Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:31][C@H:28]1[CH2:29][CH2:30][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27]1)=[O:18]
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and (3S)-1-benzylpyrrolidin-3-ylamine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 50:50:1, changing to 20:80:1, by volume, hexane:ethyl acetate: 0.88 aqueous ammonia solution, in 10% increments. The product was further purified by recrystallisation from ethyl acetate:hexane to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3S)-1-benzylpyrrolidin-3-yl]-2-piperidinecarboxamide as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:10]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: c1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A solution of benzo[d][1,3]dioxole (6.1 g, 50.00 mmol, 1.00 equiv) and N-bromo-succinamide (NBS) (9.3 g, 52.5 mmol, 1.05 equiv) in CHCl3 (25 mL) in a 100-mL round-bottom flask and allowed to react, with stirring, for 3 hr while the temperature was maintained at reflux. The resulting mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate:petroleum ether (1:20)) giving 9.5 g (90%) of 5-bromobenzo[d][1,3]dioxole as yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([C:11]([OH:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].C([O-])(=O)C.[Zn+2:18].C([O-])(=O)C>O>[CH2:1]([O:4][C:5]1[C:6]([C:11]([O-:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].[Zn+2:18].[CH2:1]([O:4][C:5]1[C:6]([C:11]([O-:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cccnc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Product: CCCOc1cccnc1C(=O)[O-]
Yield: 51.1 %

Procedure:
To a solution of 0.85 g (4.7 mmol) of 3-propoxypicolinic acid dissolved in 35 ml of water was dropwise added, while stirring, a solution of 0.52 g (2.3 mmol) of zinc acetate.dihydrate dissolved in 2 ml of water. After the dropwise addition, the mixture was stirred at room temperature for 60 minutes. When left to stand in a refrigerator overnight, no crystal was obtained, and therefore, the mixture was subjected to concentration under a reduced pressure. The solid precipitated was recrystallized from ethanol to obtain 0.50 g of crystals (yield 47.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(CC)=O>[CH2:22]([N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Clc1ccc(CC2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCN1CCCC1Cc1ccc(Cl)cc1

Procedure:
Boil 5 g of 2-(4-chlorobenzyl)pyrrolidine, 3.53 g of anhydrous potassium carbonate, 3.4 g of allyl bromide and 50 ml of ethyl methyl ketone under reflux for 1 hour. Evaporate off the solvent. Take up the residue with 50 ml of water and extract 3 times with, in each case, 30 ml of diethyl ether. Combine the ether phases and dry them over sodium sulfate. Distil off the solvent from the combined ether extract and distil the resulting residue under a vacuum to obtain 5.12 g (85% of theory) of the title compound (b.p. 84° to 87° at 0.005 mm of Hg). m.p. of the picrate (from ethanol): 115° to 117°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][SH:18].CS(O[C@@H:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]1)(=O)=O>CN(C)C=O>[C:32]([O:31][C:30]([NH:29][C@H:26]1[CH2:27][CH2:28][C@H:24]([S:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[O:6][C:2]=2[CH3:1])[CH2:25]1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c(C)o2)cc1
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
To a solution of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (920 mg, 3.49 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) maintained under an inert atmosphere of nitrogen was added cescium carnonate (2.3 g). The mixture was stirred for 20 min then tert-butyl N-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate (1.0 g, 3.58 mmol, 1.02 equiv) was added. The resulting solution was stirred at 35° C. for 50 min then the product was precipitated by the addition of 50 mL water. The precipitate was collected by filtration, washed with water and then dried under vacuum to give 1.37 g (88%) of methyl 4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 447 [M+H]+, 391, 271, 230, 115.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1(=[O:17])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)=O>O.C1(C)C=CC=CC=1>[C:24]([N:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:17])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1CCCCCN1C(=O)c1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
The comparison involves using soda instead of the Hunig base: 226.3 g of ε-caprolactam, 159.0 g of sodium carbonate and 1290 g of toluene are introduced into a 4 1 l flask. Under reflux, 281.1 g of benzoyl chloride are added dropwise over the course of 2 h at a rate such that CO2 evolution proceeds in a controlled manner. The mixture is then refluxed for a further 4 h. The reaction mixture is cooled to room temperature using water cooling (for about 15 min.), admixed with 500 g of water and vigorously stirred, and the aqueous phase is then separated off in a separating funnel. The toluene phase that remains is evaporated in a rotary evaporator at a temperature of 60° C. and residual toluene is removed in a vacuum drying oven, giving pale oil, which crystallizes upon cooling. M.p.: 69° C. The N-benzoylcaprolactam is obtained in a yield of 88% and a purity of 98%. The CO2 produced must be collected and disposed of separately.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:28]1(S(Cl)(=O)=O)C[CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH:26]5[CH2:29][CH2:28]5)(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: O=S(=O)(C1CC1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 37 %

Procedure:
According to the procedure for compound 398 using cyclopropanesulfonyl chloride (81 mg, 0.57 mmol) afforded 17.1 mg (37% yield) of 401, as a solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]2[C:17](=[O:24])[N:18]([CH3:23])[N:19]=[C:20]([Cl:22])[CH:21]=2)=[CH:13][CH:14]=1)([CH3:7])[CH3:6])C.C(=O)=O.C(#N)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:22][C:20]1[CH:21]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])=[CH:10][N:11]=2)[C:17](=[O:24])[N:18]([CH3:23])[N:19]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)CO)cn2)c1=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
2-[6-(6-Chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionic acid ethyl ester (1.23 g, 3.35 mmol, Eq: 1.00) was dissolved in anhydrous THF (25 ml) and cooled to −30° C. (dry ice/acetonitrile cooling bath) under nitrogen atmosphere A solution of lithium aluminum hydride (4.7 ml, 4.69 mmol, 1.0 M in THF) was added slowly, over 10 minutes via drop-wise addition. The mixture was stirred for 1 hour while maintaining the bath temperature at about −20° C. The reaction was carefully quenched by adding water (0.1 ml) and stirring for 10 minutes at ambient. Then a 5% aqueous solution of sodium hydroxide (0.19 ml) was added and the mixture stirred for 10 minutes. Water (0.19 ml) was added and stirring continued for 10 minutes. Finally magnesium sulfate was added and the material was filtered through a plug of celite, rinsing well with tetrahydrofuran. The combined filtrate and washes were concentrated on a rotary evaporator to about half the volume. Ethyl acetate (50 ml) and water (70 ml) was added and the material was shaken in a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×40 ml). The organics were combined, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated from hot dichloromethane/hexanes to provide the desired product as a light yellow-brown solid (1.041 g). (M+H)=325 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 6 H) 3.81 (s, 3 H) 6.92 (d, J=8.69 Hz, 1 H) 7.30 (s, 1 H) 7.36 (dd, J=8.69, 2.64 Hz, 1 H) 8.12 (d, J=2.64 Hz, 1 H) 8.28 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:17]([NH:19][C:20]1([C:31]#[N:32])[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21]1)=[O:18]>>[C:31]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:24][CH2:23][N:22]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:21]1)#[N:32]
Reactant: N#CC1(NC(=O)C(N)CC2CCCCC2)CCN(C2CCCCC2)C1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CCN(C2CCCCC2)C1

Procedure:
The title compound was prepared starting from 3-chloro benzo[d]isothiazole 1,1-dioxide and 2-amino-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 81, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 40% acetonitrile in water to acetonitrile. MS, m/z 512=M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])[N:10]=2)[N:7]=1.[Cl-].[NH4+].C([N:21](CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([NH2:21])=[O:13])[N:10]=2)[N:7]=1
Reactant: CC(C)(C(=O)O)c1cn2nc(Cl)ccc2n1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.20 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionic acid was dissolved in 8 ml of N,N-dimethylformamide; 0.892 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.321 g of ammonium chloride and 0.832 ml of triethylamine were added under ice cooling conditions, followed by stirring at room temperature for 3 hours. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 0.697 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni].C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1

Procedure:
Prepared analogously to Example Id by catalytic hydrogenation of 4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene with Raney nickel in ethyl acetate/methanol (1:1).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:28]=[CH:27][C:23]3[CH2:24][O:25][CH2:26][C:22]=3[CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:24]1[C:23]2[CH:27]=[CH:28][C:20]([O:19][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][C:22]=2[CH2:26][O:25]1
Reactant: C[C@H](C(=O)Nc1ccc(Oc2ccc3c(c2)COC3)cc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)COC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
A solution of 1,1-dimethylethyl((1R)-2-{[4-(1,3-dihydro-2-benzofuran-5-yloxy)phenyl]amino}-1-methyl-2-oxoethyl)carbamate (Intermediate 76, 130 mg, 0.326 mmol) and TFA (1 ml) in dichloromethane (4 ml) was stirred under argon at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by SCX to afford the title compound (94 mg), which was directly used in the next step.
Reaction SMILES: CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.C(O)[C@H]1[O:22][C@H:21]([O:23][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:20](O)[C@@H](O)[C@@H]1O.[CH2:39]([N:50]([CH2:55]C(O)=O)CC(O)=O)[CH2:40][N:41](CC(O)=O)CC(O)=O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH:40]1[N:41]=[CH:55][NH:50][C:39]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=C(O)Cc1cnc[nH]1
Reaction time: 0.33 h

Procedure:
The coding sequence of the VHH was subcloned in vector pET22 using the NcoI and NotI restriction sites according to the manufacturer's instructions (Novagen, Darmstadt, Germany). Transformed E. coli BL 21 (DE3) cells expressed VHHs in the periplasm after induction by IPTG 1 mM for 18 hours at 15° C. Periplasmic extracts were obtained by spheroplasting cells, suspended in 50 mM sodium phosphate buffer pH 8 containing 20% sucrose and 1 mM EDTA, and hydrolysing the peptidoglycan with 5 mg/ml lysozyme for 20 min at 4° C., in the presence of protease inhibitors (Complete™, Boehringer Mannheim, Germany). The suspension was then centrifuged 2 min at 10,000 rpm. The supernatant corresponding to the periplasmic extract was kept at 4° C. Purified VHHs were obtained by IMAC using a chelating agarose column charged with Ni2+ (Superflow Ni-NTA, Qiagen Ltd, UK) according to manufacturer's instructions. Purified VHH were dialysed against PBS and the protein content was measured using the Bradford reagent. The purity of the final preparation was evaluated by SDS-PAGE with Coomassie staining and by Western blot.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccccc1-c1cc(C=O)c[nH]1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)c1ccccc1-c1cc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (200 mg) in ethyl acetate (10 mL) was added 3-chloroperbenzoic acid (238 mg) under ice-cooling. After stirring at room temperature for 1 hr, a saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:ethyl acetate) to give the title compound as a pale-pink powder (yield 160 mg, 75%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Na+].[CH3:6][O:7][C:8]1[CH:12]=[CH:11][NH:10][C:9]=1/[CH:13]=[C:14]1\[C:15](=[O:30])[NH:16][C:17]2[C:22]\1=[C:21](C#CCCC([O-])=O)[CH:20]=[CH:19][CH:18]=2>CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1/[C:14](=[CH:13]/[C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[O:7][CH3:6])/[C:15](=[O:30])[NH:16]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)[O-])c21
Reactant: C#CCO
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material I supra) using DPPFPdCl2 (12.8 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>C(#N)C>[ClH:18].[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([N:29]([CH3:30])[CH3:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: CNC
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)c1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 120.8 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), dimethylamine hydrochloride (94 mg) and triethylamine (140 mg) were added to acetonitrile (10 ml), and the mixture was heated and stirred overnight at 60° C. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Ethanol and concentrated hydrochloric acid were added to the residue, and the mixture was concentrated again under reduced pressure. Ethanol was added to the residue, and solids were collected by filtration. The solids were washed successively with ethanol and diethyl ether to obtain the title compound (70 mg) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10](N)=[O:11])=[C:4]([F:13])[CH:3]=1.[OH-:14].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([OH:14])=[O:11])=[C:4]([F:13])[CH:3]=1
Reactant: NC(=O)Cc1c(F)cc(Br)cc1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1c(F)cc(Br)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A suspension of 2-(4-bromo-2,6-difluorophenyl)acetamide (7.20 mmol) in ethanol (10 mL) was treated with 6N aq sodium hydroxide (90 mmol) at room temperature. The vessel was then stirred in an oil bath at 80° C. After one hour the reaction mixture had turned clear. After stirring overnight, the reaction mixture was cooled to room temperature, at which point the pH was adjusted to ˜1 with 6N aq HCl. A white precipitate formed, and the solution was concentrated to a volume of ˜10 mL, at which point it was extracted three times with ethyl acetate. The combined organic layers were washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a solid (837 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.60 (s, 2 H) 7.49 (d, J=6.82 Hz, 2 H) 12.82 (br. s., 1 H).
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C([NH:50][CH2:51][C:52]([OH:54])=[O:53])(C)(C)C>C(O)(C)C>[Cl:23][C:19]1[C:18]([F:24])=[C:17]([C@@H:16]2[C@:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:14]([CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[NH:13][C@H:12]2[C:10]([NH:9][C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C:2]([CH3:1])([CH3:40])[O:41][CH2:42][C@@H:43]([OH:44])[CH2:45][NH:50][CH2:51][C:52]([OH:54])=[O:53])[N:5]=2)=[O:11])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)NCC(=O)O
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CC(C)O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC(C)(C)OC[C@@H](O)CNCC(=O)O)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (85.8 mg, 0.133 mmol), isopropyl alcohol (2 mL), and t-butyl glycine (35 mg, 0.266 mmol) was microwaved at 130° C. for 15 min. The solvent evaporated under reduced pressure. The resulting oil was dissolved in dichloromethane (2 mL) and cooled to 0° C.; then TFA (1 mL) was slowly added and stirred for 4 h. The mixture was concentrated under reduced pressure and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-{(S)-3-[2-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-2-hydroxy-propylamino}-acetic acid (18.1 mg, 19%) as an off-white powder. HRMS (ES+) m/z Calcd for C35H42Cl2F2N6O5S+H [(M+H)+]: 735.2635. found: 735.2631
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=O)=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:36]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(OC)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (40 mg, 34%).