Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:15]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH:23]([CH3:25])[CH3:24])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20][CH2:21][NH:22][CH:23]([CH3:24])[CH3:25])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(C)NCCCNC(C)C
Product: COc1ccc(S(=O)(=O)N(CCCNC(C)C)C(C)C)cc1OC

Procedure:
3,4 Dimethoxybenzenesulfonyl chloride was reacted with N,N'-diisopropylpropane-1,3-diamine by procedures following those given in Example 1 and chromatographed on Dry-column alumina with 10% methanol/ethyl acetate to provide the title compound. Treatment of this material with isopropanol/HCl gave the hydrochloride salt, m.p. 132°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[CH:68]=[CH:67][C:62]3[NH:63][C:64]([NH2:66])=[N:65][C:61]=3[CH:60]=2)[CH:52]=[CH:53][C:54]=1[C:55]([F:58])([F:57])[F:56].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[CH:68]=[CH:67][C:62]3[NH:63][C:64]([NH:66][C:11]([C:9]4[N:10]=[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]5[CH:8]=4)=[O:13])=[N:65][C:61]=3[CH:60]=2)[CH:52]=[CH:53][C:54]=1[C:55]([F:57])([F:58])[F:56]
Reactant: Nc1nc2cc(-c3ccc(C(F)(F)F)c(Cl)c3)ccc2[nH]1
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(-c3ccc(C(F)(F)F)c(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Temperature: 80 °C
Yield: 89.6 %

Procedure:
A mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid (600 mg), HBTU (900 mg), DIEA (1 mL) and 5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (794 mg) in DMF (5 mL) was heated at 80° C. for 1 hour with stirring. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution was added, and the mixture was stirred for 30 minutes at room temperature. The solid was filtered, washed with water, and dried under vacuum to get 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (890 mg). LCMS (m/z): 491.8.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].[Li+].[OH-].Cl.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.[NH2:65][CH2:66][C:67]([C:69]1[CH:74]=[CH:73][C:72]([Br:75])=[CH:71][CH:70]=1)=[O:68]>C1COCC1.CO>[C:13]([O:12][C:10]([N:8]1[CH2:9][CH:5]([C:3](=[O:4])[NH:65][CH2:66][C:67]([C:69]2[CH:74]=[CH:73][C:72]([Br:75])=[CH:71][CH:70]=2)=[O:68])[N:6]([C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:20])[CH3:21])[CH2:7]1)=[O:11])([CH3:15])([CH3:16])[CH3:14]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (460 mg, 1.18 mmol) was dissolved in THF (3 mL) and MeOH (2 mL). An aqueous solution of LiOH (49.8 mg, 1.18 mmol) was added and stirring at room temperature was continued. After the hydrolysis was complete, the reaction was neutralized with aqueous HCl (1.18 mL, 1M). The organic solvents were removed in vacuo and the aqueous suspension was frozen and lyophilized. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (4.0 mL) and HATU (448 mg, 1.18 mmol) and DIEA (152 mg, 1.18 mmol) were added. The reaction was stirred at room temperature for five minutes, after which the amino-(4′bromo) acetophenone hydrochloride salt (295 mg, 1.18 mmol) was added. Stirring at room temperature was continued. After 90 minutes, all volatiles were removed in vacuo and the crude material was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the slightly impure product 4-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1-carboxylic acid tert-butyl ester (723 mg): LCMS-ESI+: calc'd for C24H33BrN4O7: 569.4 (M+). Found: 570.4/572.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:31][CH:30]=3)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][O:44][CH2:45][CH2:46][O:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][CH:54]=1.[OH-].[NH3+]N.CCOCC>O.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[C:19]([C:56]3[CH:55]=[CH:54][C:53]([CH2:52][CH2:51][CH2:50][O:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH3:43])=[CH:58][CH:57]=3)[CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:31][CH:30]=3)[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Oc1cc(-c2ccc(OCc3ccccc3)cc2)cc(-c2ccc(OCc3ccccc3)cc2)c1)C(F)(F)F
Reactant: COCCOCOCCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: N[NH3+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOCCCc1ccc(-c2cc(-c3ccc(OCc4ccccc4)cc3)cc(-c3ccc(OCc4ccccc4)cc3)c2)cc1

Procedure:
4.00 g (6.78 mmol) trifluoromethanesulfonic acid-4,4″-bis-benzyloxy-[1,1′;3′,1″]terphenyl-5′-yl ester, 2.37 g (6.78 mmol) 2-{4-[3-(2-methoxyethoxymethoxy)-propyl]-phenyl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 2.85 g (20 mmol) sodium metaborate-tetrahydrate are dissolved in 8 ml water and 20 ml THF. 97 mg (0.135 mmol) bis(triphenylphosphine)palladium(II)chlorid and 0.01 ml hydraziniumhydroxide are added and the mixture is heated at reflux for 5 h. MTB ether is added, the aqueous layer is separated and extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is filtered through silica gel with dichloromethane/MTB ether (95:5), to give 4,4″-bis-benzyloxy-5′-(4-[3-(2-methoxy-ethoxymethoxy)-propyl]-phenyl)-[1,1′;3′,1″]terphenyl as a brown oil which is reacted in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: O=C1CCc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C1CCc2cc(-n3cccn3)ccc21
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Combine 5-fluoro-indan-1-one (1.02 g, 6.79 mmol), pyrazole (0.46 g, 6.79 mmol), and potassium carbonate (1.03 g, 7.47 mmol, 1.10 equivalents) in dimethyl sulfoxide (5 ml) in a sealed tube and heat to 100° C. for 48 hours. Cool to room temperature, dilute with ether, wash with water (2×), dry over anhydrous sodium sulfate, and concentrate to obtain the title compound as a brown solid (0.98 g, 73%). LC-MS m/z 199.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:19]([NH:18][C:7]([C:5]5[C:4](=[O:10])[N:3]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=6[CH3:17])[N:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:20][C:21]=4[F:41])=[CH:29][N:28]3[CH:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Cc1ccccc1-n1c(=O)c(C(=O)O)cn1C
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-n1c(=O)c(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)cn1C
Yield: 69.4 %

Procedure:
In the same manner as in Example 46 and using 1-methyl-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (370 mg, 1.6 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (260 mg, 0.80 mmol), HATU (610 mg, 1.6 mmol), N,N-diisopropylethylamine (410 mg, 3.2 mmol) and N,N-dimethylformamide (12 mL) as starting materials, the title compound (300 mg, 70%) was obtained as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][CH2:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][C:27](=[O:32])[N:28]3[CH3:31])=[CH:23][C:22]=2[O:33][CH3:34])[C@@H:14]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[S:12])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][CH2:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][C:27](=[O:32])[N:28]3[CH3:31])=[CH:23][C:22]=2[O:33][CH3:34])[CH:14]1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[S:12]
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(C(=S)NCCNC(=O)OC(C)(C)C)[C@H]1c1ccccc1)N(C)C(=O)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1CNC1CCCN(C(=S)NCCN)C1c1ccccc1)N(C)C(=O)CC2

Procedure:
[2-({3-[(6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-amino]-(2S,3S)-2-phenyl-piperidine-1-carbothioyl}-amino)-ethyl]-carbamic acid tert-butyl ester (800 mg, 1.38 mmol) was stirred in a mixture of 30 mL methylene chloride and 10 mL trifluoroacetic acid at room temperature for 4 hours. The solvent was removed and the residue was partitioned between ethyl acetate and satd. K2CO3. The organics were separated, dried over MgSO4, filtered, and concentrated to give 3-[(6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-amino]-2-phenyl-piperidine-1-carbothioic acid (2-amino-ethyl)-amide. Rf=0.18 (90:10:1 methylene chloride/methanol/satd. aq. NH4OH).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].Cl[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([CH:1]=[O:2])[C:4]=1[O:13][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: COC(=O)c1cccc(C=O)c1O
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C=O)c1OCC(=O)O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
A mixture of 3.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.31 g of t-butyl chloroacetate, 12.0 g of potassium carbonate and 40 ml of dimethylformamide is heated at 70° C. for 2.5 hours. After cooling, the reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is dissolved in trifluoroacetic acid and the solution is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is treated with ether to give 2.09 g of (2-methoxycarbonyl-6-formylphenoxy)acetic acid as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a mixture of (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (150 mg, 0.31 mmol) in 10 ml DCM was added TFA (10 ml). The reaction mixture was stirred at RT for 2 h. Solvent was removed and sat. NaHCO3 (10 mL) was added. The resulting mixture was extracted with DCM. The organic layer was dried and concentrated to afford (R)-5-(4-phenoxyphenyl)-7-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 83% in yield), which was subjected to the next step without any further purification.
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.CO.C(=O)(O)[O-].[Na+]>O>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of 7-ACA, 6 g of stannic chloride and 1.0 g of methanol The mixture was heated at 30° C. for 60 min while stirring to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 100 ml of water. Then, the mixture was adjusted to pH 8.0 with sodium bicarbonate at a temperature of from 0° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid, and then concentrated by evaporation under reduced pressure so that a precipitate was formed. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 5 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.49 g. The yield of the desired product was 20 %.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[C:6]([C:17](F)(F)F)=[CH:5]1)(=O)C.[NH3:21]>O1CCOCC1>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]([C:17]#[N:21])=[CH:5][NH:4][CH:8]=1
Reactant: CC(=O)n1cc(-c2cccc(Cl)c2Cl)c(C(F)(F)F)c1
Reactant: N
Solvent: C1COCCO1
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
6.4 g of N-acetyl-4-(2,3-dichlorophenyl)-3-trifluoromethylpyrrole, 15 ml of 25% aqueous ammonia solution and 60 ml of dioxane are stirred for 18 hours at 160° C. in an autoclave. The reaction mixture is cooled to room temperature and filtered, and the clear filtrate is concentrated by evaporation. The viscous residue is dissolved in ethyl acetate; the solutiion is washed firstly with water and then with a diluted sodium chloride solution; it is subsequently dried over sodium sulfate, filtered, and concentrated by evaporation. To the residue is added n-hexane, and the crystals which precipitate are filtered off and dried. The yield is 5.3 g of 4-(2,3-dichlorophenyl)-3-cyanopyrrole, m.p. 149°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[CH:25][N:26]2[NH2:29])=[CH:22][CH:21]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[CH:25][N:26]2[NH:29][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])=[CH:22][CH:21]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Nn1ccc2ccc(C(F)(F)F)cc21
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2ccc(C(F)(F)F)cc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (278 mg, 1.2 mmol) and 6-trifluoromethyl-indol-1-ylamine (200 mg, 1 mmol) in DMF (5 mL) is stirred at 50° C. for 0.5 h. The mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with Et2O/heptane overnight. The precipitate is collected by filtration, washed with H2O (50 mL) and heptane (50 mL), and dried in vacuo to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (6-trifluoromethyl-indol-1-yl)-amide (180 mg, 44%). MS: 415 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.09 (s, NH, 1H), 9.33 (s, 1H), 8.35 (d, 1H), 8.20 (d, 1H), 7.90 (s, 1H), 7.79 (m, 2H), 7.65 (m, 1H), 7.46 (m, 2H), 6.74 (d, 1H), 2.79 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:17]=2[CH2:18][CH2:19][CH:20]2[O:22][CH:21]23)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(OCC)C.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:17]3[CH2:18][CH2:19][C:20](=[O:22])[CH2:21][C:23]=3[CH:24]=[CH:25][CH:26]=2)[C:10](=[O:15])[C:11]([F:12])([F:14])[F:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC2OC32)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC(=O)C3)cc1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A solution of N-(4-cyanophenyl)-2,2,2-trifluoro-N-(1a,2,3,7b-tetrahydronaphth[1,2-b]oxiren-4-yl)acetamide (2.8 g, 7.8 mmol) in diethyl ether (80 ml) was treated with BF3.Et2O (2.0 ml, 16 mmol) and the resulting suspension was stirred at room temperature. The suspension was diluted with methylene chloride after 1 and 3 hours (80 and 40 ml) and additional BF3.Et2O (2×1.0 ml, 16 mmol) was added at 2 and 4 hour intervals. The reaction mixture was stirred overnight, then saturated NaHCO3 solution (70 ml) slowly added. The aqueous phase was separated and extracted with methylene chloride (40 ml). The organic solutions were dried (K2CO3), concentrated in vacuo, and the residue purified by chromatography on silica gel with diethyl ether:hexane (2:3 to 1:1) to give N-(4-cyanophenyl )-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide (1.17 g). 1H NMR (CDCl3, 200 MHz) δ: 2.44 (t, J=7 Hz, 2H, CH2), 2.69 (dt, J=16,7 Hz, 1H, CH2), 3.03 (dt, J=16,6 Hz, 1H CH2), 3.63 (strongly coupled AB pair, 2H, C5H2), 7.25-7.45 (m, 5H, Ar), 7.67 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H13F3N2O2 : C, 63.69; H, 3.66; N, 7.82. Found: C, 63.75; H, 3.72; H, 7.74.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=[C:5]2[C:16]([CH3:19])([CH3:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>C1COCC1>[C:16]([C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([C:25](=[O:27])[CH3:26])[CH:3]=2)[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1cc2c(cc1Br)C(C(C)(C)C)=CC(C)(C)O2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(C)=O)C(C(C)(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure H, a solution of 6-bromo-4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromene (Compound 15, 280 mg, 0.86 mmol) in THF was treated with tributyl(1-ethoxyvinyl)tin (0.58 mL, 1.7 mmol) to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:17]([O:27][CH3:28])=[N:18][CH:19]=[C:20]([Br:26])[C:21]=1[C:22]([F:25])([F:24])[F:23])[OH:15]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:17]([O:27][CH3:28])=[N:18][CH:19]=[C:20]([Br:26])[C:21]=1[C:22]([F:25])([F:23])[F:24])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(OC)ncc(Br)c2C(F)(F)F)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(Br)c2C(F)(F)F)c(OC)c1OC
Temperature: 25 °C
Yield: 82.2 %

Procedure:
20.0 g (230 mmol) of manganese dioxide was added to a solution having 4.80 g (10.3 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(5-bromo-4-trifluoromethyl-2-methoxy-3-pyridyl)methanol obtained in Step (c) dissolved in 110 ml of toluene, followed by stirring under reflux with heating for 1 hour. After cooling to room temperature, the mixture was subjected to filtration on the pad of celite and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3.93 g (yield: 82%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-bromo-4-trifluoromethyl-2-methoxypyridine (Compound No. 31).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:19]([O:52][CH3:53])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:50][CH3:51])[C@@H:29]([CH3:49])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[C@@H:4]([CH3:6])[OH:5].C=O.[C:60]([BH3-])#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:60])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:19]([O:52][CH3:53])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:50][CH3:51])[C@@H:29]([CH3:49])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[C@@H:4]([CH3:6])[OH:5]
Reactant: [BH3-]C#N
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)[C@@H](C)O)C(C)C
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H]([C@@H](C)O)N(C)C)C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
84 mg (0.105 mmol) of N-methyl-L-threonyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]-pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Example 19) were taken up in 5 ml of dioxane/water (1:1), and 31 μl (0.418 mmol) of a 37% strength aqueous formaldehyde solution and 8 mg (0.126 mmol) of sodium cyanoborohydride were added. Using 1 ml of 0.1 N hydrochloric acid, the mixture was then adjusted to pH 6-7 and stirred at 100° C. for 1 h. The reaction was then poured into a mixture of semisaturated aqueous sodium bicarbonate solution and ethyl acetate. The organic phase was separated off, washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was finally lyophilized from acetonitrile/water. This gave 72 mg (84% of theory) of the title compound in the form of a colourless foam.