Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:28])[C:9]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=2[CH:27]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][C:39]=1[C:47]([O:49][CH2:50]C)=[O:48]>>[CH3:50][O:49][C:47]([C:39]1[CH:40]=[C:41]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH2:25][CH3:26])[C:19]=4[CH:27]=3)([OH:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)[CH:42]=[CH:43][C:38]=1[Cl:37])=[O:48]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)cc21
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(Cl)c(C(=O)OC)c4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 64, step 7, trifluoromethanesulfonic acid 3-chloro-4-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 64, step 6) was reacted with 4-chloro-3-(ethoxycarbonyl)phenylboronic acid (70° C., 5.5 h) to give title compound as a white solid. MS (m/e)=596.3 [M+H+].
Reaction SMILES: [Na].CS(O)(=O)=O.O[CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20]>C(O)C>[O:20]1[C:12]2=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]2[CH2:10][CH2:9][CH2:8]1
Reactant: O=c1[nH]c2ccccc2n1CCCO
Agent: CS(=O)(=O)O
Agent: [Na]
Solvent: CCO
Product: c1ccc2c(c1)nc1n2CCCO1

Procedure:
To a solution of 0.5 parts of sodium in 40 parts of absolute ethanol are added in the cold 5.4 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate. The whole is stirred until all solid enters solution. The solution is further stirred and refluxed for 2 hours. After cooling, the reaction mixture is filtered from some inorganic matter and the filtrate is evaporated. The residue is dissolved in 80 parts of methylbenzene, boiled with activated charcoal, filtered and the filtrate is evaporated again. The solid residue is washed with cold methylbenzene and crystallized from 16 parts of methylbenzene, yielding 2.6 parts of 3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole; mp. 116.5°-118.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[NH2:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Reactant: Nc1ccc2cccnc2c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4cccnc4c3)nnc2Cl)cc1
Temperature: 220 °C
Reaction time: 0.33 h

Procedure:
(Analogous to the procedure of WO 178270). A mixture of 3,6-dichloro-4-(4-trifluoromethylphenyl)pyridazine, Example 81(d), (2.0 g, 6.8 mmol), 7-amino-quinoline (984 mg, 6.8 mmol) and ZnCl2 (980 mg, 3.4 mmol) was heated in a microwave with stirring at 220° C. for 20 min. The reaction mixture was cooled to room temperature, a second portion of 3,6-dichloro-4-(4-trifluoromethylphenyl)pyridazine (2.0 g, 6.8 mmol), was added and the mixture was heated again in microwave at 220° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with H2O (3×). The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with MeOH:CH2Cl2 (1:39), to give the title compound as a light-yellow powder. MS (ESI, pos. ion) m/z: 401 (M+1).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:15][CH2:16][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:22]=2[CH2:23]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 24.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-piperidin-1-ylethanone (8.8 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.8 mg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.[CH3:14]O.Cl>C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=O)Cc1c[nH]c2ccccc12
Yield: 94 %

Procedure:
A mixture of commercially available (1H-indol-3-yl)acetic acid (200 g, 1.14 mol), methanol (2700 mL) and a saturated solution of HCl in diethyl ether (750 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo, and the residue was subjected to aqueous work-up under alkaline conditions by the use of aqueous ammonia to yield methyl (1H-indol-3-yl)acetate as an oil (202.5 g, 94%). The crude oil was dissolved in acetic acid (2 L), and sodium cyanoborohydride (60 g, 0.95 mol) was added in portions of 1 g over a period of 8 h. The resulting mixture was stirred at room temperature for 16 h and then poured onto an ice/water mixture. Aqueous work-up under alkaline conditions gave the crude product that was purified by flash chromatography (ethyl acetate/heptane 1:1) to give the title compound (97.3 g, 48%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([NH:11][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1c(O)cccc1C(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Thionyl chloride (10 mL) was added to isonicotinic acid (370 mg, 3 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried in vacuum to get isonicotinoyl chloride. 3-Hydroxyanthranilic acid (153 mg, 1.0 mmol) and pyridine (240 mg, 3.0 mmol) were added to toluene (10 mL) and the mixture was stirred at room temperature for 30 min. Then isonicotinoyl chloride (420 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, PE: ethyl acetate 20:1 to 5:1) to obtain 3-hydroxy-2-(isonicotinamido)benzoic acid as a solid (200 mg, yield 77%). LC-MS (ESI) m/z 259 [M+1]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CC(C)=O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:10][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2)cc1

Procedure:
A mixture of 3-nitrophenol (18.49 g, 0.133 mol), anhydrous potassium carbonate (19.2 g, 0.139 mol), potassium iodide (21.0 g, 0.127 mol) and 4-methoxybenzyl chloride (19.82 g, 0.127 mol) in acetone (200 ml) was heated under reflux for 48 h.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN=C=NCCCN(C)C.Cl>CC#N.CN(C1C=CN=CC=1)C.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(I)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1cc(I)ccc1F)N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Fluoro-5-iodobenzoic acid (2 g, 0.0088 mol) was dissolved in MeCN (44 ml) and the mixture cooled to 0° C. Morpholine (0.929 ml, 1.2 eq) followed by EDCI.HCl (2.03 g, 1.2 eq) and DMAP (108 mg, 0.1 eq) were added and the mixture stirred overnight. The mixture was diluted with EtOAc, washed with NH4Cl(sat), dried (MgSO4), and concentrated. The resulting residue was then purified by silica gel chromatography (0-30% EtOAc in hexane) gave 2 g of M1-5. LCMS MH+=336.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:12])[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(O)(=O)C.Br.[H][H]>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH3:12])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: [H][H]
Reactant: COc1cc(OC)cc(C(C)CCCc2ccc(F)cc2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(CCCc1ccc(F)cc1)c1cc(O)cc(O)c1
Reaction time: 17 h

Procedure:
Fifty grams of the above-prepared 2-(3,5-dimethoxyphenyl)-5-(p-fluorophenyl)pentane, 450 ml. of acetic acid and 180 ml. of 48% HBr in water were mixed. While cooling, the mixture was saturated with hydrogen gas (approximately one-half hour). The reaction was placed in an 87° bath and stirred for 17 hours. The reaction was then concentrated in vacuo and the residue neutralized with K2CO3 and NaHCO3, extracted with ether, treated with charcoal and MgSO4 and filtered to yield 45 g. of 2-(3,5-dihydroxyphenyl)-5-(p-fluorophenyl)pentane as a brown oil which distills at 180°/0.01 mmHg.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C@@H:3]([OH:8])[C:4](C#N)=[O:5].[OH-:11].[Na+].OO.Cl>>[F:1][C:2]([F:10])([F:9])[C@@H:3]([OH:8])[C:4]([OH:11])=[O:5]
Reactant: [OH-]
Reactant: N#CC(=O)[C@H](O)C(F)(F)F
Agent: Cl
Agent: OO
Agent: [Na+]
Product: O=C(O)[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a flask charged with (S)-3,3,3-trifluoro-2-hydroxypropanoyl cyanide (139 mg, 1 mmol) was added 3 N NaOH (6 mL) and 30% H2O2 (2.25 mL). The reaction mixture was heated at 65° C. for 1 h, then at 100° C. for a further 1 h. The reaction mixture was allowed to cooled to room temperature over 1 hr, then cool to 0° C. and the solution acidified with 6 N HCl (3 mL). The aqueous portion was extracted with ether (4×10 mL). The combined organic portions were dried over MgSO4, filtered and concentrated to give (S)-3,3,3-trifluoro-2-hydroxypropanoic acid as a clear oil (129 mg, 90% yield). NMR: 400 MHz 1H (CDCl3) 4.45 ppm, 1 H, m; 2.77 ppm, 2 H, m.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C
Yield: 43 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), triethylamine (3.5 cc) and 4-(4-methylphenyl)piperazine (4.4 g) in toluene (100 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. After purification, flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (80-20 vol) as eluant, and recrystallization from boiling acetonitrile (40 cc), 2-{3-[4-(4-methylphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.5 g) is obtained, m.p. 136° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[O:16][CH2:17][C:18](=[O:25])[C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:26])[CH:9]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:27]1[C:35]2=[N:34][CH:33]=[CH:32][CH:31]=[C:30]2[C:29]([CH:36]=[C:17]2[O:16][C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[CH:9][C:10]=3[CH3:26])=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:25])=[CH:28]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCOCCO)cc2C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCOCCO)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 12.6 %

Procedure:
To a solution of ethyl 2-({4-[2-(2-hydroxyethoxy)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50 mmol) in ethanol (10 mL), L-proline (0.010 g, 0.087 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound (0.031 g, y. 15%) as solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[C:5]2[S:9][C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:11][C:4]=12)=[O:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.C(OCC)C>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:1]([OH:2])[C:3]2[CH:8]=[N:7][CH:6]=[C:5]3[S:9][C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:11][C:4]=23)=[CH:22][CH:21]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)c1cc2c(C=O)cncc2s1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2c(C(O)c3ccc(Cl)cc3)cncc2s1

Procedure:
To a solution of Example 237E (0.25 g, 0.95 mmol) in anhydrous THF (5 mL) at −5° C. was slowly added a 1 M solution of p-chlorophenylmagnesium bromide in diethyl ether (2.85 mL, 2.85 mmol). The reaction was quench after 10 minutes with dropwise addition of water (1 mL) and partitioned between dichloromethane (25 mL) and 50% sat. aq NaHCO3 (50 mL). The aqueous phase was extracted with dichloromethane (25 mL) and the organic extracts combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc/hexane as eluent to provide the title compound as a foam, which was crushed and dried in a desiccator to yield a powder (0.36 g, 100%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27]Br)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>[OH-].[Na+].C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CCBr)cc1OC
Reactant: OCC1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCC(CO)C2)cc1OC

Procedure:
A mixture of 2.30 g (0.02 mol) of 3-(hydroxymethyl)piperidine, 5.5 ml (0.04 mol) of triethylamine and 4.90 g (0.02 mol) of 2-(3,4-dimethoxy-phenyl)-ethyl bromide is refluxed for 2 hours. After cooling, the reaction mixture is dissolved in a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is washed with water, separated off, dried over magnesium sulphate, evaporated down in vacuo and purified over 300 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 2%). Yield: 4.4 g (78.7% of theory), Melting point: 87.5°-89° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[S:49]1[CH:53]=[CH:52][N:51]=[C:50]1[C:54](=[N:56]O)[NH2:55]>CN(C=O)C>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[O:15][N:56]=[C:54]([C:50]3[S:49][CH:53]=[CH:52][N:51]=3)[N:55]=2)[CH2:9]1
Reactant: NC(=NO)c1nccs1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1csc(-c2noc([C@@H]3CCNC3)n2)n1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
(R)—N—Boc-pyrrolidine-3-carboxylic acid (700 mg, 3.25 mmol, 1.1 equiv), HBTU (1.23 g, 1.1 equiv) and DIEA (1.53 mL, 3 equiv) were dissolved in DMF (15 mL). The solution was stirred 5 min and then 1,3-thiazole-2-amidoxime (5a) (422 mg, 2.95 mmol, 1 equiv) was added. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with saturated aqueous NaHCO3, once with brine, then dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in 15 mL of DMF and then heated at 110° C. for 7 h. The solvent was removed under vacuum and the residue was dissolved in AcOEt. The organic layer was washed once with HCl 1N, once with saturated aqueous NaHCO3 and once with brine, then dried over MgSO4 and evaporated under reduced pressure. The obtained product was used in the next step without further purification. Boc intermediate was dissolved in dioxane (10 mL) and HCl 4N solution in dioxane (6 mL) was added. The reaction mixture was stirred overnight at room temperature and then the product was recovered by filtration and washed with petroleum ether to give 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (yield 66% over two steps). 4,4,4-trifluorobutyric acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.4 equiv) and DIEA (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (0.62 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Beige powder; Yield 33%; 1H NMR (CDCl3) δ 8.02-8.00 (m, 1H), 7.57-7.60 (m, 1H), 3.89-4.03 (m, 2H), 3.69-3.87 (m, 2H), 3.53-3.65 (m, 1H), 2.38-2.55 (m, 6H); 13C NMR (CDCl3) cis/trans isomer mixture (60 isomer A/40 isomer B); isomer A δ 180.31, 168.50, 163.98, 153.53, 144.99, 126.94 (q, J=276 Hz), 122.87, 49.24, 45.52, 35.03, 29.05 (q, J=29 Hz), 28.86, 27.07 (q, J=3 Hz); isomer B δ 179.84, 168.31, 163.98, 153.38, 144.94, 126.92 (q, J=276 Hz), 122.81, 49.43, 45.25, 36.82, 30.28, 29.05 (q, J=29 Hz), 27.24 (q, J=3 Hz). tR LCMS 4.6 min. Purity >99%; MS [M+H]+ m/z 347.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[O:21][C:20]([C:22]#[N:23])=[CH:19][CH:18]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[O:21][C:20]([C:22]#[N:23])=[CH:19][CH:18]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: N#Cc1ccc(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(C#N)o2)C1=O
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of (2-oxopyrrolidin-3-(S)-yl)carbamic acid tert-butyl ester (1.56 g, 7.8 mmol) in 80 mL of THF:DMF (5:1) is treated with 5-bromomethylfuran-2-carbo-nitrile (3.23 g, 16 mmol) and sodium hydride (60%) (0.32 g, 8 mmol) as described in EXAMPLE 122, Part F. After addition, the solution is allowed to warm to ambient temperatures. After 5 hours, the solution is quenched by the addition of sat. NH4Cl. The solution is diluted with EtOAc and washed with H2O (3x) and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 80% EtOAc/hexanes to afford [1-(5-cyanofuran-2-ylmethyl)-2-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester (2.38 g, 7.8 mmol) as a white solid. A portion of this material (1.28 g, 4.2 mmol) is treated as described in EXAMPLE 122, Part G to yield the title compound (1.1 g, 4.55 mmol).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4F)cc(F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3F)cc(F)c2O1

Procedure:
The title compound was prepared (0.132 g, 92%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.20 g, 0.48 mmol) and methylamine (0.30 g, 9.6 mmol). mp >250° C. (dec).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:3]1.Br[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:22]2[S:26][C:25]([NH2:27])=[N:24][N:23]=2)[CH2:3]1
Reactant: Nc1nnc(Br)s1
Reactant: CC1CCCN(Cc2cccc(OCCCCN)c2)C1
Product: CC1CCCN(Cc2cccc(OCCCCNc3nnc(N)s3)c2)C1
Yield: 54 %

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 4-[3-[(3-methylpiperidin-1-yl) methyl]phenoxy]-butanamine and 5-bromo-1,3,4-thiadiazole2-amine. Yield: 54% of theoretical: melting point: 123°-124° C.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][Mg]Br>C1COCC1>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([OH:25])[CH3:26])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C=O)n2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C(C)O)n2)cc1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A stirred solution of 3-(6-[3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enal (1.41 g, 4.24 mmol) in anhydrous THF (50 ml) at -78° C. was treated dropwise with a solution of methyl magnesium bromide (1.56 ml, 3.0M in diethylether, 4.67 mmol). The reaction mixture was allowed to warm slowly to room temperature (~2 hours). The reaction was quenched with water (3 ml) and THF removed under reduced pressure. The residue was taken up in 1M HCl and then basified with solid sodium bicarbonate to pH 8. The product was extracted with ethyl acetate (×3). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography eluting with 5% methanol in DCM. Product containing fractions were combined and solvent removed to provide 4-(6-[3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-but-3E-en-2-ol as a pale brown foam (544 mg, 37%). 1H-NMR; δ (CDCl3), 7.43 (1H, t, J=7.8 Hz), 7.24-7.18 (3H, m), 7.11-7.06 (3H, m), 6.94 (1H, dd, J=15.6 and 5.8 Hz), 6.71-6.64 (2H, m), 4.60-4.55 (1H, m), 3.23 (2H, d, J=7.0 Hz), 2.58 (4H, bs), 2.41 (3H, s), 1.82-1.77 (4H, m), 1.41 (3H, d, J=6.5 Hz).