Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2N=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:47][NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.S([O-])(O)(=O)=O.[Na+]>CN(C)C=O.ClCCl.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:48]([CH3:47])[CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(CCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.4 %

Procedure:
(2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (1.40 g, 4.3 mmol) was dissolved in N,N-dimethylformamide (5 ml) and dichloromethane (5 mL). Hydroxy-7-azabenzotriazole (0.59 g, 4.3 mmol) was added as a solid. The solution was cooled to 0 ° C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.99 g, 5.2 mmol) was added. The solution was stirred for 20 min at 0° C. N-Methyl-N-phenethylamine (0.86 ml, 6.0 mmol) was added. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with water (300 ml) and ethyl acetate (150 ml). 10% sodium hydrogen sulfate solution (80 ml) was added. The phases were seperated. The aqueous phase was extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (200 ml) and dried over magensium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane 1:1 as eluent to give 1.89 g of N-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:13]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:25]4[C:30]([Cl:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=4[Cl:36])[CH:21]=3)[N:16]=2)[CH2:12][CH:11]([C:37]([O:39]C)=[O:38])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:13]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:25]4[C:26]([Cl:36])=[C:27]([O:34][CH3:35])[CH:28]=[C:29]([O:32][CH3:33])[C:30]=4[Cl:31])[CH:21]=3)[N:16]=2)[CH2:12][CH:11]([C:37]([OH:39])=[O:38])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1C[C@H](NC(=O)OC(C)(C)C)[C@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CC(C(=O)O)C[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Methyl (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-quinazolin-2-yl)amino)cyclopentane-1-carboxylate (0.662 g, 1.119 mmol) was taken up in methanol (10 ml), THF (4 ml) and treated with 10 ml of 1N NaOH. The reaction mixture was stirred at room temperature for 2 hours. The organic solvents were removed under reduced pressure, then the aqueous layer was acidified with 1N HCl to pH ˜2. The aqueous layer was extracted with EtOAcx3. The organic layers were combined, dried over sodium sulfate, and the solvent removed to give crude (3S,4R)-3-((tert-butoxycarbonyl)amino)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclopentane-1-carboxylic acid (0.580 g, 1.00 mmol, 91% yield) which was carried on with further purification. MS (ES+) C27H30Cl2N4O6 requires: 577, found: 578 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]Cl)([O-:3])=[O:2].[OH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][N:15]([CH2:16][CH2:17][OH:18])[CH2:14][CH2:13][OH:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: OCCNCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1SN(CCO)CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 379 g (2 mol) of 2-nitrophenylsulphenyl chloride in 2 l of methylene chloride is added to a solution of 210 g (2 mol) of bis(2-hydroxyethyl)amine and 202 g (2 mol) of triethylamine in 3 l of methylene chloride in the course of 90 minutes, the temperature rising from 21° to 34°. The mixture is subsequently stirred at room temperature for 2 hours and is left to stand overnight and the solution is washed six times with 1 l of water each time, dried with sodium sulphate and concentrated in vacuo. The residue is an orange-yellow solid product of melting point 82°-86°, which is sufficiently pure for further reaction. Yield: 499 g.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3].C(N(CC)CC)C.[CH:24]1[N:25]=[CH:26][N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12>ClCCCl>[CH:24]1[N:25]=[C:26]([C:2]([C:4]2[CH:5]=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])=[O:3])[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12
Reactant: c1ccn2cncc2c1
Reactant: COC(=O)c1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)c2ncc3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.6 g (0.023 mol) of methyl 5-(chlorocarbonyl)-2-nitrobenzoate and 3.4 ml (0.024 mol) of triethylamine are added to 1.3 g (0.011 mol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836] dissolved in 100 ml of 1,2-dichloroethane. The mixture is stirred at ambient temperature for 4 hours. The reaction medium is concentrated under reduced pressure and then the residue is taken up in dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by column chromatography on silica gel, elution being carried out with dichloromethane. After evaporation, 3.1 g of a yellow solid are collected. Melting point: 151° C.; 1H NMR (d6-DMSO): 3.92 (3H, s), 7.39-7.42 (1H, m), 7.50-7.54 (1H, m), 8.00 (1H, s), 8.10 (1H, d), 8.25 (1H, d), 8.69 (1H, d), 8.76 (1H, s), 9.78 (1H, d)
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[BH4-].[Na+]>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1Cc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Product: CC1=Cc2ccccc2C1
Yield: 83.1 %

Procedure:
Analogously to Example D, 5.0 g (34 mmol) of 2-methyl-1-indanone (5) were reduced with 1.94 g (51 mmol) of NaBH4. The alcohol, which was not purified further, was then further reacted in the presence of 0.2 g of p-toluenesulfonic acid in 100 ml of toluene at 80° C. Chromatography on 100 g of silica gel (hexane/methylene chloride 9:1) gave 3.68 g (82%) of 2-methylindene (6).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>CO>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1
Solvent: CO
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In an atmosphere of argon, 50 g (290.7 mmols) of 4-bromoaniline was dissolved in 580 ml of methanol, and the solution obtained was cooled to 0° C., and thereafter 32.6g (1.1-fold equivalent weight) of acetic anhydride was dropwise added thereto. Thereafter, the solution obtained was restored to room temperature, followed by stirring for 1 hour, and the crystals deposited were filtered off. To the residue obtained by vacuum concentration of the filtrate, 250 ml of water was added, and the crystals deposited were collected by filtration, which was then washed with water, followed by natural drying to obtain 65.5 g of N-acetyl-4-bromoaniline (yield: 100%; a white solid).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:37])[C:18]([N:21]2[C:26](=[O:27])[CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24](=[N:34][OH:35])[O:23][C:22]2=[CH2:36])([CH3:20])[CH3:19])[CH:12]=[C:13]([Cl:15])[CH:14]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:37])[C:18]([N:21]2[C:26](=[O:27])[CH:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24](=[N:34][O:35][C:1](=[O:3])[CH3:2])[O:23][C:22]2=[CH2:36])([CH3:20])[CH3:19])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=C1OC(=NO)C(c2ccccc2)C(=O)N1C(C)(C)C(=O)Nc1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Product: C=C1OC(=NOC(C)=O)C(c2ccccc2)C(=O)N1C(C)(C)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 0 °C

Procedure:
Acetic anhydride (3 ml) was added to a stirred solution of N-(3,5-dichlorophenyl)-2-(2,3-dihydro-6-hydroxyiminomethylene-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (0.4 g) in pyridine (3 ml) at -5° C. After 1.5 hours the mixture was poured into ice/water and extracted (ethyl acetate). The extract was washed with hydrochloric acid (2M) and with brine, dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with hexane/ethyl acetate to give N-(3,5-dichlorophenyl)-2-(6-acetoxyiminomethylene-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 118, 0.32 g) as an off-white solid, m.p. 125-127° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>[Pd].CO>[F:20][C:17]([F:18])([F:19])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccnc1Oc1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cccnc1Oc1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 3a (20 g, 70 mmol) in a 1:4 mixture of ethyl acetate and methanol (250 mL) was added palladium on charcoal (10% wt, 1.0 g, 0.90 mmol), and the mixture was stirred under an atmosphere of hydrogen. After 3 h, the solution was filtered over Celite® and the resulting solution was concentrated. 3b was recrystallized from ethyl acetate to afford 17.5 g of white crystals (97% yield). [M+H]+=255.20.
Reaction SMILES: [NH:1]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14](O)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl.[NH2:29][CH:30]1[CH2:38][CH2:37][C:36]2[C:32](=[CH:33][NH:34][N:35]=2)[CH2:31]1>>[CH2:3]([C@@H:2]([NH:1][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])[C:10](=[O:11])[N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([NH:29][CH:30]1[CH2:38][CH2:37][C:36]2[C:32](=[CH:33][NH:34][N:35]=2)[CH2:31]1)=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC1CCc2n[nH]cc2C1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCc2n[nH]cc2C1
Yield: 80 %

Procedure:
The title compound was prepared from Boc-D-PheL-Pro-OH and 5-amino-4,5,6,7-tetrahydro-2H-indazole dihydrochloride using the procedure of EXAMPLE 6, and was obtained as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.Cl.[C:14]1([CH2:20][C@H:21]([N:37]=[N+:38]=[N-:39])[C@@H:22]([OH:36])[C@H:23]([OH:35])[C@@H:24]([N:32]=[N+:33]=[N-:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.C(OCC)C>[C:14]1([CH2:20][C@H:21]([N:37]=[N+:38]=[N-:39])[C@@H:22]([O:36][S:2]([CH3:1])(=[O:4])=[O:3])[C@H:23]([OH:35])[C@@H:24]([N:32]=[N+:33]=[N-:34])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]([C@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-])[C@H](Cc1ccccc1)N=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 13.5 μL (0.170 mmol) of methanesulfonyl chloride in 300 μL of methylene chloride was slowly added to a cold (0° C.) solution of 80 mg (0.23 mmol) of the subtitled intermediate of Preparation 1D and 32 μL (0.23 mmol) of triethylamine in 0.6 mL of methylene chloride. The reaction mixture was warmed to room temperature, allowed-to react for 15 minutes and then poured into 50 mL of a 3:2 mixture of diethyl ether and 0.1N hydrochloric acid. The resulting layers were separated and the organic layer was washed with a half-saturated sodium bicarbonate solution and then reduced to dryness under reduced pressure to provide a foam. This foam was purified using column chromatography (eluted with a 1:2 ethyl acetate/methylene chloride solution). The fractions containing the desired product were combined and reduced to dryness under reduced pressure to provide 100 mg of a 60:40 mixture of the desired subtitled intermediate and the starting material, 1,6-diphenyl-2(S),5(S)-diazido-3(R),4(R)-dihydroxyhexane.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][C:15]1[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[N:16]=1.[CH3:27][O:28][C:29](=[O:42])[CH2:30][C:31]1[C:35]2[C:36]([F:41])=[CH:37][C:38](O)=[CH:39][C:34]=2[S:33][CH:32]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:27][O:28][C:29](=[O:42])[CH2:30][C:31]1[C:35]2[C:36]([F:41])=[CH:37][C:38]([O:22][CH2:21][C:20]3[C:15]([CH3:14])=[N:16][C:17]([C:23]([F:24])([F:26])[F:25])=[CH:18][CH:19]=3)=[CH:39][C:34]=2[S:33][CH:32]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(F)c12
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a mixture of tri-n-butylphosphine (0.655 mL), (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (167 mg), methyl(4-fluoro-6-hydroxy-1-benzothiophen-3-yl)acetate (210 mg) and THF (dry) (15 mL) was added ADDP (662 mg, 2.62 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. To the residue was added IPE and the insoluble materials were removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) and silica gel column chromatography (EtOAc/hexane) to give the title compound (310 mg). The crystals were recrystallized from acetone-hexane.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]([CH3:21])=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:19]([CH3:21])[CH3:18])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Yield: 13 %

Procedure:
To a mixture of solid 2,7-dibromo-9H-fluorene (1 g, 3.1 mmol) and solid potassium hydroxide (freshly ground, 530 mg, 9.4 mmol) was added acetone (15 mL). The reaction immediately turns dark. After 3 hours the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concentrated to a dark blue-green oil. This oil was dissolved in dichloromethane (10 mL) and formic acid (˜10 drops) was added until the solution was bright orange. After concentration, the resulting residue was purified by flash column chromatography to yield 2,7-dibromo-9-(propan-2-ylidene)-9H-fluorene (145 mg, 13%) as an orange solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:23]C(=O)OC(C)(C)C)[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:11][CH:10]=1>>[NH2:23][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=1)[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NC(CCNS(C)(=O)=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCC(N)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
TFA (4 mL) was added to tert-butyl 1-(4-chlorophenyl)-3-(methylsulfonamido)propylcarbamate (Intermediate 115) (275 mg, 0.76 mmol) and stirred at 20° C. for 2 hours. The reaction was vacuumed to dryness. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford N-(3-amino-3-(4-chlorophenyl)propyl)methanesulfonamide (113 mg, 56.7%) as a colourless gum.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1.C(O)C.[C:23]1([N:29]=[C:30]=[S:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:31])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(NNC(=O)c2ccc(Cl)cc2)cc1
Reactant: S=C=Nc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NNc1ccc(NC(=S)Nc2ccccc2)cc1)c1ccc(Cl)cc1

Procedure:
1-(4-Chlorobenzoyl)-2-(4-aminophenyl)hydrazine hydrochloride (2.0 g, 0.0067 mole) was mixed with ethanol (125 ml) and water (25ml). Phenyl isothiocyanate (1.1 g, 0.01 mole) was added to the mixture along with sodium acetate (0.82 g, 0.1 mole) in water (10 ml). The reaction mixture was stirred and refluxed for 5 minutes, then was stirred at room temperature for 11/2 hours. The mixture was chilled in ice and then filtered. The product was washed with ethanol and dried to give an off-white solid. Yield 1.9 g (71%), m.p. 197.5°-199° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[C:26]([C:28]1[C:29](=[O:48])[N:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[C:26]([C:28]1[C:29](=[O:48])[N:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH:31]=[C:32]([C:2]2[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:12][CH2:13]3)=[O:10])[N:7]=2)[CH:33]=1)#[N:27]
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(C#N)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)Cn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc(C#N)c1=O
Temperature: 80 °C
Yield: 46.7 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (150 mg, 0.41 mmol), methyl 2-(3-cyano-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate (244 mg, 0.61 mmol) and tetrakis(triphenylphosphine)palladium (0) (47 mg, 0.041 mmol) in 1,2-dimethoxyethane (4.5 mL), 2 M Na2CO3 (613.5 μL, 1.23 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 22 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield methyl 2-(3-cyano-5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetate (100 mg, 46.8%). ESI-MS m/z calc. 522.5. found 532.5 (M+1)+. Retention time 1.86 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH:9](N(CC)C(C)C)(C)[CH3:10].[Cl-].[Li+].C([Sn](CCCC)(CCCC)CCCC)=C.[F-].[K+]>CN(C)C=O.C(Cl)Cl.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>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH:9]=[CH2:10])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1cnc(N)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 60.7 %

Procedure:
A solution of 2-amino-5-bromopyrazine (500 mg, 2.87 mmol) in N,N-dimethylformamide (15 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol), N,N-diisopropylethylamine (1.25 mL, 7.18 mmol), lithium chloride (426 mg, 0.06 mmol), and vinyltri-n-butyltin (840 μL, 2.87 mmol), and the reaction was heated at 120° C. for 4 h. After such time, the reaction was cooled to 25° C., treated with a saturated aqueous potassium fluoride solution (10 mL), and stirred at 25° C. overnight for 16 h. The solution was then diluted with methylene chloride (25 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/3 to 1/4 hexanes/ethyl acetate) afforded 2-amino-5-vinylpyrazine (211 mg, 61%) as a light yellow solid: EI-HRMS m/e calcd for C6H7N3 (M+) 121.0640, found 121.0642.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].CCN(CC)CC.[Cl:23][CH2:24][C:25](Cl)=[O:26].C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[Cl:23][CH2:24][C:25]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:14][CH3:15])[CH:4]=2)[CH2:13][CH2:12]1)=[O:26]
Reactant: COc1cc(N2CCNCC2)ccc1Br
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Br

Procedure:
Protocol S was followed using 1-(4-bromo-3-methoxyphenyl) piperazine, Et3N, chloroacetyl chloride and methylene chloride. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1) afforded the title compounds as a white solid