Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[CH2:28]([O:30][C:31]([C:33]1[CH:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:54])[NH:46][CH2:47][C:48]3C=N[CH:51]=[CH:52][CH:53]=3)=[CH:41][CH:40]=2)[C:37]([C:55](=[O:57])[NH2:56])=[C:36]([CH2:58][CH3:59])[NH:35][C:34]=1[CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)=[O:32])[CH3:29].FC(F)(F)C(O)=[O:72]>C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:32])[C:33]1[C:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:54])[NH:46][CH2:47][C:48]3[O:72][CH:51]=[CH:52][CH:53]=3)=[CH:41][CH:40]=2)=[C:37]([C:55](=[O:57])[NH2:56])[C:36]([CH2:58][CH3:59])=[N:35][C:34]=1[CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[CH3:29]
Reactant: CCOC(=O)C1=C(CCc2ccc(F)cc2)NC(CC)=C(C(N)=O)C1c1ccc(C(=O)NCc2cccnc2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc(CC)c(C(N)=O)c1-c1ccc(C(=O)NCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
An aqueous solution of CAN (1 M, 1 mL) was added to 2 mL of DCM solution of compound 16 (˜0.25 mmol) and trifluoroacetic acid (0.1 mL). The resulting mixture was vigorously stirred for 20 min at r.t. The organic layer was separated, washed with water, dried over MgSO4, and concentrated in vacuo to yield the crude product. Purification by preparative LCMS (PE SCIEX, C18, acetonitrile—water with 0.035% trifluoroacetic acid) yielded the title compound in 18.5 mg yield. LC/MS (gradient 40-99%, 5 min.) RT=3.215. Calculated mass=243.2. Mass observed=243.7. 1H NMR (500 MHz, CDCl3): δ 0.88 (t, 3H), 1.36 (t, 3H), 2.98 (bq, 2H), 3.07 (bq, 2H), 3.15 (bq, 2H), 3.94 (q, 2H), 4.65 (d, 2H), 5.61 (bs, 1H), 6.32 (m, 1H), 6.36 (m, 1H), 6.61 (bt, 1H), 6.96 (t, 2H), 7.18 (t, 2H), 7.39 (s, 1H), 7.40 (d, 2H), 7.81 (d, 2H).
Reaction SMILES: [Cl:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:23][C@@H:22]([OH:24])[C@H:21]([OH:25])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=[CH:32][N:31]=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>[Cl:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:35]3[C:30]([CH3:29])=[N:31][CH:32]=[N:33][CH:34]=3)[C:15]([N:19]3[CH2:23][C@@H:22]([OH:24])[C@H:21]([OH:25])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Cc1ncncc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@H](O)C2)c(I)c1
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+]
Product: Cc1ncncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1C[C@@H](O)[C@H](O)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N-(4-(chlorodifluoromethoxy)phenyl)-6-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-5-iodonicotinamide (Stage 282.1, 100 mg, 0.190 mmol) and 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (Stage 297.1, 62.8 mg, 0.285 mmol), Pd(Ph3P)4 (21.98 mg, 0.019 mmol) and K2CO3 (79 mg, 0.571 mmol) were added to a vial and flushed with argon. DMF (2 mL) was added and the mixture was stirred at 100° C. for 2 h. The solvent was evaporated off under reduced pressure. The crude product was dissolved in MeOH, filtered through a PL-resin Si-Thiol cartridge, the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 14-25% to 55% MeCN in 20 min) and followed by preparative SFC (Column Diol, from 20% to 25% in 6 min). The purified product was lyophilized in water/min vol. MeCN to afford the title product as a white powder. UPLC-MS (Condition 3), tR=0.86 min, m/z=492.2/494.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH2:21][C:22]#[C:23][C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]3[CH2:39][CH2:38]3)=[C:32]([Cl:40])[CH:31]=2)[N:27]=[CH:26][N:25]=1)[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>ClCCl>[NH2:15][C@@H:16]([CH2:21][C:22]#[C:23][C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]3[CH2:39][CH2:38]3)=[C:32]([Cl:40])[CH:31]=2)[N:27]=[CH:26][N:25]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](CC#Cc1cc(-c2ccc(OC3CC3)c(Cl)c2)ncn1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CC#Cc1cc(-c2ccc(OC3CC3)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Trifluoroacetic acid (6 ml) was added dropwise to a stirred solution of methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]pent-4-ynoate (2.26 g, 4.8 mmol) in dichloromethane (20 ml) and the mixture was stirred at room temperature overnight. After this time the reaction mixture was concentrated and the resulting residue redissolved in DCM (20 ml) before being washed with saturated sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (1.64 g, 92% yield) as a brown oil. Tr=1.63 min m/z (ES+) (M+H+) 372, 373.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[C:15]([F:19])=[CH:16][CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[OH-].[K+].C([O:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46])(=O)C>ClCCl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:45](=[O:46])[C:44]([OH:43])([CH3:49])[CH3:48])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)O)c1
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-5-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 61) (100 mg, 0.208 mmol) in dichloromethane (0.5 mL), pyridine (0.5 mL) and potassium hydroxide (11.67 mg, 0.208 mmol) was treated with 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.054 mL, 0.37 mmol) and the mixture was stirred for 2.5 h. The reaction mixture was concentrated in vacuo and the orange residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (58 mg, 49%). LCMS (System A) RT=1.04 min, ES+ve m/z 567/569 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, light yellow solid (75 mg, 64%), MS (ISP) m/z=471.4 [(M+H)+], mp 168.5° C., was prepared in accordance with the general method of example 48 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and benzene-sulfonyl chloride.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.[C:18](Cl)(=[O:22])[C:19](C)=[CH2:20]>C(C(C)=O)C>[C:18]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:16][CH:17]=1)(=[O:22])[CH:19]=[CH2:20]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: C=CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
1.3 g (16.25 mmoli) of NaOH 50% water solution, were added to a solution of 3 g (15.21 mmol) of 4-hydroxybenzophenone in 20 cc of methyl ethyl ketone. After 30 minutes under stirring, a solution of 1.59 g (15.21 mmol) of methacryloyl chloride in 5 mL of methyl ethyl ketone were added dropwise. After the addition the reaction mixture was stirred for 1 hour, filtered and the solvent was evaporated. The oil residue was purified by flash chromatography on silica gel (eluent CH2Cl2) to obtain 2.74 g of a colourless liquid.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]3[CH:43]=[CH:42][C:23]([C:24]([C@:26]([C@H:30]([C@@H:32]([C@@H:34]([C:36]([O:38]CC=C)=[O:37])[OH:35])[OH:33])[OH:31])([OH:29])[CH:27]=[O:28])=[O:25])=[CH:22][CH:21]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCCC1>O1CCCC1>[C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]3[CH:43]=[CH:42][C:23]([C:24]([C@:26]([C@H:30]([C@@H:32]([C@@H:34]([C:36]([OH:38])=[O:37])[OH:35])[OH:33])[OH:31])([OH:29])[CH:27]=[O:28])=[O:25])=[CH:22][CH:21]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=CCOC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@](O)(C=O)C(=O)c1ccc(N2CCC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: C[C@@H](N[C@H]1CCCN(c2ccc(C(=O)[C@](O)(C=O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O)cc2)C1)c1cccc2ccccc12
Yield: 38.4 %

Procedure:
In 6 ml of tetrahydrofuran was dissolved 615 mg of allyl 2-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethyl]aminopiperidin-1-yl]-benzoyl]-D-glucuronate, and the mixture was stirred under ice-cooling and in nitrogen atmosphere. To the mixture were added 91 μl of pyrrolidine, and then, 123 mg of tetrakistriphenylphosphine palladium, and the resulting mixture was stirred for 30 minutes. The residue obtained by concentration under reduced pressure was purified by LC-MS. Ether was added to the obtained solid, the solid was pulverized, collected by filtration, and dried to obtain 220 mg of 2-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethyl]aminopiperidin-1-yl]-benzoyl]-D-glucuronic acid (Example 12.030 in the following Table X). (HPLC purity: 67.7%)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:29]([O:40][CH3:41])=[C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:27]3[C:26]([F:25])=[CH:31][C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[C:29]([O:40][CH3:41])[CH:28]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)OC(C)(C)C

Procedure:
trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.60 g, 1.36 mmol), tert-butyl N-[5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.0 g, 2.72 mmol), palladium tetrakistriphenyphosphine(0.094 g, 0.082 mmol) and sodium carbonate (0.35 g, 3.27 mmol) were mixed with ethylene glycol dimethyl ether (14 mL) and water (7 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)carbamate (0.264 g, 35%). 1H NMR (DMSO-d6) δ 1.49 (s, 9H), 1.97 (m, 6H), 2.16 (s, 3H), 2.33 (m, 5H), 2.53 (m, 4H), 3.84 (s, 3H), 4.64 (m, 1H), 7.60 (d, J=6.78 Hz, 1H), 7.83 (d, J=11.96 Hz, 1H), 8.20 (s, 1H), 8.24 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=555.3, Rt=2.00 min.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[O:26]1[C:31]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[CH2:30][NH:29][CH2:28][CH2:27]1.[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[C:53](O)=[O:54].C(N(CC)CC)C>CN(C=O)C>[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[C:53]([N:29]1[CH2:30][C:31]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:26][CH2:27][CH2:28]1)=[O:54]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: O=C(O)c1nc2ccccc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)c1nc3ccccc3s1)CCO2
Reaction time: 16 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.45 g) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.8 g), 1,3-benzothiazol-2-carboxylic acid (0.588 g) and triethylamine (1.51 mL) in DMF (15 mL) and the resulting mixture stirred for 16 h. The volume of DMF was reduced in vacuo and the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a yellow oil. Yield 0.83 g.
Reaction SMILES: CC(C)([O-])C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O.CO>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][C:17]#[N:18])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC#N)cc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a suspension of potassium tert-butoxide (2.36 g, 20 mmol, 4 eq.) in THF (15 mL), a solution of tosylmethyl isocyanide (1.95 g, 10 mmol, 2 eq.) in THF (5 mL) was added at −78° C. The mixture was stirred at −78° C. for 15 min. A solution of 3-chloro-4-methoxybenzaldehyde (879 mg, 5 mmol, 1 eq.) in THF (5 mL) was added dropwise. The resulting mixture was stirred for 1.5 hours at −78° C. To the cooled reaction mixture, methanol (5 mL) was added. The mixture was then heated at reflux for 30 min. The solvent was removed in vacuo. The residue was partitioned between water (20 mL) and AcOEt (10 mL). The aq. phase was extracted with AcOEt (2×10 mL). The comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 50 fractions of 45 mL, Heptane to Heptane+25% AcOEt) to yield (3-chloro-4-methoxy-phenyl)-acetonitrile as a pale yellow oil that solidified upon standing.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>Cl>[C:14]([NH:18][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)N
Agent: Cl
Product: CC(C)(C)NCC(O)COc1ccc(C=O)cc1

Procedure:
To 4-(2,3-epoxypropoxy)benzaldehyde (20 g.) is added tert. butylamine (50 ml.) and the resulting solution is refluxed 17 hours. The excess tert. butylamine is removed by heating at atmospheric pressure to yield a solid residue. To this residue is added 6 N hydrochloric acid (200 ml.) and the resulting mixture is heated 5 hours on a steam bath. The solution is cooled and concentrated to 100 ml. on a steam bath under reduced pressure (20 mm. Hg.). The concentrated solution is made basic to pH 10 with saturated aqueous sodium carbonate and extracted with chloroform. The chloroform extract is concentrated to a solid which after recrystallization from acetonitrile yields 18 g. of 4-(3-tert.butylamino-2-hydroxypropxy)benzaldehyde, m.p. 123°-125.5° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1)[CH2:6][NH:7]C(=O)OC(C)(C)C)(=[O:3])[CH3:2].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:23])([F:24])[F:25])=[CH:17][N:16]=1
Reactant: CC(=O)NC(CNC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC(CN)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.30 g of tert-butyl 2-(acetylamino)-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethylcarbamate (0.034 mol) are diluted in a mixture of dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL). After stirring overnight at room temperature, the reaction mixture is concentrated to dryness to yield to 1.34 g of desired product N-{2-amino-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}acetamide trifluoroacetate (99%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[C:25]([Br:29])(Br)(Br)Br.OC[CH2:32][S:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1>C(Cl)Cl.O>[Br:29][CH2:25][CH2:32][S:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1
Reactant: Nc1ncc(SCCO)s1
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Nc1ncc(SCCBr)s1

Procedure:
Triphenylphosphine (12.1 g), imidazole (3.86 g), and carbon tetrabromide (4.44 g) were added to a suspension of 5-(2-hydroxyethylthio)thiazol-2-amine (2.00 g) in methylene chloride (74.6 mL) under cooling with ice, and the mixture was stirred under cooling with ice for 4 hours. Methylene chloride (200 mL) and water (100 mL) were added to the reaction mixture, and the mixture was extracted. The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (neutral spherical silica gel, ethyl acetate:hexane=1:10 and then 1:2) and washed with hexane to give the title compound as white powder crystals (1.06 g, yield: 39%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:17]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:8])[CH:14]([CH3:16])[CH3:15]
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(=O)N(CC(C)C)C2=O
Temperature: 140 °C

Procedure:
N-Isobutyl-4-methylphthalimide is prepared as described in Example 2, starting with 6.0 g of 4-methylphthalic anhydride, 3.7 cm3 of isobutylamine and a catalytic amount of para-toluenesulphonic acid in 60 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for three hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 50 cm3 of saturated aqueous sodium bicarbonate solution, and the mixture is then extracted twice with 75 cm3 of dichloromethane. The organic extracts are combined, dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C., giving 6.7 g of N-isobutyl-4-methylphthalimide in the form of a white solid melting at 102° C.
Reaction SMILES: [C:1]1([S:7]([CH2:9][Br:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[C:13]=1[CH3:20].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:37]([F:41])([F:40])([F:39])[F:38]>C(OCC)C>[F:38][B-:37]([F:41])([F:40])[F:39].[Br:10][CH2:9][S+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]1[CH:16]=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]([CH3:20])[C:12]=1[CH3:11]
Reactant: Cc1ccc(C)c(C)c1C
Reactant: O=S(CBr)c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1cc([S+](CBr)c2ccccc2)c(C)c(C)c1C
Reaction time: 3 h

Procedure:
Bromomethyl phenyl sulfoxide (1 g, 4.58 mmol) of example 32 was dissolved in dry diethyl ether (30 mL) under an argon atmosphere. 1,2,3,4-tetramethylbenzene (0.678 g, 1.09 eq) was added to the previous solution and then the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.77 mL, 1 eq) was added slowly, maintaining the same temperature. The mixture was stirred until the reaction was complete. After 3 hours at −60° C., HBF4 in diethyl ether was added (54%, 1.11 mL; 1.75 eq). The resulting suspension was stirred for 30 minutes. The precipitated tetrafluoroborate salt formed was isolated by filtration and dried under vacuum. 1.24 g (62%) of the desired product was obtained as a white solid. mp: 140-142° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: Cc1cccc(N=C=S)c1C
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cccc(C)c2C)C1=S
Yield: 41.5 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 16.3 g of 2,3-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.3 g) as a light pink solid, m.p. 120°-121° C. Anal. Calcd. for. C13H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.72; H,. 6.44; N, 11.47. Mass spectrum (El, M.+) m/z 248.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].C(=O)(O)[O-].[K+].[C:20](O)(=O)[CH3:21]>O>[CH3:20][C:21]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=3
Reactant: COc1ccc2c(NN)nccc2c1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: COc1ccc2c(ccn3c(C)nnc23)c1
Yield: 24 %

Procedure:
1-Hydrazino-6-methoxyisoquinoline (9.6 g., 0.05 mol.) was dissolved in glacial acetic acid (190 ml.) and the solution was heated at reflux for four hours. Excess acetic acid was removed in vacuo to provide a brown oil. The oil was slurried in water and was treated with potassium bicarbonate to yield a solid. The solid was treated with decolorizing carbon and was recrystallized three times from benzene to give the productin a yield of 24%; m.p. 183°-184°C.