Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][CH:19]=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:20].C([O-])(=O)C.[Na+].[I:26]Cl>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([I:26])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:20]
Reactant: ClI
Reactant: Cc1cc(-c2cc(C(F)F)n3nccc3n2)ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cc(C(F)F)n3ncc(I)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.3 %

Procedure:
To a stirred solution of 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (5.1 g, 17.4 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.61 g, 19.6 mmol) and drop wise a solution of iodine monochloride (3.19 g, 19.6 mmol) in acetic acid (10 mL). The reaction mixture was stirred at room temperature for 19 h, diluted slowly with water (300 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (7.03 g, 96%) as a yellow solid. MS (EI) 419.9 [(M)+]; mp 144° C.
Reaction SMILES: [C:1]([NH:6][C:7](=[NH:10])OC)([O:3][CH2:4][CH3:5])=[O:2].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>CO>[C:1]([NH:6][C:7]([NH:21][CH2:20][CH2:19][S:18][CH2:17][C:16]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:11])=[NH:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCOC(=O)NC(=N)OC
Solvent: CO
Product: CCOC(=O)NC(=N)NCCSCc1[nH]cnc1C

Procedure:
A solution of N-carbethoxy-O-methylisourea (1.46 g.) and 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (1.71 g.) in methanol (25 ml) was stirred at room temperature for 7 days. The white solid formed during the reaction was collected and recrystallised from methanol to give N-carbethoxy-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-guanidine m.p. 196°-197°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.C(Cl)(Cl)Cl.CO>[CH3:25][S:26]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[CH2:6][CH2:5]1)(=[O:28])=[O:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1

Procedure:
A mixture of tert-butyl [1-(2-hydroxyethyl)piperidin-4-yl]carbamate (Intermediate 7, 1.7 g, 7 mmol) in dry dichloromethane (20 mL) and triethyl amine (1.4 mL, 9.8 mmol) was treated at 0° C. with methanesulfonyl chloride (0.65 mL, 8.4 mmol). After 45 minutes the reaction was complete by TLC (chloroform/methanol 6:1, rf 0.54). Potassium phosphate buffer (pH 7, 1M, 50 mL) was added, dichloromethane was removed under reduced pressure and it was extracted with ice-cold ethyl acetate (2×100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1>C(OCC)(=O)C.CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:31])([F:32])[F:30])=[CH:12][N:11]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-(3-methoxy-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I5) (0.358 g, 0.572 mmol) in ethyl acetate (25 mL) and dimethylformamide (5 mL) was added 10% Pd/C (0.200 g). The mixture was evacuated and backfilled three times with hydrogen gas then stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a plug of Celite, washing with ethyl acetate then the filtrate was evaporated in vacuo and dried under high vacuum to give the title compound (I6) (0.360 g, 100%) as a viscous yellow oil; 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.00-3.20 (m, 8H), 3.59 (t, 4H, J=4.8 Hz), 3.67 (s, 3H), 3.75 (s, 2H), 3.90 (s, 3H), 6.55-6.57 (m, 2H), 7.19-7.26 (m, 4H), 7.75 (s, 1H), 8.26 (d, 1H, J=9.4 Hz) and 8.50 (s, 1H). LCMS Method B: rt 6.55 min; m/z 630.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[N:9][C:8]([C:25]1[NH:29][C:28](=[O:30])[NH:27][N:26]=1)=[CH:7]2.[ClH:31].CCOC(C)=O>>[ClH:31].[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[N:9][C:8]([C:25]1[NH:29][C:28](=[O:30])[NH:27][N:26]=1)=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cc3cccc(F)c3c(O[C@H]3CCNC3)n2)[nH]1
Yield: 100 %

Procedure:
A solution of (S)-tert-butyl 3-((8-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (90 mg, 0.224 mmol) in HCl/EtOAc (4M, 10 mL) was stirred at RT for 2 hours. The mixture was subsequently concentrated in vacuo to give an HCl salt of title compound (80 mg, 100%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].CS([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=O)=O.[OH:19][C@@H:20]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33](O)[CH:32]=1)[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[NH4+].[Cl-]>CN(C=O)C>[OH:19][C@@H:20]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:36]=1)[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCOCC2)c1

Procedure:
Cs2CO3 (2.34 g, 7.18 mmol) was added to a solution of (tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (1.05 g, 5.41 mmol) and Intermediate I (1.13 g, 4.23 mmol) in anhydrous DMF (11 mL) and the reaction mixture was heated at +70° C. under Ar for 22 hrs. Aqueous NH4Cl (25%) was added and the reaction mixture was extracted with MTBE twice. Combined organic layers were washed with brine, concentrated under reduced pressure. Purification by flash chromatography (25%-100% EtOAc-hexanes gradient) gave (R)-tert-butyl (3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propyl)carbamate as a colorless oil. Yield (0.47 g, 30%); 1H NMR (400 MHz, DMSO-d6) δ 7.18 (t, J=8.0 Hz, 1H), 6.85-6.84 (m, 2H), 6.76-6.74 (m, 2H), 5.15 (d, J=4.4 Hz, 1H), 4.49 (q, J=4.4 Hz, 1H), 3.88-3.84 (m, 2H), 3.79 (d, J=6.4 Hz, 2H), 2.94 (q, J=6.4 Hz, 2H), 1.70-1.62 (m, 4H), 1.38-1.26 (m, 11H).
Reaction SMILES: [Na].[I-].[K+].Br[C:5]1[CH:9]=[CH:8][S:7][CH:6]=1.[CH2:10]([OH:13])[CH2:11][OH:12]>[Cu]=O>[OH:12][CH2:11][CH2:10][O:13][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1
Reactant: OCCO
Reactant: Brc1ccsc1
Agent: O=[Cu]
Agent: [I-]
Agent: [K+]
Product: OCCOc1ccsc1

Procedure:
Using the same reaction conditions as those of Example 7, sodium (2.0 g) in ethylene glycol (125 ml), copper (II) oxide (1.25 g) and potassium iodide (0.05 g) were reacted with 3-bromothiophene (5.0 g, 0.031 mol). Chromatography of the crude product on a silica column eluted initially with dichloromethane, then with a mixture of dichloromethane/methanol (95:5) yielded 3-(hydroxyethoxy)thiophene, as a white solid (1.9 g, 43%). M.p. 38°-39° C. (Found: C, 49.2; H, 5.3; S, 21.9. Calculated for C6H8O2S: C, 50.0; H, 5.6; S, 22.3%); EI m/e Intensity (%): 144 (100, M+), 100 (47, C4H4OS), 45 (17, C2H5O); δH(CDCl3) 6.10-7.11 (3H, m), 4.16 (2H, m), 3.84 (2H, m); δC(CDCl3): 60.8, 71.4, 97.7, 119.4, 124.8, 157.4 ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1cccnc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCc1cccnc1
Reaction time: 3 h
Yield: 64.5 %

Procedure:
A mixture of 3-pyridineethanol (4 g), 1,6-dibromohexane (23.78 g), TAB (0.5 g) and 2N sodium hydroxide (50 ml) was vigorously stirred for 3 h. The mixture was diluted with water (75 ml), extracted with ethyl acetate and the combined organic extracts were washed with brine (150 ml), dried and evaporated. The resulting oil was purified by FCC eluting with hexane→hexane-ethyl acetate (19:1) to give 3-[2-[(6-bromohexyl)oxy]ethyl]pyridine (6 g). A solution of this bromocompound (5 g) and benzylamine (15 ml) was stirred at 140° under nitrogen for 1 h. The cooled reaction mixture was partitioned between sodium bicarbonate (150 ml) and ethyl acetate (50 ml). The organic layer was washed with brine (50 ml), dried and concentrated to give a yellow oil. The excess benzylamine was removed by distillation and the resulting oil was purified by FCC eluting with System C (95:5:1) to give the title compound as a yellow oil (4 g), t.l.c. (System A 80:20:1) Rf 0.5.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2cccc(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3-fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester according to the method of Example 21. 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, 1H, J=3.5 Hz, 1.17 Hz), 7.41 (dd, 1H, J=5.1 Hz, 1.17 Hz), 7.19-7.16 (m, 3H), 7.08 (dd, 1H, J=5.1 Hz, 3.91 Hz), 6.81 (d, 2H, J=8.6 Hz), 6.75-6.62 (m, 3H), 4.17 (t, 2H, J=6.6 Hz), 3.26 (d, 1H, J=13.7 Hz), 3.14 (d, 1H, J=13.69 Hz), 2.98 (t, 2H, J=6.65 Hz), 2.36 (s, 3H), 1.45 (s, 3H). HRMS (ES+) m/z exact mass calcd for C26H25FNO5S 482.1437, found 482.1454.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N

Procedure:
The title compound was prepared from (2-nitro-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example A22) (10.38 g, 32.2 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light brown solid (8.76 g, 93%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:15])[C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.CS(C)=O.[CH2:20]([O:27][CH2:28][C:29]([C:32]1[O:33][C:34]2[C:35](=[C:37]([C:49]#[N:50])[C:38]([CH3:48])=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:40]=2F)[N:36]=1)([CH3:31])[CH3:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH2:20]([O:27][CH2:28][C:29]([C:32]1[O:33][C:34]2[C:35](=[C:37]([C:49]#[N:50])[C:38]([CH3:48])=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:40]=2[N:12]2[CH2:13][CH2:14][C@H:10]([N:9]([CH3:15])[CH3:8])[CH2:11]2)[N:36]=1)([CH3:31])[CH3:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)COCc3ccccc3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)COCc3ccccc3)nc2c1C#N
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Triethylamine (222 μl, 1.59 mmol), (3S)-3-(dimethylamino)pyrrolidine (152 μl, 1.19 mmol) were added to a dimethyl sulfoxide (16.5 ml) solution of 2-[2-(benzyloxy)-1,1-dimethylethyl]-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-66) (330 mg, 0.796 mmol), followed by stirring overnight at 90° C. After cooling, the reaction liquid was diluted with ethyl acetate, washed three times with saturated brine, then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain the entitled compound (369 mg, 91%) as a pale brown oil.
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].CN(C)[CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O1CCCC1.CCOCC>[CH2:1]=[CH:2][CH:7]=[CH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(=O)C=CN(C)C
Reactant: C=CBr
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC=CC(=O)CCCCC
Temperature: 25 °C

Procedure:
To a solution of Grignard reagent prepared from vinyl bromide (10.7 g), and magnesium (2.43 g) in dry tetrahydrofuran (40 ml) is added gradually a solution of 1-(dimethylamino)-1-octen-3-one (16.9 g), described in Example 37, in dry tetrahydrofuran (20 ml). The mixture is stirred and heated to reflux for 1 hr. The reaction mixture is cooled to room temperature, diluted with ether, washed with hydrochloric acid (10 ml), followed by saturated ammonium chloride solution. The ether extract is dried, and the solvent is removed. The residue is chromatographed to yield the title compound, λmaxEtOH 260 nm (ε=17,050), γmaxfilm 1686, 1668 cm-1.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)N1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:40])[N:18]([CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)[CH2:25][CH2:24]3)[C:19]2=[O:22])=[CH:15][C:14]=1[S:41]([NH2:44])(=[O:43])=[O:42].C(O)(=O)C>C(OCC)(=O)C>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:40])[N:18]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=4)[CH2:27][CH2:28]3)[CH:19]2[OH:22])=[CH:15][C:14]=1[S:41]([NH2:44])(=[O:43])=[O:42]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3cccc(C(F)(F)F)c3)CC1)C2=O
Agent: O=C1NC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2c(cc1Cl)C(O)N(C1CCN(Cc3cccc(C(F)(F)F)c3)CC1)C2=O

Procedure:
A mixture of the 1,3-dioxoisoindole of part (a), (8.1 g., 0.0161 mole), zinc dust (5.78 g., 0.088 mole) and 150 ml. of acetic acid was stirred for 0.5 hr. at 50°-70°, cooled. Residual material, obtained by concentration of the filtrate in vacuo, was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and the aqueous layer re-extracted with ethyl acetate. Combined extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with ethyl acetate provided 6-chloro-2,3-dihydro-1-hydroxy-3-oxo-2-[1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-1H-isoindole-5-sulfonamide as a white solid, m.p. 204°-205°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[S:26][C:25]=1[C:35]([NH2:37])=[O:36]>C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:23][C:24]3[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:26][C:25]=3[C:35](=[O:36])[NH:37]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
To a stirred solution of 1-acetyl-4-piperidone (0.130 g, 0.920 mmol) and p-toluenesulfonic acid monohydrate (0.004 g, 0.02 mmol) in acetic acid (4 mL) was added 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.050 g, 0.23 mmol). The mixture was heated at 80° C. for 5 h. Then, the reaction was allowed to cool to room temperature and concentrated. The obtained residue was dissolved in methanol (25 mL) and the solution was stirred with solid NaHCO3 (1.5 g) for 20 min. Then, the solution was filtered, and the filtrate was concentrated. The obtained residue was triturated with H2O. The obtained yellow solid was triturated with hot ethyl acetate to give the title compound (0.0407 g, 52%) as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.N1C=CC=CC=1.[C:18]([C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[S:29](Cl)(=[O:31])=[O:30])#[N:19]>CC#N.CN(C=O)C>[C:18]([C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1)(=[O:31])=[O:30])#[N:19]
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (16.4 g, 0.11 mol) and pyridine (10.3 g, 0.13 mol) in MeCN/DMF (400 mL/100 mL) was added 2-cyano-4-nitrobenzene-1-sulfonyl chloride (24.7 g, 0.1 mol) at 0° C., then the solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, and DCM and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:31])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1.[H][H]>[Pt].CO>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:33][CH:32]=2)[CH2:12][CH2:13]1)=[O:31]
Reactant: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 45 %

Procedure:
To 1 part of a solution of 2 parts of thophene in 40 parts of ethanol are added 18 parts of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-nitrobenzamide and 200 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 7.5 parts (45%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide; mp. 113.2° C. The mother liquor is evaporated, yielding a second fraction of 6 parts (36%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide as an oily residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([OH:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:43][C:44]1[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([F:52])[CH:45]=1.O>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[C:48]([C:47]1[CH:50]=[CH:51][C:44]([CH2:43][O:38][C:36]2[CH:37]=[C:32]([C@@H:26]([NH:25][C:24]([C@@H:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]4)[CH2:19]3)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:33]=[N:34][CH:35]=2)=[CH:45][C:46]=1[F:52])#[N:49]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(C#N)c(F)c2)c1
Temperature: 0 °C
Yield: 4.5 %

Procedure:
To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 200 mg, 0.37 mmol) in DMF (5 mL) was added sodium hydride (60%, 9.6 mg, 0.24 mmol) and the mixture was cooled to 0° C. 4-(Bromomethyl)-2-fluorobenzonitrile (70.5 mg, 0.33 mmol) in DMF (3 mL) was added while stirring and the mixture was warmed to room temperature. After one hour water, brine and ethyl acetate were added. Phases were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to yield 10 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(4-cyano-3-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.