Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.O>[C].[Pd].C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C=C2CCCCC2=O)cc1
Agent: [Pd]
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cc2ccccc2O)cc1
Temperature: 170 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
In a 100-ml, four-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were placed 20.0 g (0.1 mole) of the 2-(4-methylbenzylidene)cyclohexanone produced in Example 4 and 40 ml of diphenyl ether in this order. The flask inside was purged with nitrogen. Thereto was added 2.0 g (10 wt. %, 0.47 mmole as palladium) of 5% palladium carbon (containing 50% of water, a product of N.E. CHEMCAT CORPORATION, a standard product). The system was made vacuum using an aspirator and then returned to ordinary pressure using nitrogen; this operation was repeated three times. Then, the system was stirred at 170° C. for 1 hour while the moisture was discharged out of the system, and further was stirred at 210° C. for 2 hours. The system was cooled to room temperature. 200 ml of toluene was added to the system. Filtration was conducted to remove the palladium carbon. The filtrate was extracted with 100 ml of a 10% aqueous sodium hydroxide solution, and this operation was repeated twice. The aqueous layer was washed with 50 ml of toluene. To the resulting aqueous layer was added 35% hydrochloric acid until the aqueous layer became acidic, after which the aqueous layer was extracted with 150 ml of ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution in this order. The ethyl acetate layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove ethyl acetate, to obtain 11.6 g of brown crystals. Yield: 59% The purity of the intended product in the crystals was 91% as measured by gas chromatography.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(=S)=S>[C:5]1([CH3:11])[CH:10]=[CH:9][C:8]([C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(C)cc1
Yield: 84.1 %

Procedure:
Anhydrous aluminum chloride (89.6 g, 0.67 mol) was added to a solution of toluene (28.5 g, 0.31 mol) in 120 mL of dry carbon disulfide. The mixture was heated to reflux and acetic anhydride (24.5 g, 0.24 mol) was added over one hour. Heating was continued for an additional hour. The solvent was removed by distillation. The reaction mixture was cooled and slowly poured into a well-stirred mixture of ice and hydrochloric acid. The mixture was extracted several times with ether. The combined extracts were washed with water and 10% sodium hydroxide, dried over calcium chloride, filtered, and the solvent was removed. Distillation gave the desired product 1-p-tolyl-ethanone (27.08 g). 1E1 NMR (300 MHz, DMSO-d6) δ 2.36 (s, 3H), 2.50 (s, 3H), 7.32 (d, 2H), 7.85 (d, 2H); ELMS (M+): 134.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:18][CH:19]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(COC(=O)N2CCC(CNc3ncc(F)cn3)CC2)cc1

Procedure:
The solution of (4-methyl-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2a) (0.20 g, 0.76 mmol), 2-chloro-5-fluoro-pyrimidine (EXAMPLE 71, Step 1) (0.10 g, 0.76 mmol) and triethylamine (0.21 mL, 1.53 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (10 CH2Cl2:1-10 IPA:89-80 hexane) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-methyl-benzyl ester. M.S.(M+1):359.33
Reaction SMILES: [ClH:1].CC(C1C=C(C=C(C(C)(C)C)C=1O)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])(C)C.[C:39]([C:43]1[CH:44]=[C:45]([CH2:54]C(O)=O)[CH:46]=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]=1[OH:49])([CH3:42])([CH3:41])[CH3:40].C(C1C=C(C=C(C(C)(C)C)C=1O)C(O)=O)(C)(C)C>>[ClH:1].[CH3:42][C:39]([C:43]1[CH:44]=[C:45]([CH2:54][C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[NH:25])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[O:10])[CH:46]=[C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]=1[OH:49])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(CC(=O)O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C(=O)N2CCN(c3ccc(NC(=N)c4cccs4)cc3)CC2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: Cl
Product: CC(C)(C)c1cc(CC(=O)N2CCN(c3ccc(NC(=N)c4cccs4)cc3)CC2)cc(C(C)(C)C)c1O

Procedure:
The experimental protocol used is the same as that described for the compound 9, with 3,5-di-tert-butyl-4-hydroxyphenylacetic acid replacing the 3,5-di-tert-butyl-4-hydroxybenzoic acid in the first stage of synthesis. Yellow powder. Melting point: 176-180° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([CH3:29])([CH3:28])[C:26]#N)[CH:20]=2)=[N:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1.CO.[OH-:32].[Na+].C(OCC)(=O)C.[OH2:40]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([CH3:29])([CH3:28])[C:26]([OH:40])=[O:32])[CH:20]=2)=[N:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1
Reactant: O
Reactant: CC(C)(C#N)c1cc(-c2cnc(N)c(-c3cc(-c4ccccc4)no3)n2)ccn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C(=O)O)c1cc(-c2cnc(N)c(-c3cc(-c4ccccc4)no3)n2)ccn1
Temperature: 110 °C
Yield: 42 %

Procedure:
2-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]-2-methyl-propanenitrile (90 mg, 0.2353 mmol) was added to methanol (3 mL) followed by the addition of 1 M sodium hydroxide (705.9 μL of 1 M, 0.7059 mmol). The mixture was heated in the microwave for 90 minutes at 110° C. The reaction was cooled to ambient temperature and diluted with ethyl acetate/water. The organic layer was washed with brine (×1). The aqueous layer was acidified to pH3 with 1 M hydrochloric acid, extracted with ethyl acetate (×3) and the combined organic extracts washed with brine (×1). The extracted organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield 2-[4-[5-amino-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-2-pyridyl]-2-methyl-propanoic acid as white solid (40 mg, 42%) LC/MS m/z 401.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:17]([CH2:18]O)=[C:16]3[C:11]([NH:12][C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]3[CH3:20])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.CS([Cl:37])(=O)=O.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:17]([CH2:18][Cl:37])=[C:16]3[C:11]([NH:12][C:13]([CH3:22])([CH3:23])[C:14](=[O:21])[N:15]3[CH3:20])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1-c1ccc2c(c1CO)N(C)C(=O)C(C)(C)N2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1ccc2c(c1CCl)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
7-(5-Chloro-2-methoxyphenyl)-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 13-1, 1.34 g, 3.71 mmol) was dissolved in anhydrous dichloromethane (19 mL), and triethylamine (621 μL, 4.46 mmol) and methanesulfonyl chloride (316 μL, 4.08 mmol) were added thereto successively. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added to the reaction mixture, washed with water (200 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.14 g) as a colorless amorphous product. (Yield 81%)
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([NH:16][C:17](=[O:80])[C@H:18]([CH2:76][CH:77]([CH3:79])[CH3:78])[NH:19][C:20](=[O:75])[C@H:21]([C:71]([CH3:74])([CH3:73])[CH3:72])[NH:22][C:23](=[O:70])[C@H:24]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69])[NH:25][C:26](=[O:61])[C@H:27]([CH2:52][CH2:53][C:54](=[O:60])[O:55]C(C)(C)C)[NH:28][C:29](=[O:51])[C@H:30]([CH2:43][C:44](=[O:50])[O:45]C(C)(C)C)[NH:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH:11](OC)[O:12]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl.O>[CH2:1]([S:8][CH2:9][C@H:10]([NH:16][C:17](=[O:80])[C@H:18]([CH2:76][CH:77]([CH3:78])[CH3:79])[NH:19][C:20](=[O:75])[C@H:21]([C:71]([CH3:72])([CH3:73])[CH3:74])[NH:22][C:23](=[O:70])[C@H:24]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69])[NH:25][C:26](=[O:61])[C@H:27]([CH2:52][CH2:53][C:54](=[O:55])[OH:60])[NH:28][C:29](=[O:51])[C@H:30]([CH2:43][C:44](=[O:45])[OH:50])[NH:31][C:32](=[O:42])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)[C@H](CSCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CSCc1ccccc1)C(C)(C)C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
56 mg (0.049 mmol) of N1-[2-(benzylthio)-1(R)-(dimethoxymethyl)ethyl]-N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucinamide were dissolved in 10 ml of trifluoroacetic acid/dichloromethane (1:1) containing 3 drops of water and the solution was stirred for 90 minutes. The solution was evaporated to dryness under a vacuum and the residue was re-evaporated twice with toluene. The solid was triturated with 10 ml of diethyl ether to give 40 mg of 3-(benzylthio)-2(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propionaldehyde as a white solid. MS: m/e 927.6 (M+H]+.
Reaction SMILES: [CH2:1]=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[N+:14]([O-:16])=[O:15]>O.CO>[N+:14]([C:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:16])=[O:15]
Reactant: C=C(C(=O)OCC)C(=O)OCC
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(CC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Freshly distilled diethyl methylene-malonate (8.0 g, 0.046 mol) was added dropwise with stirring over a 10 min period to a solution of 16 g (0.1 mol) of nitroform in 25 ml of water and 40 ml of methanol at 0°-5°. The mixture was stirred 16 hrs at room temperature and was then extracted with 100 ml of methylene chloride. The methylene chloride solution was washed with 10% sodium bicarbonate and with water, dried over sodium sulfate and stripped of solvent under vacuum. Column chromatography on 200 g of silica gel (CCl4 --CH2Cl2), filtration through charcoal and removal of solvent gave 13.0 g (87%) of diethyl 2,2,2-trinitroethylmalonate, mp 24°-25°; NMR (CDCl3), 4.23 (q, 4 H, J=7 Hz, CH2CH3), 3.80 (m, 3 H, CH--CH2) and 1.33 (t, 6 H, J=7 Hz, CH3); IR (neat) 1730 (C=O) and 1600 (NO2) cm-1.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:13]C#N)=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.OP([O-])(O)=O.[K+]>CCO>[C:1]([C:5]1[C:6]([SH:13])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Agent: O=P([O-])(O)O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CCO
Product: Cc1cc(S)c(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and condenser were added 35 g (158 mmol) of 5-tert-butyl-2-methyl-4-thiocyanato-phenol prepared in Example GGG, dithiothreitol (25.61 g, 166 mmol), EtOH (250 mL), and 0.02M KH2PO4 buffer solution (25 mL), respectively. The reaction was heated to reflux; after 2 hours, additional dithiothreitol (5.0 g, 32.4 mmol) and 0.02M KH2PO4 buffer solution (25 mL) were added. After 2 hours at reflux, the solution was cooled to room temperature and concentrated. The reaction was quenched with brine and extracted with 1:1 Et2O:hexanes. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was submitted to column chromatography (100% CHCl3, silica gel) to yield the title compound. 1H NMR (CDCl3) δ 1.45 (s, 9 H), 2.15 (s, 3 H), 3.43 (s, 1 H), 4.56 (br s, 1 H), 6.82 (s, 1 H), 7.05 (s, 1 H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[CH:31]=[CH:30][C:11]([C:12]([C:14]2[CH2:15][C:16]([F:29])([CH:26]=[CH:27][N:28]=2)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[O:13])=[CH:10][CH:9]=1.[CH2:32]([OH:34])[CH3:33].[CH:35]1C=CC=C[CH:36]=1>>[CH2:35]([O:18][C:17]([O:34][CH2:32][CH3:33])([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]1([F:29])[CH:26]=[CH:27][N:28]=[C:14]([C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:31][CH:30]=2)[CH2:15]1)[CH3:36]
Reactant: c1ccccc1
Reactant: CCO
Reactant: O=C(C1=NC=CC(F)(C(=O)Nc2ccccc2)C1)c1ccc(Cl)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(Nc1ccccc1)(OCC)C1(F)C=CN=C(C(=O)c2ccc(Cl)cc2)C1
Yield: 75 %

Procedure:
To a mixture of phosphorus pentachloride (7.3 g) in benzene (250 ml), 2-(4-chlorobenzoyl)-4-fluoro-isonicotinanilide (12 g) was added, and the mixture was refluxed for 2 hours under stirring. After cooling, the solvent was completely distilled off under vacuum. The resulting residue was gradually added to an ethyl alcohol solution of potassium hydroxide (3.7 g) and allowed to react at room temperature over a period of 2 hours. After completion of the reaction, ethyl alcohol was distilled off under vacuum. The resulting residue was extracted, after addition of water, with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. Thereafter, the ethyl acetate was distilled off under vacuum. Upon recrystallizing the resulting residue with a mixed solvent of ethyl acetate and n-hexane, the titled compound was obtained in an amount of 10.7 g (yield: 75%). m.p. 96°-97° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([O:20][C:3](=[O:4])[NH:2][CH3:1])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 96.5 %

Procedure:
5.7 g (0.1 mol) of methyl isocyanate and a few drops of dibutyl-tin dilaurate were added, while stirring, to 25.8 g (0.1 mol) of 1-(2,4-dichlorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)-ethane in 250 ml of ethyl acetate. The mixture was stirred overnight at 60°-65° C. It was then allowed to cool and the crystalline precipitate was filtered off and washed with ether. 30.4 g (97% of theory) of 1-(2,4-dichlorophenyl)-1-methylcarbamoyloxy-2-(1,2,4-triazol-1-yl)-ethane of melting point 204° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9](OC(=O)C)(=[O:11])C.[CH3:16][O:17]S([O-])(=O)=O.C([N+](CC)(CC)C)C>C(O)(=O)C>[CH3:9][O:11][CH:8]([O:17][CH3:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COS(=O)(=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1F
Agent: CC[N+](C)(CC)CC
Solvent: CC(=O)O
Product: COC(OC)c1ccccc1F

Procedure:
Electrolyte: 1013 g (9.206 mol) of 2-fluorotoluene, 675 g of acetic anhydride, 338 g of triethylmethylammonium methyl sulfate and 4727 g of acetic acid
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCC.CO>C(Cl)Cl>[C:7]([NH:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](N)CO
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: CC[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.1 %

Procedure:
To a stirred solution of (R)-(−)-2-aminobutan-1-ol (10 g, 112.18 mmol) in CH2Cl2 (500 mL) under Ar at RT, was added Pri2NEt (30 mL, 172.22 mmol) followed by trityl chloride (35.4 mL, 126.98 mmol). The reaction mixture was stirred at RT for 48 h, when TLC (55:40:5 hexane/Et20/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue precipitated from Me2CO (50 mL) with hexane (900 mL) with stirring, the precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (1 L), filtered, and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil (32 g, 86%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.56 (t, 3H, J=7.41, —NHCH(CH2CH3)CH2OH), 1.10 (m, 2H, —NHCH(CH2CH3)CH2OH), 2.21 (m, 1H, —NHCH(CH2CH3)CH2OH), 2.72+3.00 (2×m, 2H, —NHCH(CH2CH3)CH2OH), 4.28 (t, 1H, J=5.26 Hz, —NHCH(CH2CH3)CH2OH), 7.14-7.49 (m, 15H, 3×Bz).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[C:15](=[O:23])[N:14]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:13]3[CH2:34][CH2:35][C:36](=[O:37])[C:12]2=3)=[C:7]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:6]=1)#[N:4].CO.Cl>O1CCCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15](=[O:23])[N:14]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)[C:13]3[CH2:34][CH2:35][C:36](=[O:37])[C:12]2=3)=[C:7]([S:38]([CH3:41])(=[O:39])=[O:40])[CH:6]=1)#[N:4]
Reactant: CCOC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC(=O)O
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide solution (1.0 M, 10.0 mL, 10.0 mmol) is added to a solution of ethyl 2-(4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetate (intermediate 29, 1.80 g, 3.20 mmol) in tetrahydrofuran (40 mL), and the mixture is stirred at room temperature over night. Another portion of aqueous sodium hydroxide solution (4.0 M, 2.0 mL, 8.0 mmol) and methanol (5.0 mL) is added, and mixture is stirred over night. Aqueous hydrogen chloride (1.0 M, 10 mL) is added, and the mixture is extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, and the residue is purified reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 229 mg; ESI mass spectrum: [M+H]+=534; Retention time HPLC: 0.96 min (Z018_S04).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].[CH3:29][Br:30]>CC(C)=O>[Br-:30].[CH3:29][N+:23]1([CH2:22][CH:21]([N:10]2[C:9]3[CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH2:1][CH2:2][CH3:3])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CBr
Reactant: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: CC(C)=O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)C[N+]1(C)CCCC1)c1ccccc1S2
Product: [Br-]
Temperature: 20 °C

Procedure:
A solution of N-propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (5.5 g), in acetone (15 cc) is introduced, dropwise and with stirring during 30 minutes, into a solution of methyl bromide (9.5 g) in acetone (90 cc), and stirring is maintained for 16 hours at a temperature in the region of 20° C. The suspension obtained is filtered and the solid is washed with acetone (3×1 cc), drained and dried at 40° C. under reduced pressure (5 mm Hg; 0.7 kPa). This amorphous white solid (4.8 g) is dissolved in acetonitrile (12 cc) under reflux. The crystals formed after cooling are drained, washed with ice-cold acetonitrile (3×3 cc) and dried at 40° C. under reduced pressure (5 mm Hg; 0.7 kPa). 1-Methyl-1-[2-(2-propylcarbamoyl-10-phenothiazinyl)propyl]pyrrolidinium bromide, L series (2.05 g), is thereby obtained in the form of a crystalline white solid, m.p. 258° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH2:6].Br[C:8](=[CH:11]OC(C)C)[CH:9]=[O:10].C1(N2C(C=O)=CN=C2C)CC1>>[S:1]1[CH2:5][CH2:4][N:3]2[C:8]([CH:9]=[O:10])=[CH:11][N:6]=[C:2]12
Reactant: CC(C)OC=C(Br)C=O
Reactant: NC1=NCCS1
Agent: Cc1ncc(C=O)n1C1CC1
Product: O=Cc1cnc2n1CCS2

Procedure:
2,3-Dihydro-imidazo[2,1-b]thiazole-5-carbaldehyde was prepared from 4,5-dihydro-thiazol-2-ylamine and and 2-bromo-3-isopropoxy-propenal in the same manner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[C:3]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1
Reactant: OCc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(-c2ccc(CO)nc2)c1
Reaction time: 0.33 h

Procedure:
5-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 148.1, 60 mg, 0.134 mmol), (6-(hydroxymethyl)pyridin-3-yl)boronic acid (41.1 mg, 0.269 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol) and Na2CO3 (42.8 mg, 0.403 mmol) were added to a MW vial and treated with a mixture of DME (570 μL), water (163 μL) and EtOH (81 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min and then at 130° C. for 20 min, diluted with DME (2 mL) and treated with Si-Thiol (Silicycle, 1.44 mmol/g, 46.7 mg, 0.067 mmol). The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 15% to 20% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.95 min, m/z=475.4 [M+H]+, m/z=473.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.07-3.22 (m, 4H) 3.48-3.62 (m, 4H) 4.63 (s, 2H) 5.54 (br. s, 1H) 7.38 (d, J=8.53 Hz, 2H) 7.60 (d, J=8.03 Hz, 1H) 7.82-7.92 (m, 2H) 8.11 (d, J=8.28 Hz, 1H) 8.13-8.16 (m, 1H) 8.75-8.79 (m, 1H) 8.79-8.86 (m, 1H) 10.38 (br. s, 1H).