Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>C(OCC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:23])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
Dissolve Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine (47.6 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid(0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine, methyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=O)OC(C)(C)C)[CH2:3][CH2:2]1.[CH3:15]CN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2[N:32]=[N:33][N:34](C)[N:35]=2)[CH:28]=[C:27](Cl)[N:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:24][C:25]1[N:26]=[C:27]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][CH3:8])[CH2:5][CH2:6]2)[CH:28]=[C:29]([C:31]2[N:32]([CH3:15])[N:33]=[N:34][N:35]=2)[CH:30]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nnc(-c2cc(Cl)nc(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CNC1CCN(c2cc(-c3nnnn3C)cc(Cl)n2)CC1

Procedure:
tert-Butyl piperidin-4-ylcarbamate (87 mg, 0.44 mmol) and DIEA (76 μl, 0.44 mmol) were added to a solution of 2,6-dichloro-4-(2-methyl-2H-tetrazol-5-yl)-pyridine (100 mg, 0.44 mmol) in anhydrous NMP (2 ml). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 15 minutes, diluted with EtOAc (25 ml) and washed with water (4×25 ml). The organic phase was dried over Na2SO4 and concentrated in vacuo to give a brown solid. This sample was treated with 4 N HCl/dioxane (8 ml) for 45 minutes. The solvent was removed under reduced pressure and the material was dried in vacuo.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN([CH:11]=[O:12])C.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:15][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=1[CH:11]=[O:12]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC1=C(Cl)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cyclohexanone (1.34 g, 13.6 mmol) in toluene at room temperature was added DMF (1.58 mL, 20.5 mmol) and phosphorus oxychloride (1.88 mL, 20.5 mmol). The reaction was stirred overnight at room temperature, and then diluted with H2O and stirred for 30 minutes. 4N Aqueous NaOH (10 mL) was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH:1]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:2]([C:9]([N:11]1[CH2:47][CH2:46][CH2:45][C@H:12]1[C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:35](OCC1C=CC=CC=1)=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=O)[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[OH2:55].[NH2:56][NH2:57]>CN(C=O)C>[NH:1]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:2]([C:9]([N:11]1[CH2:47][CH2:46][CH2:45][C@H:12]1[C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:35]([NH:56][NH2:57])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=[O:55])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: O
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Reactant: NN
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NN)[C@@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
The substance [45] (67.22 g, 90 mM) was dissolved in DMF (300 ml), hydrazine hydrate (45.6 ml, 0.95 M) was added, and the mixture was stirred at room temperature overnight. The DMF was removed in vacuo and the residue was dissolved in ethyl acetate (800 ml). This solution was washed with water, dehydrated with anhydrous sodium sulfate and concentrated in vacuo to obtain the powdered substance [46] (55 g, yield: 91.1%).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][NH:4][CH2:3]1.Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:4]1[CH2:3][C:2](=[O:1])[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(CCN(C)C)C3
Temperature: 50 °C
Yield: 38.1 %

Procedure:
Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (183 mg, 0.75 mol) was dissolved in DMF (20 ml) and 2-chloro-N,N-dimethylethanamine hydrochloride (107 mg, 0.75 mmol), and K2CO3 (207 mg, 1.5 mmol) were subsequently added. The reaction was stirred at 50° C. until the starting material was disappeared. The reaction mixture was then diluted with CH2Cl2 (15 ml) and washed with water three times. The organic layer was dried with MgSO4. Evaporation of most of the solvent and the crude product was purified by chromatography column on silica gel (elution with CH2Cl2/MeOH/NH3.H2O) to provide 0.09 g of methyl 2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate. MS (ESI) m/e [M+1]+ 316.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:25][O:24][N:23]([CH3:22])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=1
Reactant: CNOC
Reactant: CCCCCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCc1ccc(C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96.4 %

Procedure:
To a solution of 4-pentylbenzoic acid (5 g, 0.026 mol) in 260 ml of CH2Cl2 containing molecular sieves (4 Å), two drops of DMF was added, and then oxalyl chloride (5.45 g, 0.043 mol) was added dropwise. After stirring for 4.5 h the mixture was filtered, concentrated on the rotatory evaporator and pumped for 15 min. The residue was redissolved in 130 ml of CH2Cl2 and N,O-dimethylhydroxylamine HCl (3.04 g, 0.031 mol) was added at room temperature. After cooling the solution to 0° C., 5.3 ml of pyridine (0.065 mol) was added and the solution was stirred at 23° C. for 18 h. The solution was concentrated on the rotatory evaporator and the residue was partitioned between brine and a mixture of ether and CH2Cl2 (1:1). The organic layer was separated, dried and concentrated to yield 5.9 g (98%) of 2, which was used without further purification in the subsequent step. 1H NMR (100 MHz, CDCl3) δ 0.9 (t, 3H), 1.45 (m, 6H), 2.6 (t, J=6.4 Hz, 2H), 3.3 (s, 3H), 3.5 (s, 3H), 7.2 (d, J=8.0 Hz, 2H), 7.6 (d, J=8.2 Hz, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH2:27])=[O:26])[CH2:21][CH2:20]1>O1CCCC1.O>[C:25]([CH:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1)(=[O:26])[NH2:27]
Reactant: NC(=O)C1CCNCC1
Reactant: BrCCOc1ccccc1CCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C1CCN(CCOc2ccccc2CCc2ccccc2)CC1
Yield: 82.3 %

Procedure:
A solution of 2 g of 2-(2-bromoethoxy)bibenzyl and 1.7 g of 4-piperidinecarboxamide in 20 ml of tetrahydrofuran and 10 ml of water was stirred at 70° C. for 10 hours. The reaction mixture was concentrated and to the residue was added 1 N NaOH aqueous solution. The resultant crystals were filtered, washed well with water and then recrystallized from ethanol to give 1.9 g (82% yield) of 2-[2-(4-carbamoylpiperidino)ethoxy]bibenzyl, m. p. 60°-63° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 81.6 %

Procedure:
Using general procedure A, 3-methylbenzylamine (198 μL, 1.58 mmol) and 1-Boc-4-piperidone (300 mg, 1.51 mmol) afforded 4-(3-methylbenzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (375 mg, 82%).
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C:25]2([C:35]3=[CH:36][C:37]4OCO[C:38]=4[CH:42]=[C:34]3O[CH2:32]2)C1=O.BrCC1C=CC=CC=1[CH:52]([F:54])[F:53].CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:53][CH:52]([F:54])[C:34]1[CH:42]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:25][CH:32]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: FC(F)c1ccccc1CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1C(Cc2ccccc2C(F)F)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-(difluoromethyl)benzene to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 3′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one was obtained (52%) as a colorless solid: mp 191-193° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.67 (d, J=7.4 Hz, 1H), 7.52-7.46 (m, 2H), 7.37 (s, 1H), 7.26-7.20 (m, 3H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.24 (s, 1H), 5.17-5.04 (m, 2H), 4.77 (ABq, 2H), 4.20-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.3, 144.7, 142.6, 138.3, 134.5 (t, JC-F=3.8 Hz), 132.1, 131.9, 131.8 (t, JC-F=21.3 Hz), 129.3, 128.3, 127.4, 127.0 (t, JC-F=7.7 Hz), 124.3, 123.7, 121.5, 114.9 (t, JC-F=236.0 Hz), 111.8, 109.8, 99.3, 80.1, 64.7, 64.1, 57.8; MS (ES+) m/z 435.7 (M+1).
Reaction SMILES: [OH-:1].[Na+].[ClH:3].Cl.Cl.C([O:13][C:14]([C:16]1([C:19](=[O:51])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([N:37]4[CH2:42][CH2:41][CH:40]([N:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)[CH2:39][CH2:38]4)=[O:36])[CH:29]=3)=[CH:23][C:22]=2[F:50])[CH2:18][CH2:17]1)=[O:15])C1C=CC=CC=1>O1CCCC1>[OH2:13].[OH2:1].[ClH:3].[ClH:3].[ClH:3].[F:50][C:22]1[CH:23]=[C:24]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)=[O:36])[CH:29]=2)[CH:25]=[CH:26][C:21]=1[NH:20][C:19]([C:16]1([C:14]([OH:15])=[O:13])[CH2:18][CH2:17]1)=[O:51]
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Product: O
Reaction time: 0.7 h

Procedure:
A 5N sodium hydroxide aqueous solution (40 ml) was added at room temperature to a solution of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride (20 g) in tetrahydrofuran (200 ml) and stirred for 2 hours and 42 minutes. After completion of the reaction, the reaction mixture was allowed to stand and the layers were separated. The obtained organic layer was added dropwise over a period of 1 hour and 5 minutes at room temperature to a suspension solution of acetone (200 ml), water (20 ml), 35% hydrochloric acid (16 ml) and seed crystals (0.2 g) of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride dihydrate obtained by the method described in Example 8-2 in WO 2008/026577. The mixture was stirred for 2 hours and 28 minutes at room temperature, and after confirming the crystal precipitation, acetone (100 ml) was added and the mixture was further stirred for 1 hour and 25 minutes. The obtained solid was collected by filtration and dried to give 19.2 g of the title compound.
Reaction SMILES: C(O[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5])C.[CH3:20][NH2:21]>C(O)CCC>[CH3:20][NH:21][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: CCOC(=O)CCCCCc1cccc2cncn12
Reactant: CN
Solvent: CCCCO
Product: CNC(=O)CCCCCc1cccc2cncn12

Procedure:
A solution of 3.9 g of 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath for 56 hours in a pressure bottle. The reaction mixture is evaporated to dryness; the resulting product is first crystallized from ether and then recrystallized from 1:1 ethyl acetate-ether to yield the 5-[5-(N-methylcarbamoyl)pentyl]-imidazo[1,5-a]pyridine melting at 118°-22°.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH:21]=O)=[CH:15][CH:14]=2)[CH2:3]1.O.[NH2:25][NH2:26]>CO.O>[CH3:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][NH:26][N:25]=3)=[CH:15][CH:14]=2)[CH2:3]1
Reactant: C[C@H]1C[C@H](C)CN(CCCOc2ccc(C(=O)CC=O)cc2)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: C[C@H]1C[C@H](C)CN(CCCOc2ccc(-c3cc[nH]n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of trans-3,5-dimethyl-1-{3-[4-(3-oxopropanoyl)phenoxy]propyl}-piperidine (200 mg) in a mixture of hydrazine hydrate (50 μL) and methanol (4 mL) is stirred for one hour at room temperature. The mixture is diluted with water and extracted twice with ethyl acetate, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel. Fractions containing the expected product are pooled, concentrated under reduced pressure and salted with oxalic acid to afford 142 mg of trans-3,5-dimethyl-1-{3-[4-(pyrazol-3-yl)phenoxy]propyl}piperidine, oxalate as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)=[O:18])[CH2:14][CH2:15]1)#[N:12]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCOCC2)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC4CCOCC4)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2,4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-(tetrahydro-pyran-4-yloxy)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 169) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 576.2 (M−H)−.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:10][C:11]([CH:13]1[CH2:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2C(O)C1)=[O:12])[CH3:9].N1C=CC=CC=1.Cl>O.CCOC(C)=O>[C:5]([O:4][CH:1]1[C:16]2[CH:20]=[CH:19][S:18][C:17]=2[CH2:21][CH:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1Cc2sccc2C(O)C1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1Cc2sccc2C(OC(C)=O)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Acetic anhydride (4.1 ml) was added to a mixture of 6-ethoxycarbonyl-4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene (2.06 g) and pyridine (8 ml) under water cooling, and was stirred at r.t. for 2.5 hours. The reaction mixture was added into a mixture of AcOEt and water, and was adjusted to pH 1.6 with 6N HCl. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (sat. NaHCO3 aq.), water, and brine, and dried over MgSO4, and then evaporated in vacuo to give 4-acetoxy-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2.36 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:17][CH:13]([F:18])[O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][CH:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)F)cn1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a RBF were added 5-hydroxy-2-pyridinecarboxylic acid methyl ester (1.2 ml, 9.94 mmol), sodium chlorodifluoroacetate (3.3 g, 21.54 mmol), and cesium carbonate (9.7 g, 29.8 mmol) in DMF (20 ml). The reaction mixture was heated to 100° C. for 3 h. Then it was cooled to RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine and dried over MgSO4. It was filtered and concentrated. The crude product was purified by flash chromatography eluting with a gradient of 5% to 50% EtOAc in hexane, to provide methyl 5-(difluoromethoxy)picolinate (1.4962 g, 7.37 mmol, 74.1% yield). MS m/z: 204.3 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([I:17])=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[OH-].[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([I:17])=[CH:15][N:16]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]2=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccccc1-c1ccc2[nH]cc(I)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccccc4F)ccc32)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
A solution of 5-(2-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (227 mg, 0.671 mmol) in THF (7 mL) was treated with TsCl (141 mg, 0.738 mmol, Fluka) and solid NaOH (32.2 mg, 0.806 mmol, VWR). The reaction was stirred at 23° C. under N2. After 45 min, the solution was diluted with EtOAc (100 ml) and washed with brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 10-25% EtOAc/hexane), affording 5-(2-fluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (238 mg, 72%). MS (ESI, pos. ion) m/z: 493.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:27])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:39][OH:40].C(N(CC)CC)C>O1CCCC1.CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([NH:39][OH:40])=[NH:24])=[C:21]([F:27])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Yield: 69.5 %

Procedure:
To a stirred solution of 0.84 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-benzonitrile in 5 mL of tetrahydrofuran and 5.6 mL of methanol were added 1.14 g of hydroxylamine hydrochloride followed by 1.8 mL of triethylamine. The reaction mixture was stirred at reflux temperature for 2 h and then at room temperature overnight. The reaction mixture was refluxed for an additional 2 h and then concentrated under reduced pressure. The residue was taken up into dichloromethane then water was added. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.840 g of crude product as a yellow gum. Precipitation in heptane afforded 620 mg of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-N-hydroxy-benzamidine as a beige powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([NH:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[O:38])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)/[S:34][C:33]1=[O:38]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: NCCN1C(=O)S/C(=C\c2ccc(O)cc2)C1=O

Procedure:
The title compound 30f was prepared from 4-hydroxybenzaldehyde (76 mg, 0.62 mmol), compound 29 (250 mg, 0.62 mmol) and piperidine (20.0 μL, 0.19 mmol) in a manner similar to that described for 30a in 43.0% (102 mg) yield as a yellow solid.