)C.C(O)(=O)C.[Cu](Br)Br>[Br:18][CH:9]([S:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:17]
Reactant: Br
Reactant: O=C(CSc1ccccc1)c1ccccc1F
Agent: Br[Cu]Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1F)C(Br)Sc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 1-(2-fluorophenyl)-2-(phenylthio)ethanone (413 mg) in ethyl acetate (6 mL) were added copper (II) bromide (419 mg) and a 47% solution (2 drops) of hydrogen bromide in acetic acid and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield 503 mg, yield 92%).
Reaction SMILES: Cl[C:2]([C@H:4]1[C@H:6]([CH:7]=[C:8]([Cl:13])[C:9]([F:12])([F:11])[F:10])[C:5]1([CH3:15])[CH3:14])=[O:3].N1C=CC=CC=1.[C:22]([CH:24]([OH:38])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23]>O>[Cl:13][C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C@@H:6]1[C@H:4]([C:2]([O:38][CH:24]([C:22]#[N:23])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:26]=2)=[O:3])[C:5]1([CH3:15])[CH3:14]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the residue of (+)-cis/trans-1-chlorocarbonyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane (obtained in Example 18) was added a mixture of pyridine (0.12 g) and (+)-α-cyano-3-phenoxybenzyl alcohol (0.33 g) and the mixture thus obtained was stirred for a period of 16 hours at the ambient temperature. Water (20 ml) was added and the mixture extracted with diethyl ether (3×10 ml). The combined extracts were washed with water, saturated sodium bicarbonate solution, and water and dried over anhydrous sodium sulphate. After removal of the ether by evaporation under reduced pressure the residual oil was subjected to preparative thick-layer chromatography, using 2 mm thick silica on glass with chloroform as eluent, to yield (+)-α-cyano-3-phenoxybenzyl (+)-cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (Rf 0.52), and the corresponding trans isomers (Rf 0.42), each containing about 90-95% of the Z-isomer. Spectral data: infra red (CHCl3) 1740, 1660, 1590, 1480, 1460 cm-1 ; n.m.r. (CCl4): 6.90-7.50π, 1.60-2.70π, 1.50-1.00τ, and specific peaks at 6.3 τ (benzylic H), 6.85, 6.50, 6.11 and 5.84 π (vinylic H) tentatively assigned to the Z-cis, E-cis, Z-trans and E-trans isomers respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1.O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][CH:7]([OH:31])[C:6]=2[CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (2 gm) was suspended in methanol (48 ml) & water (12 ml) and then added sodium borohydride (0.236 gm.) at 25° C. and the reaction mixture was stirred for 1hr. To the reaction mixture was added water (12 ml) and stirred for 2 hours at 25-30° C. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (1.70 gm).
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=O>>[Cl:26][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)c(Cl)c3)cs2)c1
Yield: 75.9 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (213 mg, 1.00 mmol) obtained in Example 1b and 2-bromo-1-(3,4-dichlorophenyl)ethanone (268 mg, 1.00 mmol) to give the title compound (290 mg, 76%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.O1CCOCC1>O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Nc1ccncc1
Reactant: Fc1ccccc1-c1cc(Cl)c2cccnc2n1
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccccc1-c1cc(Nc2ccncc2)c2cccnc2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 259 mg (1.00 mmol) 4-chloro-2-(2-fluorophenyl)-[1,8]naphthyridine and 104 mg (1.10 mmol) 4-aminopyridine in 5 ml dioxane 236 mg (2.10 mmol) potassium tert.-butylate were added, the mixture heated to 80° C. and kept at this temperature for 1 hr. After cooling to ambient temperature water was added to the reaction mixture. The precipitate formed was filtered off, washed with water and dried in vacuum. This yielded [2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine as beige crystals; HPLC-MS: [M+H] 317. 1H-NMR (d6-DMSO): δ [ppm]=7.34 (d, J=5.9 Hz, 2H), 7.38 (dd, J1=11.8 Hz, J2=8.2 Hz, 1H), 7.41 (t, J=7.4 Hz, 1H), 7.57 (m, 1H), 7.66 (dd, J1=8.3 Hz, J2=4.1 Hz, 1H), 7.83 (s, 1H), 8.12 (t, J=7.8 Hz, 1H), 8.46 (d, J=5.9 Hz, 2H), 8.81 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 9.1 (dd, J1=4.3 Hz, J2=1.8 Hz, 1H), 9.67 (bs, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH:11]=[CH:10][C@H:9]([N:12]2[C:16]3[N:17]=[C:18]([S:22][CH2:23][CH2:24][CH3:25])[N:19]=[C:20](Cl)[C:15]=3[N:14]=[N:13]2)[C:6]21[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[C:26]1([C@@H:32]2[CH2:34][C@H:33]2[NH2:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.OC(C(O)C([O-])=O)C([O-])=O.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([O:4][C@@H:5]1[CH:11]=[CH:10][C@H:9]([N:12]2[C:16]3[N:17]=[C:18]([S:22][CH2:23][CH2:24][CH3:25])[N:19]=[C:20]([NH:35][C@@H:33]4[CH2:34][C@H:32]4[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:15]=3[N:14]=[N:13]2)[C:6]21[CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CCCSc1nc(Cl)c2nnn([C@H]3C=C[C@@H](OC(C)=O)C34CC4)c2n1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccccc2)c2nnn([C@H]3C=C[C@@H](OC(C)=O)C34CC4)c2n1

Procedure:
To a solution of the product of step f) (0.5 g) and (1R-trans)-2-phenyl-cyclopropanamine, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described by L. A. Mitscher et al., J. Med. Chem. 1986, 29, 2044) (0.4 g) in dichloromethane (50 ml) was added N,N-diisopropylethylamine (2 ml) and the resulting solution was stirred and heated at reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by chromatography (SiO2; 4:1 isohexane:ethyl acetate) to give the subtitle compound (0.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Cl:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Cl:31]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.75 mmol) in dry CHCl3 (20 mL), NCS (0.08 g, 0.6 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×100 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by Flash column chromatography to yield ethyl 2-(4-amino-3-chloro-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.15 g) as thick syrup.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](Cl)=[O:18].Cl.[C:21]1([C:27]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:46]1([C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH:34]3[C:17](=[O:18])[CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH3:8])[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: COc1ccccc1CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)C1NCC2C1C(c1ccccc1)(c1ccccc1)CC(O)C2(O)c1ccccc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
4.2 cm3 of triethylamine and then 2.4 g of (2-methoxyphenyl)acetic acid chloride in 50 cm3 of dichloromethane are added to a solution of 4.5 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindole-4,5-diol hydrochloride in 100 cm3 of dichloromethane, cooled to 0° C. The reaction mixture is stirred at room temperature for 90 minutes; it is washed with twice 10 cm3 of water, and is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid which has crystallized is taken up in. 100 cm3 of diisopropyl ether and then filtered off and washed with 50 cm3 of a saturated solution of sodium bicarbonate and then 50 cm3 of diisopropyl ether. 4.35 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(2-methoxyphenyl)- acetylperhydroisoindole-4,5-diol are obtained in the form of a light beige solid which melts at 278° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@:20]([O:51][CH3:52])([NH:21][C:22](=[O:50])[C:23](=[N:29][O:30]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:53])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(=O)(O)[O-].[Na+]>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([NH:21][C:22](=[O:50])[C:23](=[N:29][OH:30])[C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)([O:51][CH3:52])[C:19](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CO[C@@]1(NC(=O)C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccco2)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO[C@@]1(NC(=O)C(=NO)c2ccco2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21

Procedure:
t-Butyl (6R,7S)-3-acetoxymethyl-7-methoxy-7-[2-triphenylmethoxyimino-2-(fur-2-yl)-acetamido]-ceph-3-em-4-carboxylate (syn isomer) (713.3 mg, 0.966 mmole) was treated with trifluoroacetic acid (10 ml) and anisole (5 ml) for a total of 40 mins. and then added slowly to rapidly stirred saturated aqueous sodium bicarbonate (600 ml.). The mixture was extracted with ethyl acetate (2×150 ml), covered with ethyl acetate (200 ml), and adjusted to pH 2 with orthophosphoric acid. The organic layer was combined with the ethyl acetate wash (200 ml) of the aqueous layer, dried, and evaporated to a brown foam. Chromatography on three 40 × 20 cm. preparative-layer plates in chloroform-methanol-formic acid (90:16:2) provided a sample of the title compound as a pale-yellow foam containing ca 21/2mole-equivalents water (i.r. and microanalysis) (137 mg, 0.283 mmole, 29%) paper chromatography Rf 0.26, Rf/Rf cephaloram 0.58, λmax (pH 6 buffer) 272.5 nm (ε 16,400).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:20]1([CH2:23][C:24](O)=[O:25])[CH2:22][CH2:21]1>>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:24](=[O:25])[CH2:23][CH:20]1[CH2:22][CH2:21]1)=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CC1CC1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Product: O=C(CC1CC1)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 114 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and cyclopropylacetic acid. m.p.: 72-75° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[N:23]=1>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:30]#[C:29][C@@:27]([OH:31])([C:24]4[N:23]=[C:22]([CH3:21])[O:26][N:25]=4)[CH3:28])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(=O)O)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 35 °C

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (150 mg, 0.39 mmol) in piperidine (1.5 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (45.5 mg, 0.04 mmol), copper(I) iodide (7.4 mg, 0.04 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (120 mg, 0.79 mmol). The reaction was warmed to 35° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (eluent: DCM containing a 1-15% MeOH gradient followed by 85:15 DCM:7M ammonia in methanol). The partially purified product was suspended in 2M aqueous citric acid (3 mL) and extracted with 3:1 chloroform/isopropanol (5×5 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to furnish the title compound as a yellow-brown solid: 1H NMR (500 MHz, DMSO) delta 1.91 (3H, s), 2.64 (3H, s), 6.81 (1H, s), 7.27 (1H, d, J=5.9 Hz), 7.54 (1H, dd, J=8.4, 1.2 Hz), 7.80 (2H, s), 8.22 (1H, d, J=8.3 Hz), 8.42 (1H, d, J=6.0 Hz), 8.97 (1H, s), 13.92 (1H, s); LC-MS: m/z=+406.00 (M+H)+.