Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]=[C:5]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][NH:6][CH:5]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)CCN=C2CCc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(s1)CCNC2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 740 mg 2-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-6,7-dihydro-thieno[3,2-c]pyridine in 7.4 mL methanol was added portion wise 82 mg (2.17 mmol) NaBH4 at room temperature. The mixture was stirred at room temperature for 30 minutes, cooled in an ice bath and quenched with water and 1N HCl. The methanol was removed in vacuo and the residue stirred in water. The mixture was basified with a 2M Na2CO3 solution and extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 630 mg (87%; over two steps) of the title compound as yellow oil. MS(m/e): 326.1 (MH+).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)C>C(O)C.O.Cl>[NH:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[CH:21][CH:22]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(OCCOc2ccc(C(N)=O)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(OCCOC2CCNCC2)cc1
Yield: 9.7 %

Procedure:
4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (4.3 g.) in ethanol (60 ml.), water (30 ml.) and 2 N hydrochloric acid (10 ml.) was heated under reflux for 24 hours then the solvent evaporated in vacuo. The residue was taken up in water and extracted three times with chloroform, the aqueous phase was adjusted to pH 12 with sodium carbonate solution and extracted three times with chloroform. The combined chloroform extracts were discarded, the aqueous phase was saturated with sodium chloride and extracted with chloroform, the chloroform layer dried (Na2SO4), and the solvent evaporated in vacuo to give 4-[2-(4-piperidyloxy)ethoxy]benzamide (0.36 g.). The aqueous phase was concentrated in vacuo and the residual solid extracted with refluxing ethyl acetate (200 ml.).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Cl)[C:3](Br)=[O:4].[NH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.[OH-].[Na+]>C(#N)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:3]1=[O:4]
Reactant: O=C(Br)C(Br)CCCl
Reactant: N#Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1ccc(N2CCC(Br)C2=O)cc1

Procedure:
2-Bromo4-chlorobutyryl bromide (BCBB, 145.7 g, 0.540 mole) was added via an addition funnel to a cold (5° C.), well stirred slurry of 4-aminobenzonitrile (4-ABN, 55.0 g, 0.466 mole), Na3PO4 (42 g, 0.256 mole) and acetonitrile (550 mL) in a 1 liter flask while maintaining a temperature below 30° C. during the addition. The addition funnel was rinsed with acetonitrile (55 mL). Upon completion of the coupling (determined by LC), a 50 wt % solution of NaOH (56 mL, 1.061 mole) was added via an addition funnel while maintaining the reaction temperature below 30° C. Upon completion of the reaction (determined by LC), the slurry was filtered through a pressure filter (10 micron polypropylene filter cloth). The flask and the cake were washed with acetonitrile (256 mL). The filtrate and the wash were combined to afford a solution of 4-(3-bromo-2-oxopyrrolidin-1-yl)benzonitrile in acetonitrile (of about 17 wt %). Qualitative LC analysis showed the product with 91.8 to 95 area % purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.[CH3:24][Mg]Br.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](=[O:9])[CH3:24])[CH:7]=1
Reactant: CON(C)C(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Reactant: C[Mg]Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
8-Chloro-5-(3-fluorophenyl)-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide (0.15 g, 0.45 mmol) was stirred in tetrahydrofuran (0.73 mL) and cooled to 0° C. A solution of 3.0 M methylmagnesium bromide (0.52 mL, 1.57 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was cooled to 0° C. and a solution of 1.0 M hydrogen chloride in water (1.8 mL) was added. The mixture was poured into saturated sodium bicarbonate and extracted into ethyl acetate 3×. The ethyl acetate extracts were combined and washed with water, dried over sodium sulfate, filtered, concentrated and purified by flash column chromatography with ethyl acetate in hexanes (0-80%) to give the desired compound (0.12 g, 93%). LCMS calculated for C15H11ClFN2O (M+H)+: m/z=289.1. found: 288.9. 1H NMR (300 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.62 (m, 2H), 7.50 (m, 2H), 7.40 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Yield: 96 %

Procedure:
Dissolve 4-bromo-2-fluoro-benzoic acid (15 g, 68.5 mmol) in methanol (70 mL). Add concentrated sulfuric acid (500 μl) to the solution and heat the mixture to reflux for 20 h under a nitrogen atmosphere. Cool the mixture to room temperature and concentrate in vacuo. Dissolve the residue in EtOAc (200 mL) and wash successively with saturated aqueous NaHCO3 (50 mL) and water (2×50 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (15.4 g, 96%). GC-MS m/z: 232 (M+).
Reaction SMILES: N[C:2]1[CH:7]=CC=C[CH:3]=1.C=CC.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:2]([CH3:7])[CH3:3])[C:13]=1[NH2:14]
Reactant: Nc1ccccc1
Reactant: Nc1ccccc1Cl
Solvent: C=CC
Product: CC(C)c1cccc(Cl)c1N

Procedure:
2-chloro-6-isopropyl aniline was prepared by the method of Example 2 using an H-Y zeolite catalyst for the condensation of aniline and propylene. 2-chloroaniline and propylene were fed to the reactor in a 1:5 mole ratio and LHSV of 0.25 based on 2-chloroaniline. The reaction was conducted at 250° C. and 1343 psig. The effluent product stream was analyzed by gas chromatography. Conversion of 2-chloroaniline was 72%.
Reaction SMILES: BrC1N(C(NC2C=CC=CC=2)=O)C(C2C=CN=C3NC(C4C=CC(N(C)C)=CC=4)=NC=23)CNC1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].O=[CH:68][CH2:69][CH2:70][NH:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75]>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:68]([CH2:69][CH2:70][NH:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(C4CNCC(Br)N4C(=O)Nc4ccccc4)ccnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Reaction time: 6 h
Yield: 37 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (64 mg, 0.16 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.49 mmol, 0.49 mL) and tert-butyl 3-oxopropylcarbamate (prepared according to the procedure described in Tetrahedron 2003, 59, 1719) (1.1 eq, 0.18 mmol, 31 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (31 mg, 37%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.35 (s, 9H, C(CH3)3), 2.58 (s, br, 4H, piperazine N(CH2)2), 2.89 (t, J=5.5 Hz, 2H, CH2CH2NH), 3.30 (hidden by DMSO peak, 2H, CH2CH2NH), 3.57 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 3.59 (s, 2H, NCH2Ar), 6.92 (s, br, 1H, NH), 7.38 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.76 (dt, J=7.7, 1.5 Hz, 1H, pyridine H-4), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.48 (dd, J=4.8, 1.5 Hz, 1H, pyridine H-6), 8.54 (d, J=1.5 Hz, 1H, pyridine H-2), 12.79 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: C(OP([CH2:8][C:9]([O:11]CC)=[O:10])OCC)C.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([C:22](=O)[CH3:23])[S:20][CH:21]=1>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:22]([CH3:23])=[CH:8][C:9]([OH:11])=[O:10])[S:20][CH:21]=1
Reactant: CCOC(=O)CP(OCC)OCC
Reactant: CC(=O)c1cc(Br)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A solution of ethyl (diethoxyphosphino)acetate (34 mL, 171 mmol) in THF (35 mL) was added dropwise via addition funnel, over 20 minutes, to a 0° C. suspension of NaH (6.9 g, 60% oil dispersion, 172 mmol) in THF (200 mL). The resulting mixture was stirred at 0° C. for 30 minutes, then treated with a solution of 1-(4-bromo-2-thienyl)ethanone (23.6 g, 115 mmol) in THF (75 mL). The reaction was warmed to room temperature, stirred for 4 hours, quenched with water, neutralized with 2N HCl, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was dissolved in ethanol (350 mL) and THF (190 mL), treated with 2N LiOH (115 mL), stirred overnight at room temperature, and concentrated. The remaining aqueous solution was washed with diethyl ether, acidified with 2N HCl, and filtered. The filter cake was washed with water and dried to provide 22.38 g (79% yield) of the desired product as a mixture of E and Z isomers. MS (ESI(+)) m/e 244.7, 246.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26](SC)=[N:25][C:24]2=[O:30])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][CH2:39][NH2:40])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:41])[NH:37][CH2:38][CH2:39][NH:40][C:26]1[S:27][C:23](=[CH:22][C:20]2[CH:19]=[CH:18][C:4]([O:5][C:6]3[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=3[C:14]([F:15])([F:17])[F:16])=[C:3]([O:2][CH3:1])[CH:21]=2)[C:24](=[O:30])[N:25]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Product: COc1cc(C=C2SC(NCCNC(=O)OC(C)(C)C)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
(2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-carbamic acid tert-butyl ester was prepared using 4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile and (2-Amino-ethyl)-carbamic acid tert-butyl ester as described in Example 5C.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[C:9]([S:11][CH:12](C)C)[C:8]([S:15][CH:16](C)C)=[CH:7][C:6]=1[S:19][CH:20](C)C)(C)C.[Na].CI>N1C=CC=CC=1>[CH3:20][S:19][C:6]1[CH:7]=[C:8]([S:15][CH3:16])[C:9]([S:11][CH3:12])=[CH:10][C:5]=1[S:4][CH3:1]
Reactant: CC(C)Sc1cc(SC(C)C)c(SC(C)C)cc1SC(C)C
Agent: [Na]
Solvent: c1ccncc1
Solvent: CI
Product: CSc1cc(SC)c(SC)cc1SC
Temperature: 10 °C
Reaction time: 0.67 h
Yield: 65.7 %

Procedure:
Into a 3-neck 1 liter flask equipped with a thermometer, magnetic stirring bar, and gas inlet and outlet tubes was placed a solution of 25 g (66.72 millimoles) of the product of Example 1 in 300 ml of dry pyridine. The mixture was heated rapidly to 105°-110° C. and 8.29 g of Na pellets (360 millimoles) were added rapidly against a nitrogen flow. The reaction mixture was maintained below reflux but above 100° C. for 1 hour until all of the sodium had reacted. The mixture was then cooled to 10° C. and methyl iodide (24 ml) was added slowly by means of a syringe. The resulting mixture was stirred for 40 minutes and quenched with 350 ml of saturated aqueous NaCl. Water was then added to form a dilute suspension which was filtered under suction and washed copiously with water to yield a yellow, crystalline solid. The solid was washed with 150 ml of -10° C. methanol to yield 11.5 g (66%) of white product; mp:127°-129° C.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C@H:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.[H-].[Na+].O1CCCC1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>O>[CH3:23][S:20]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[C@@H:10]1[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:2](=[O:1])[N:11]1[S:43]([CH3:42])(=[O:45])=[O:44])[C:16]#[N:17])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-4-(2,5-Dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 11 mg, 0.29 mmol) and tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 10 min. Methanesulfonyl chloride (16 μL, 0.22 mol) is added, and the mixture is heated at 50° C. for 2 h. The mixture is cooled at room temperature, diluted with water (0.5 mL) and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 37 mg; ESI mass spectrum [M+H]+=568; Retention time HPLC: 0.81 min (005_CA01).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(Cl)=O)(C)C.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=1[CH2:59][C:60](Cl)=[O:61]>>[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=1[CH2:59][C:60]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:61]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Product: COc1ccc(OC)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with 2,5-dimethoxyphenylacetyl chloride, mp 150°-152° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH2:30][F:31])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH2:30][F:31])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OCF
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OCF
Yield: 65.7 %

Procedure:
37.4 mg of N-iodosuccinimide was added little by little to a solution containing 47.8 mg of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine obtained in Example 111 and 4.0 ml of N,N-dimethylformamide under stirring in an ice-bath, followed by stirring overnight as it was. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was successively washed with an aqueous sodium thiosulfate solution, water and brine, and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 43.9 mg of the target compound.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1>CN(C=O)C>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Ic1cccs1
Solvent: CN(C)C=O
Product: c1csc(-c2cccs2)c1
Yield: 97 %

Procedure:
21 g of 2-iodo-thiophene was dissolved in 50 ml of DMF in 3-necks-bottle (250 ml). 10 g of Cu powder was then added into the solution and refluxed for 15 hours. Then the solution was filtered and the DMF was removed under reduced pressure. The crude product was further purified by column chromatography and both 2,2'-bithiophene (97%) as well as 2,2':5',2"-terthiophene (2%) were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.CO[C:21](OC)([N:23]([CH3:25])[CH3:24])[CH3:22]>>[CH3:24][N:23]([CH2:21][CH:22]=[N:18][C:16]([C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12)=[O:17])[CH3:25]
Reactant: NC(=O)c1cnn2c(-c3cccnc3)ccnc12
Reactant: COC(C)(OC)N(C)C
Product: CN(C)CC=NC(=O)c1cnn2c(-c3cccnc3)ccnc12
Temperature: 120 °C

Procedure:
A mixture of 10.0 g of 7-(3-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared as described in Example 9) and 50.0 ml of N,N-dimethylacetamide dimethyl acetal are heated at 120° C. for 2 hours. After cooling, the reaction mixture is evaporated in vacuo to give an oil. The oil is triturated with diethyl ether to separate a yellow solid. The solid is collected by filtration, washed with ether, air dried, then dried in vacuo to give 12.37 g of the desired product as a tan solid, mp 124°-127° C.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([O:14][CH3:15])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[CH:19]=[O:20].C(OCC)(=O)C>CN(C=O)C.[Cu]>[CH3:15][O:14][C:7]1[CH:6]=[C:3]([CH:4]=[O:5])[C:2]([C:17]2[C:18]([CH:19]=[O:20])=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[C:9]([O:10][CH3:11])[C:8]=1[O:12][CH3:13]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1cc(C=O)c(Br)c(OC)c1OC
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(-c2ccc([N+](=O)[O-])cc2C=O)c(OC)c1OC
Yield: 57.7 %

Procedure:
A mixture of 2-bromo-3,4,5-trimethoxybenzaldehyde (prepared as described in Example 1, starting materials, 1.00 g, 3.64 mmol) and 2-chloro-5-nitrobenzaldehyde (obtained from Aldrich; 241.9 mg, 1.30 mmol) in dry DMF (2 mL) was added to a stirred, boiling suspension of copper bronze (0.91 g, 14.3 mmol) in dry DMF (5 mL) over a period of 30 minutes. After 8 hours TLC (petroleum ether-ethyl acetate 4:1) indicated the consumption of the starting materials. The mixture was cooled, passed through a Celite plug and diluted with toluene, which was distilled off to afford a dark oil. Column chromatography (petroleum ether 60-80°—ethyl acetate 2:1) afforded a sample of 4,5,6-trimethoxy-4′-nitrobiphenyl-2,2′-dicarbaldehyde (259 mg) containing traces of a second compound. This mixture was dissolved in ethanol (5 mL) and treated with a solution of sodium borohydride (0.2 g) in water (1.5 mL). After stirring for 40 minutes, the mixture was added to 1 M aqueous hydrochloric acid (20 mL). The precipitated product was collected on a filter, washed with water and recrystallised from ethanol, which gave the 2′-hydroxymethyl-4,5,6-trimethoxy-4′-nitrobiphenyl-2-yl)methanol as a white powder (113 mg, 25%), which was used for further reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5]O)[CH:3]=[O:4].[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>ClCCl>[CH3:7][C:2]([CH3:1])([CH2:3][OH:4])/[CH:5]=[CH:13]/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)CO
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(C)(C)CO
Yield: 58.9 %

Procedure:
A solution of 2,2-dimethyl-3-hydroxypropanal (22 g, 0.22 mol) and (carboethoxymethylene)triphenylphosphorane (75 g, 0.22 mol) in dry dichloromethane (150 ml) was refluxed for 46 h. The solvent was then evaporated and the crude product was distilled at 15 Torr through a very short column. The distillate was separated into two fractions by redistillation through a 40-cm Widmer column. The first fraction gave 22.3 g (60%) of ethyl trans-4,4-dimethyl-5-hydroxypent-2-enoate, b.p. 133 136° C./15 Torr, nD23 1.4641. 1H NMR (CDCl3): (=1.10 [s, 6H, C(CH3)2], 1.25 (t, 3H, CH3CH2), 3.40 (s, 2H, CH2), 3.80 (br. s, 1H, OH), 4.15 (q, 2H, CH2CH3), 5.80 (d, 1H, J=16 Hz, 3-H), 6.94 (d, 1H, J=16 Hz, 2-H). Anal. Calcd. for C9H16O3: C, 62.76; H, 9.36. Found: C, 62.92; H, 9.50.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21]C)=[O:20].CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[O:14]=[C:11]1[NH:12][CH2:13][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([CH:3]=2)[O:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([OH:21])=[O:20])[CH2:10]1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C1C[C@H](c2ccc(Cl)c(Br)c2)CN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1C[C@H](c2ccc(Cl)c(Oc3cccc(C(=O)O)c3)c2)CN1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of (4R)-4-(3-bromo-4-chlorophenyl)pyrrolidin-2-one (0.1 g, 0.36 mmol) and methyl 3-hydroxybenzoate (0.055 g, 0.36 mmol) in dioxane (1 mL) was added N,N-dimethylglycine (0.011 g, 0.11 mmol), copper(I) iodide (0.02 g, 0.11 mmol) and cesium carbonate (0.23 g, 0.72 mmol). The mixture was stirred overnight at 100° C. The mixture was then diluted with ethyl acetate (50 mL), washed with a 10% aq. HCl solution then brine, and concentrated to give 3-[5-((3R)-5-oxopyrrolidin-3-yl)-2-chlorophenoxy]benzoic acid, which was treated with HCl as described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride to provide the title compound (22). MS (ESI) m/z 350.07 (M+H)+.