Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]S.COC(OC)CCl.[Na].[CH2:16]([SH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([S:23][C:3]([O:6][CH3:7])([O:2][CH3:1])[CH3:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: SCc1ccccc1
Reactant: COC(CS)OC
Agent: COC(CCl)OC
Agent: [Na]
Product: COC(C)(OC)SCc1ccccc1

Procedure:
Several processes for making 2-mercaptoacetaldehyde dimethylacetal (I, R1 =R2 =CH3) are reported by Parham et al., J. Am. Chem. Soc. 75, 2065-2069 (1953). These processes involve reaction of 2-chloroacetaldehyde dimethyl acetal with (1) benzylmercaptan sodium salt to produce benzyl-(1,1-dimethoxy ethyl)sulfide which was then reduced with sodium/ammonia to the desired acetal; (2) sodium sulfide to form 1,1,1', 1'-tetramethoxyethyl disulfide followed by reduction of said disulfide using sodium/ammonia or lithium aluminum hydride; and (3) sodium polysulfide to give a mixture of polysulfides which was reduced with sodium/ammonia. A fourth process described in said reference comprises the action of potassium hydrosulfide on diethyl or dimethyl bromoacetal to produce the corresponding dialkyl mercaptoacetal.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][C:17]1[CH:44]=[C:43]2[C:20]([CH2:21][CH2:22][C:23]3[C:24]2=[N:25][O:26][C:27]=3[C:28]2[C:32]([C:33]([F:36])([F:35])[F:34])=[C:31]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:30][N:29]=2)=[CH:19][C:18]=1O.CCCCCC>N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:18]1[CH:19]=[C:20]2[C:43](=[CH:44][C:17]=1[CH3:16])[C:24]1=[N:25][O:26][C:27]([C:28]3[C:32]([C:33]([F:34])([F:35])[F:36])=[C:31]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:30][N:29]=3)=[C:23]1[CH2:22][CH2:21]2)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc2c(cc1O)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Yield: 77.1 %

Procedure:
Trifluoromethanesulfonic anhydride (0.074 mL, 0.440 mmol) was added to a solution of 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Preparation 64C, 0.121 g, 0.293 mmol) in pyridine (5 mL) at 0° C. over a period of 5 min. The reaction mixture was stirred at 0° C. for ten minutes and then at room temperature overnight. The reaction mixture was concentrated, and the yellowish-brown residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The ethyl acetate layer was washed sequentially with 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was collected, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with a mixture of 15% ethyl acetate:85% hexane to yield 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl trifluoromethanesulfonate as a tan solid (0.123 g, 0.226 mmol, 77%). The product had an HPLC ret. time=4.52 min (condition B). LC/MS M+1=545.2.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:25][C:24]=1[C:32]([F:33])([F:35])[F:34]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: COc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 70 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-(methyloxy)-3-(trifluoromethyl)benzoyl chloride. MS (ESI): m/z 467 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1)=[O:8].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[N:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[O:11]=[C:10]1[C:5]2[C:6](=[CH:12][C:2]([NH:1][C:23]([NH:22][C:15]3[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=3[Cl:13])=[O:24])=[CH:3][CH:4]=2)[C:7](=[O:8])[NH:9]1
Reactant: O=C=Nc1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2c(c1)C(=O)NC2=O)Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 4 h

Procedure:
5-Aminophthalimide (100 mg, 0.62 mmol) and 2,4,6-trichlorophenyl isocyanate (150.9 mg, 0.68 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([NH2:17])[N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([NH2:17])[N:14]=[C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Reactant: OB(O)c1ccccc1Cl
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: O
Solvent: CC#N
Product: Nc1nc2c(c(-c3ccccc3Cl)n1)CN(Cc1ccccc1)CC2
Temperature: 95 °C
Yield: 61.2 %

Procedure:
6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-ylamine (1.92 g., 7 mmoles) and 2-chlorophenylboronic acid (1.09 g., 7 mmoles) were mixed and stirred in a mixture of acetonitrile and water (50:50, 32 mls); anhydrous potassium carbonate (1.93 g., 14 mmoles) was then added to the stirred reaction mixture under nitrogen. Pd(PPh3)4 (0.2 g.) was then added to the reaction mixture which was stirred and heated at 95° C. for 3 hours also under nitrogen. The reaction mixture was then allowed to cool to room temperature and a beige solid formed. This suspension was quenched with water (150 mls) and the solid filtered and washed with water (100 mls) dried in a vacuum desiccator. The product was then eluted through a ‘silica plug’ in ethyl acetate, after evaporation the solid was slurried in ether to give, after filtering and drying a white solid (1.5 g., 61.2% yield). LC-MS (retention 2.65 mins, mass 351 M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:10][N:11]3[C:16](O)=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:36]>C1(C)C=CC=CC=1>[Cl:36][C:16]1[N:11]2[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[CH:14][CH:15]=1
Reactant: Oc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(Cl)ccnc23)cc1
Temperature: 100 °C

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (I-12A-1a; 2.00 g, 5.61 mmol) and diisopropylethylamine (4.0 ml, 22 mmol) in toluene (60 ml) at room temperature was added POCl3 (2.1 ml, 22 mmol), dropwise. The mixture was heated at 100° C. for 7 hours, concentrated, in vacuo, and the purified by silica gel chromatography using 10% hexanes in methylene chloride as eluant to afford I-13A-1a (1.72 g, 82%) as a solid: +APcI MS (M+1) 374.1; 1H NMR (400 MHz, CD2Cl2) δ 8.49 (d, J=4.6 Hz, 1H), 7.54–7.38 (m, 6H), 7.28 (d, J=8.7 Hz, 2H), 7.12 (d, J=4.2 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.S(Cl)(Cl)(=O)=O.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:30](=[O:32])[CH3:31])=[N:22][CH:23]=2)=[CH:13][CH:12]=3)[CH2:6][CH2:7]1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(c2cnc3ccc(-c4ccc(N)nc4)cc3n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccc3ncc(N4CCN(C)CC4)nc3c2)cn1
Temperature: 50 °C
Reaction time: 48 h
Yield: 58.8 %

Procedure:
A solution of 5-[3-(4-methyl-1-piperazinyl)-6-quinoxalinyl]-2-pyridinamine (0.46 mmol) in pyridine (3 ml) was treated with a sulfonyl chloride, acyl chloride or anhydride such as acetic anhydride (0.56 mmol) and heated at 50° C. for 18 hour. The reaction mixture was treated with another portion of acetic anhydride (0.10 mmol) and stirred for another 2 days. The reaction mixture was diluted with water and saturated sodium bicarbonate (aq) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was taken into hot ethyl acetate and diluted with hexanes and cool to 0° C. The reaction mixture was filtered and washed with hexanes to give the title compound (98 mg, 58%). MS(ES)+ m/e 321 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.N1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1c(=O)sc2cnc(N)nc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of 88 (0.22 g, 0.44 mmol) in THF (5 mL) in a plastic vial was added HF/pyridine (0.70 mL). The reaction was stirred for 2 h, concentrated and purified by flash column chromatography (silica, MeOH/CHCl3: gradient=5-10%) to afford 0.17 g (100%) of the title compound as a white solid: mp 109-111° C.; 1H (400 MHz, d6-DMSO) δ 8.37 (s, 1H), 6.91 (s, 2H), 6.00 (m, 2H), 5.48 (t, J=6.0 Hz, 1H), 4.91 (t, J=6.0 Hz, 1H), 4.04 (dd, J=10.4, 6.0 Hz, 1H), 3.64 (m, 1H), 3.52 (m, 1H), 2.08 (s, 3H), 2.05 (s, 3H); MS (+)-ES [M+H]+ m/z 385.3. Elemental Analysis calc'd for C14H16N4O7S.0.5 CH3OH.0.2 CHCl3: C, 41.61; H, 4.32; N, 13.21; S 7.56: Found: C, 41.73; H, 4.29; N, 12.86; S, 7.33.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[N:15][OH:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)CC(=NO)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A solution of 7-nitrotetralone (4.20 g, 22.0 mmol) in methanol (100 mL) was cooled to 0° C., and hydroxylamine (1.68 g, 23.2 mmol) and sodium acetate (3.69 g, 46.4 mmol) were added. The reaction was then stirred at room temperature for 12 h. The methanol was evaporated at reduced pressure and dichloromethane (100 mL) was added. The mixture was washed with water, dried over NaSO4 and evaporated at reduced pressure to yield the title compound (4.37 g, 97%). MS (DCI/NH3) m/e 207 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29](=[O:34])[C:30]([O:32][CH3:33])=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:29]([C:30]([O:32][CH3:33])=[O:31])=[O:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and methyl cloro(oxo)acetate (18 mg, 150 μmol). Yield 18 mg (82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:40][C:39]3[CH:41]=[CH:42][C:36]([F:35])=[CH:37][CH:38]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: Nc1ccc(F)cc1
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNc1nc(-c2cccc(C(=O)Nc3ccc(F)cc3)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 77.2 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (15 mg, 0.03 mmol) in CH2Cl2 (3 mL) were added 4-flouroaniline (0.003 mL, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (13 mg, 72%). LC-MS m/z 562 (M+H)+; 1H-NMR (MeOD) δ 2.81 (s, 6H), 3.21 (m, 2H), 3.59 (m, 2H), 4.53 (s, 2H), 7.17 (m, 4H), 7.53 (m, 1H), 7.72 (m, 3H), 7.80 (d, 1H), 8.10 (d, 1H), 8.16 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([OH:26])[C@H:5]([S:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[NH2:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O>[NH2:25][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[S:14][C@H:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C@H:4]([OH:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)[C@@H](O)[C@H](Sc1ccc2ccccc2c1N)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc([C@@H](Sc2ccc3ccccc3c2N)[C@H](O)C(=O)O)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A mixture of 6.6 g (0.017 mol) of (±)-(R*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid methyl ester, 45 ml ethanol and 100 ml 1N sodium hydroxide was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ether. The aqueous solution was chilled, then neutralized with acetic acid and extracted with ethyl acetate (3×60 ml). The combined extracts were washed with water (50 ml) and dried (MgSO4). Removal of the solvent gave 5.5 g of crude (±)-(R*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid which was dissolved in methylene chloride and chromatographed on a column using 55 g of silica gel. The column was eluted with 50 ml portions of methylene chloride. Fractions 12-17 were collected, and the solvent was removed under reduced pressure to afford 1.3 g (20%) of (±)-(R*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid. The analyzed sample was recrystallized from ether, mp 160°-161°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH3:23])[CH:20]([CH3:24])[O:19]1>>[CH3:24][CH:20]1[CH:21]([CH3:23])[O:22][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:19]1
Reactant: COc1ccccc1N
Reactant: CC1OC(CBr)OC1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1NCC1OC(C)C(C)O1
Temperature: 100 °C

Procedure:
2-Methoxyaniline (87 ml; 0.7 mole) and sodium carbonate (31.66 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (25 mls) was added and the reaction mixture was heated at a temperature of 100° C. for a period of about 4 hours. After this time the reaction mixture was filtered and additional sodium carbonate (5.00 grams) was added to the filtrate. The mixture was then distilled under reduced pressure to yield the desired product N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline boiling at 125° to 128° C. at 0.1 mm of Hg pressure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1CCN(Cc2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 216 h

Procedure:
(3R)-1-Benzyl-3-hydroxypyrrolidine (500 μL) and imidazole (466 mg) were dissolved in N,N-dimethylformamide (15 mL), and tert-butyldiphenylsilyl chloride (1.57 mL) was added to the solution under ice cooling, followed by stirring at room temperature for 9 days. The solvent was distilled away under reduced pressure, and the residue was partitioned by adding methylene chloride and water. The organic layer was dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The residue was subjected to silica gel flash column chromatography (hexane ethyl acetate=3:1), to thereby give the title compound (1.27 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([Li])CCC.[CH:24](OCC)=[O:25].C(OCC)(=O)C>CCOCC>[CH2:1]([O:3][P:4]([C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13]([CH:24]=[O:25])=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC=O
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 22.4 %

Procedure:
To a solution of [Difluoro-(4-iodo-phenyl)-methyl]-phosphonic acid diethyl ester (1.6 g, 4.1 mmol) in anhydrous ether (40 mL) at -78° C. was added dropwise n-butyl lithium (2.5 M in hexanes, 2.5 mL, 6.1 mmol). The brown solution was stirred at -78° C. for 2 minutes. Ethyl formate (0.66 mL, 8.2 mmol) was then added, and the reaction was stirred for 10 minutes at -78° C. The mixture was then quenched with saturated ammonium chloride (10 mL) and warmed to room temperature. The reaction was then diluted with ether. The organic layers were washed with saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a yellow oil. Chromatography of the residue [3:7, ethyl acetate:hexanes] gradient to (1:1)] afforded the aldehyde (268 mg, 22%) as a clear oil. 1H NMR (400 MHz, DMSO): δ 10.28 (s, 1H), 8.25 (d, 2H), 7.97 (d, 2H), 4.42 (m, 4H), 1.40 (t, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[C:25](O)=[O:26])/[C:12](=[O:18])[NH:13]2.[CH3:29][NH:30][CH2:31][CH:32]([OH:39])[CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:39][CH:32]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:31][N:30]([CH3:29])[C:25]([C:24]1[CH:23]=[C:22]([CH3:28])[NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH:17]=[CH:16][CH:15]=2)=[O:26]
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]1
Reactant: CNCC(O)CN1CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)CC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]1

Procedure:
2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (115 mg, 0.3 mmol) was coupled with 1-methylamino-3-pyrrolidin-1-yl-propan-2-ol (3 eq.), EDC (2 eq.), HOBt (1 eq.) in DMF (1.5 mL) to give 108 mg of the titled compound as a yellow solid. MS 521.2 [M++1].
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Br:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CCBr
Reactant: Nc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1ccc(NC(=O)CCBr)cc1
Temperature: 80 °C
Yield: 64.7 %

Procedure:
A solution of 7.02 g of p-aminoaniline in 150 ml of toluene was added 9.12 ml of triethylamine and stirred at 80° C. while adding dropwise a solution of 11 g of β-bromopropionyl chloride in 30 ml of toluene. After the mixture was reacted for 30 minutes colored resinous substance which formed was removed, and the reaction mixture was washed with water and dried. Removal of the solvent by distillation gave 10.1 g of N-(β-bromopropionyl)-p-aminoaniline as oily product. Production of the compound was confirmed by IR and NMR spectra.
Reaction SMILES: S(=O)(=O)(O)O.C=O.[C:8]([O-:11])(=[O:10])[CH3:9].[Na+].[C:13]([O:16][C:17](=O)C)(=[O:15])[CH3:14]>>[C:8]([O:11][CH2:17][O:16][C:13](=[O:15])[CH3:14])(=[O:10])[CH3:9]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)OCOC(C)=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 2856.3 %

Procedure:
5 g of concentrated sulphuric acid are added dropwise to a suspension of 300 g of paraformaldehyde in 1,020 g of acetic anhydride in the course of 5 minutes, during which the temperature rises from room temperature to about 100° C. When the addition had ended, the mixture is heated to 150° C. and is stirred at this temperature for 3 hours. It is then cooled to room temperature, 25 g of sodium acetate are added and the volatile constituents are distilled off in vacuo. About 1,300 g of distillate are thereby obtained, and are then fractionated, with addition of 10 g of sodium acetate, over a 50 cm packed column. 1,150 g (87.1% of theory) of methylene diacetate of boiling point 96° to 99° C. under 90 mbar are thereby obtained.