Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:9]([O:8][C:7]2[CH:30]=[CH:31][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1)=[N+:33]=[N-:34]
Reactant: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(C(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccc(C(C)C)cc1
Yield: 91.4 %

Procedure:
In a similar manner to that described in Reference example 3 (h), a reaction was carried out using ethyl 2-(4-isopropylphenoxy)-3-[4-(2-methanesulfonyloxyethoxy)phenyl]propionate (19.6 g), which is the product of Reference example 5(g), and sodium azide (7.06 g), and the reaction mixture was treated to afford the desired compound (15.8 g) as a syrup.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].I[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1>>[CH3:14][C:9]1[CH:8]=[C:7]([N:1]2[CH2:4][CH2:3][C:2]2=[O:5])[CH:12]=[C:11]([CH3:13])[CH:10]=1
Reactant: O=C1CCN1
Reactant: Cc1cc(C)cc(I)c1
Product: Cc1cc(C)cc(N2CCC2=O)c1
Yield: 94.9 %

Procedure:
Using general procedure A, 2-azetidinone (88 mg, 1.24 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 1:1; 15 mL fractions). Fractions 5-10 provided 173 mg (95% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.01 (s, 2H), 6.76 (s, 1H), 3.61 (t, J=4.5 Hz, 2H), 3.10 (t, J=4.5 Hz, 2H), 2.32 (s, 6H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]([CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[N:9]=[C:8]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(O)(=O)C.[Pt]=O>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]([C:10]2[N:11]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[N:7]=[C:8]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[CH3:22])=[CH:18][CH:17]=1
Reactant: CN(c1ccc([N+](=O)[O-])cc1)c1nc(N2CCOCC2)nc(-n2ccnc2)n1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CN(c1ccc(N)cc1)c1nc(N2CCOCC2)nc(-n2ccnc2)n1
Yield: 34.5 %

Procedure:
2-(1-Imidazolyl)-4-[N-methyl-N-(4-nitrophenyl)amino]-6-morpholino-1,3,5-triazine (115 mg, 0.30 mmol) was dissolved in acetic acid (10 ml) and was catalytically reduced with platinum oxide at room temperature under normal pressure. The reaction mixture was filtered and was evaporated under reduced pressure. The obtained residue was added with dichloromethane and aqueous solution of saturated sodium bicarbonate, and then was shaken for mixing. The organic layer was separated from the mixture, washed with water, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography, using ethyl acetate as eluant, to obtain 36.5 mg (yield: 34.4%) of the titled compound as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][NH2:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[C:21]([C:22]#[N:23])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([O:24][CH3:25])=[CH:17][CH:18]=2)[N:13]=1>CN(C)C=O>[CH3:25][O:24][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:21]3[C:22]([NH2:23])=[N:10][N:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:12]3=[N:13]2)=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: COc1ccc2cc(C#N)c(Cl)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3c(N)nn(-c4ccccc4)c3nc2c1
Temperature: 25 °C

Procedure:
To a suspension of 4.8 g sodium hydride (60%) in 200 ml dimethylformamide at 0° C. was added a solution of 9.9 ml phenylhydrazine in 250 ml dimethylformamide over a 15 min period. The mixture was stirred and allowed to warm to room temperature for 1 hour. 2-Chloro-7-methoxy-3-quinolinecarbonitrile (Example 3c) (19.68 g) was then added in portions. The reaction mixture was stirred overnight at room temperature, and then heated on a steam bath for two hours. Since starting material was still present, additional sodium hydride (3.2 g) was added and heating continued until thin layer chromatography indicated that no starting material remained. The mixture was quenched in saturated ammonium chloride solution and the mixture worked up in ethyl acetate solution. The crude product was purified by chromatography and recrystallized from ethyl acetate to give 2.3 g 7-methoxy-1-phenyl-1H-pyrazolo[3,4-b]quinolin-3-amine, brown solid, m.p. 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CN1CCOCC1.[CH3:40][CH:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1>CN(C)C=O.ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:47][CH:44]3[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]3)=[O:20])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CC1CCC(N)CC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC1CCC(NC(=O)c2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
To a dichloromethane (4 ml) suspension of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added thionyl chloride (1.00 ml) and N,N-dimethylformamide (one drop). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness and the residue thus obtained was dissolved in dichloromethane (6 ml). To the resulting solution were added N-methylmorpholine (51.8 μl, 0.472 mmol) and 4-methylcyclohexylamine (37.4 μl, 0.283 mmol). The resulting mixture was stirred at room temperature for 18 hours, followed by dilution with dichloromethane. The diluted mixture was washed sequentially with 1N hydrochloric acid, water and brine, dried over magnesium sulfate and concentrated. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated to give a white solid. The solid thus obtained was recrystallized from ethyl acetate-hexane to give the title compound (70.3 mg, 0.135 mmol, 57%) as a white powder.
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>>[C:23]1(=[O:32])[N:22]([CH2:21][CH2:20][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][N:8]4[CH:16]=[CH:17][CH:18]=[C:7]4[C@@H:6]3[CH2:1]2)[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]12
Reactant: c1ccc2c(c1)Cn1cccc1[C@@H]1CNCCN21
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ccccc3Cn3cccc3[C@@H]2C1

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bS)-1,2,3,4,10,14b-hexahydropyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a quantitative yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:18])=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(OCc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 36 h
Yield: 92.4 %

Procedure:
To a solution of 33 (452 mg, 2.00 mmol) in CCl4 (20 mL) were added N-bromosuccinimide (373 mg, 2.10 mmol) and silica gel (1 g) and the mixture was stirred in the dark at room temperature for 36 hours. Then, the mixture was filtered and the filtrates were washed with satured solution of sodium thiosulphate (10 mL). The organic phase were dried over Na2SO4, filtered and concentrated on vacuo to give 564 mg of bromoaryl 34. Yield 93%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.32-7.51 (m, 6H), 6.92 (d, J=3.0 Hz, 1H), 6.68 (dd, J1=8.7 Hz, J2=3.0 Hz, 1H), 5.04 (s, 2H), 3.31 (sep, J=6.9 Hz, 1H), 1.22 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ ppm: 158.4, 148.5, 136.7, 133.2, 128.6, 128.1, 127.5, 115.0, 114.0, 113.3, 70.2, 33.0, 22.7; HRMS (EI) m/z: calcd for C16H17BrO: 304.0463. found: 304.0465.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([O:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(C)c(C#N)c(O)n1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C#N)c(OCc2ccccc2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile (85.0 g, 0.574 mol) and benzyl chloride (87.0 g, 0.688 mol) in toluene (800 mL) was added Ag2O (146 g, 0.631 mol). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was filtered through CELITE® and the solids washed with CH2Cl2. The filtrate was concentrated under vacuum and purified by column chromatography (petroleum ether/EtOAc) to give 2-(benzyloxy)-4,6-dimethylpyridine-3-carbonitrile (Cpd W, 89 g, 65%) as a white solid.
Reaction SMILES: ClB(Cl)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH:23]=[O:24].[OH-].[Na+]>ClCCl.C(OCC)C.O.C(N(CC)CC)C>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([CH3:19])=[CH:17][C:16]=1[CH:23]([C:22]1[C:21]([F:20])=[CH:28][CH:27]=[CH:26][C:25]=1[F:29])[OH:24]
Reactant: O=Cc1c(F)cccc1F
Reactant: COc1cc(N)ccc1C
Agent: ClB(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cc(N)c(C(O)c2c(F)cccc2F)cc1C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
To 6.05 g of dichlorophenylborane dissolved in 40 ml of dichloromethane, at −20° C., are successively added 5.226 g of 3-methoxy-4-methylaniline dissolved in 50 ml of dichloromethane, and 13.4 ml of triethylamine dissolved in 25 ml of dichloromethane. After 30 minutes at −20° C., 5.412 g of 2,6-difluorobenzaldehyde dissolved in 60 ml of dichloromethane are introduced. After 24 hours at room temperature, the mixture is hydrolysed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. To the oil obtained, dissolved in 80 ml of diethyl ether, are added 80 ml of 2M sodium hydroxide solution and the mixture is left stirring for 18 hours. The phases are separated by settling and the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is solidified with n-pentane to give 5.069 g of the expected product.
Reaction SMILES: [NH2:1][CH:2]([CH3:10])[CH:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[OH:4].C(N(C(C)C)CC)(C)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:10][C@H:2]1[C@H:3]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)[O:4][C:21](=[O:23])[NH:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)C(O)c1nccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1NC(=O)O[C@H]1c1nccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of diastereoisomers of 2-amino-1-thiazol-2-yl-propan-1-ol (4.20 g, 18.2 mmol) was dissolved in 160 mL of CH2Cl2. Diisopropylethylamine (11.1 mL, 63.6 mmol) was added at 0° C., followed by triphosgene (2.70 g, 9.09 mmol) dissolved in 40 mL of CH2Cl2. The reaction mixture was stirred at room temperature for 2 hours and then diluted with CH2Cl2. The organic solvents were separated, washed with aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (80 g SiO2) using EtOAc in hexane from 0% to 100 in order to give the title compound as a single enantiomer (2.16 g, 64%). LC-MS: [M+H] 185.3; Rt 0.45 min; (LCMS method 1). 1H NMR (400 MHz, CHCl3-d): 7.75 (d, 1H), 7.35 (d, 1H), 5.60 (br s, 1H), 5.32 (d, 1H), 4.18-4.09 (m, 1H), 1.45 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:29][CH:30]([C:36](=[O:38])[CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([NH:29][CH:30]([C:36](=[O:38])[CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Reactant: CCOC(=O)C(N)C(C)=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)C(NC(=O)CCC(=O)OC(C)(C)C)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
4-Tert-butoxy-4-oxobutanoic acid (1.7 g) and N-methylmorpholine (1.1 mL) were dissolved in tetrahydrofuran (60 mL), and the solution was cooled to 0° C. Isobutyl chloroformate (1.3 mL) was added thereto, and the mixture was stirred at 0° C. for 30 minutes. A solution of ethyl 2-amino-3-oxobutanoate hydrochloride (1.8 g) in N,N-dimethylformamide (30 mL) was added thereto, and the mixture was stirred at 0° C. for 5 minutes. Then, N-methylmorpholine (1.1 mL) was added thereto, and the mixture was stirred at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Moritex Corporation, elution solvent: hexane/ethyl acetate) to obtain the title compound (2.2 g) as a yellow oil (yield: 72%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:25])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][C:16]=1[O:23][CH3:24].CCCCCCC>ClCCl>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:25])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Cl:3])=[CH:17][C:16]=1[O:23][CH3:24]
Reactant: COc1cc(CO)ccc1NC(=O)Nc1ccccc1C
Reactant: O=S(Cl)Cl
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1cc(CCl)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
7.65 ml (104.8 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 15 g (52.4 mmol) of 4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl alcohol in 300 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 3 hours, allowed to stand overnight and then poured onto 1000 ml of n-heptane. The heptane was decanted off from the deposited oil, the residue was again suspended with n-heptane and the heptane was decanted off. This process was repeated a further two times. The residue was then dissolved in dichloromethane and poured into 800 ml of ice-cold diisopropyl ether. It was subsequently stirred with ice cooling for 2 hours, and the product was filtered off with suction and washed with diisopropyl ether. After drying over phosphorus pentoxide, 12 g (75%) of the title compound were obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([O:28][CH3:29])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>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.O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:2][C:3]2[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=2)=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
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: [K+]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Yield: 36.1 %

Procedure:
4-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 164, 100 mg, 0.27 mmol), (4-chloro-2-methoxyphenyl)boronic acid (55 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmol), aqueous potassium carbonate solution (1.8 M, 0.45 mL, 0.804 mmol) and tetrahydrofuran (15 mL) were combined and stirred under nitrogen at reflux for 6 hours. After cooling, the mixture was filtered through Celite™ and the filtrate evaporated. The residue was dissolved in water (20 mL) and acidified with aqueous potassium hydrogen sulphate solution (0.5 M) to pH 2 and the mixture extracted with ethyl acetate (1×30 mL). The organic layer was separated and back-washed with brine (2×20 mL). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give an orange oil. The oil was purified using silica gel column chromatography eluting with heptane to ethyl acetate:heptane 1:1 to give a solid. The solid was further purified by reverse phase HPLC to give the title compound (38 mg, 36%) as a white solid.
Reaction SMILES: Cl.[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[CH3:20][O:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C1(C)C=CC=CC=1>[CH3:20][O:21][CH2:22][CH2:23][C@@H:24]1[NH:25][CH2:26][CH2:27][N:19]([C:8]2[C:7]3[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:14][C:13]=3[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH2:29]1
Reactant: COCC[C@H]1CNCCN1
Reactant: CC(C)c1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)cc32)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 2-isopropyl-4H-3-thia-4,9-diaza-benzo[f]azulene-10-ylamine hydrochloride (0.32 g, 1.07 mmol) to a solution of (S)-2-(2-methoxy-ethyl)-piperazine (0.31 g, 2.15 mmol) in dimethyl sulfoxide: toluene (1:3, 4 mL). Add diisopropylethylamine (0.19 mL, 1.09 mmol), heat to 110° C. and stir. After an overnight period, cool to ambient temperature to give crude title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[N:18][C:6]2[NH:7][C:8]3[CH:13]=[N:12][C:11]([C:14]([NH:16][NH2:17])=[O:15])=[CH:10][C:9]=3[C:5]=2[CH:4]=1.[N:20]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>O>[Br:2][C:3]1[CH:19]=[N:18][C:6]2[NH:7][C:8]3[CH:13]=[N:12][C:11]([C:14]([N:16]=[N+:17]=[N-:20])=[O:15])=[CH:10][C:9]=3[C:5]=2[CH:4]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (3.0 mL, 90 mmol) was added dropwise to a suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid hydrazide (530 mg, 1.73 mmol) in water (12.4 mL). Once homogeneous, the solution was cooled to 0° C. and a solution of 3N sodium nitrite in water (0.60 mL, 2.0 mmol) was added to the mixture. After 1 h, added another 1.03 eq. of 3N sodium nitrite in water (0.60 mL, 2.0 mmol) and allowed the reaction to warm to ambient temperature over night. After 17 h at room temperature, the reaction was cooled to 0° C. and a solution of 3N sodium nitrite in water (0.60 mL, 2.0 mmol) was added and then warmed to room temperature. The reaction was made basic with a solution of saturated sodium bicarbonate, and the solid precipitate was collected by filtration, washed with water, and dried in a dessicator under vacuum to provide a solid material that was 70% pure by LCMS analysis.
Reaction SMILES: C([N:8]([CH2:33][C@H:34]([OH:56])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([O:43]CC2C=CC=CC=2)=[C:39]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:38]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C@@H:22]([CH:28]([CH3:30])[CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:56][C@H:34]([CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:38]=1)[CH2:33][NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C@H:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:28]([CH3:30])[CH3:29])=[O:20])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](NC(=O)c1ccc([C@H]2CC[C@H](NC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(C)C
Reaction time: 3 h

Procedure:
A suspension of 1.35 g (0.35 mmol) of ethyl trans-(2S)-2-[(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}benzoyl)amino]-3-methylbutanoate and of 0.177 g of palladium-on-charcoal (10% Pd, 50% in water) in 15 ml of ethanol is placed under hydrogen atmosphere and stirred for 3 h. The catalyst is subsequently filtered off and the solvents are evaporated under reduced pressure. The title compound is obtained in the form of a white solid (0.138 g, 44%) after purification on silica gel (eluent: dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradient in 30 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16]>CC(C)=O>[CH3:13][O:14][C:15]([NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[NH:12][C:18]([NH:17][C:15]([O:14][CH3:13])=[O:16])=[S:19])=[O:16]
Reactant: COC(=O)N=C=S
Reactant: C#CCSc1ccc(N)c(N)c1
Solvent: CC(C)=O
Product: C#CCSc1ccc(NC(=S)NC(=O)OC)c(NC(=S)NC(=O)OC)c1
Reaction time: 8 h

Procedure:
4 G. of 1,2-diamino-4-propargylthiobenzene in 40 ml. aceton is treated with 10 g. of methoxy carbonyl isothiocyanate. The mixture is left overnight at room temperature, stripped under vacuum and the residue triturated with ether. Recrystallization from methanol gives pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-propargylthio-benzene.