Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[S:12].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[S:10][C:11](=[S:12])[NH:13][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
10 g of 4-fluorobenzaldehyde was dropwise added at room temperature to a solution having 10.8 g of rhodanine and 20 g of sodium acetate suspended in 100 ml of acetic acid. The obtained mixture was reacted under reflux for two hours and then cooled to room temperature. Then, this reaction mixture was put into about 500 ml of water, and a solid product thereby obtained was collected by filtration, washed with water and dried to obtain 16.4 g of 5-(4-fluorobenzylidene)rhodanine.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC1C=NC(C2C=CC(O[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:49][CH2:50][C:51]([O:54][C:55]([F:68])([F:67])[C:56]([F:66])([F:65])[O:57][C:58]([F:64])([F:63])[C:59]([F:62])([F:61])[F:60])([F:53])[F:52])=CC=2)=NC=1)CCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:49][CH2:50][C:51]([O:54][C:55]([F:67])([F:68])[C:56]([F:65])([F:66])[O:57][C:58]([F:63])([F:64])[C:59]([F:60])([F:61])[F:62])([F:53])[F:52])=[C:18]([F:23])[CH:17]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)c(F)c2)nc1
Reactant: CCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)c(F)c2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyloxy-2-[4-hydroxy-3-fluorophenyl)pyrimidine (1.5 g, 4.7 mmol) with 5-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)pentyl chloride (2.45 g, 5.1 mmol, Example 22). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (210° C. at 0.5 torr), to provide a yield of 2.6 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]2[S:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.S(Cl)([Cl:15])=O>CN(C)C=O>[Cl:15][C:8]1[S:9][C:5]2[C:4]([F:12])=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[N:7]=1
Reactant: Fc1cc(F)c2sc(S)nc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cc(F)c2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.6 %

Procedure:
To a suspension of 2 g (9.841 mmol) 5,7-difluoro-benzothiazole-2-thiol in 10.7 mL (147.6 mmol) thionyl chloride was added drop wise 215 □L N,N-dimethylformamide at room temperature. The mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 659 mg (32.6%) of the title compound as an off-white solid. MS(m/e): 205 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:8][S:9][CH3:10])[C:5]([OH:7])=[O:6].I[CH3:12]>CN(C=O)C>[CH3:12][O:3][CH:4]([CH2:8][S:9][CH3:10])[C:5]([OH:7])=[O:6]
Reactant: CSCC(O)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CSC)C(=O)O
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
To a stirred solution of sodium hydride (0.176 g, 4.41 mmol) in DMF (5 mL) was added a solution of 2-hydroxy-3-(methylthio)propanoic acid (0.25 g, 1.836 mmol) in 1 mL DMF at 25° C. and stirred for 10 min Vigorous bubbling was observed upon addition of NaH. Then iodomethane (0.126 mL, 2.020 mmol) was added and the solution was stirred at 25° C. overnight. The reaction was quenched by addition of 2 N HCl, extracted with 3×10 mL of EtOAc, the combined organic layers were washed with water (2×20 mL), concentrated and purified by column chromatography, eluted with 0-100% EtOAc/hexane, gave 2-methoxy-3-(methylthio)propanoic acid (126 mg, 0.839 mmol, 45.7% yield) as colorless oil: 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 4.03 (dd, J=6.9, 4.4 Hz, 1H), 3.51 (s, 3H), 2.98-2.93 (m, 1H), 2.86 (dd, J=14.1, 6.9 Hz, 1H), 2.21 (s, 3H); EIMS m/z 150.
Reaction SMILES: [C:1]1([C@H:7]([NH:41][C:42]([O:44][C@@H:45]2[CH:50]3[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]3)[CH2:46]2)=[O:43])[C:8]2[CH:9]=[C:10]([CH:38]=[CH:39][CH:40]=2)[O:11][CH2:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH:31]4OCC[O:32]4)=[O:26])[CH2:21][CH2:20]3)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1>[C:1]1([C@H:7]([NH:41][C:42]([O:44][C@@H:45]2[CH:50]3[CH2:49][CH2:48][N:47]([CH2:52][CH2:51]3)[CH2:46]2)=[O:43])[C:8]2[CH:9]=[C:10]([CH:38]=[CH:39][CH:40]=2)[O:11][CH2:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH:31]=[O:32])=[O:26])[CH2:23][CH2:24]3)=[O:18])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)N3CCC(C(=O)OCCCC4OCCO4)CC3)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: C1CCOC1
Product: O=CCCCOC(=O)C1CCN(C(=O)c2ccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)propyl 1-(4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoyl)piperidine-4-carboxylate in THF (4.7 mL) was added 2 M aqueous hydrochloric acid (4.7 mL). The reaction mixture was stirred at RT for 4 hours. The reaction mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic phase removed and the aqueous phase was extracted with further ethyl acetate (×2). The combined organic phases were washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used directly in the next step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:28][C:29]([CH3:34])([CH3:33])[C:30]([NH2:32])=[O:31])[CH:26]=[CH2:27]>>[CH2:25]([N:28]1[C:29]([CH3:34])([CH3:33])[C:30](=[O:31])[N:32]=[C:21]1[C:10]1[C:9]([CH3:24])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)[CH:26]=[CH2:27]
Reactant: C=CCNC(C)(C)C(N)=O
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: C=CCN1C(c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)=NC(=O)C1(C)C

Procedure:
Compound 10 was synthesized from 4a (253 mg, 0.66 mmol) and 5e (148 mg, 1.05 mmol) as a white solid (171 mg, 53%) in a manner similar to that described in Example 36. 1H NMR (600 MHz, CDCl3) δ 7.41 (d, 1H), 7.27-7.23 (m, 3H), 7.13 (d, 1H), 7.04 (d, 2H), 5.93-5.88 (m, 1H), 5.13-5.07 (m, 2H), 4.54 (d, 2H), 2.37 (s, 3H), 1.40 (s, 6H); ESMS m/z: 487.1 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Brc1ccc(C2OCCO2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1cccc(Cc2ccc(C3OCCO3)s2)c1
Reaction time: 0.33 h
Yield: 19 %

Procedure:
n-Butyl lithium (2.6N hexane solution, 15.6 mL, 39 mmol) was added dropwise to a solution of 2-(5bromo-thiophen-2-yl)-[1,3]dioxolane (7.0 g, 30 mmol) in tetrahydrofuran (40 mL) at from −75° to −68° C., and the solution was stirred for 20 minutes. 3-Chlorobenzyl bromide (4.3 mL, 33 mmol) was added dropwise to this reaction solution at from −75° C. to −68° C., and the solution was stirred for 20 minutes. The cold bath was removed, and the reaction solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (1.6 g, 5.7 mmol, 19.0%) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[CH:4]([CH3:13])[CH2:3]1.[H-].[Na+].S(OC)(O[CH3:21])(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC=CC=1>[CH3:21][O:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1
Reactant: CC1=C2CCC(C)(O)CC(C)C2CC1
Reactant: COS(=O)(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C1CC(C)(OC)CCC2=C(C)CCC12
Yield: 74 %

Procedure:
9.6 g of 6-hydroxy-1,6-dimethyl-4-methyl-2,3,3a,4,5,6,7,8-octahydroazulene in 300 ml of absolute benzene were heated to reflux for 15 hours with 4.8 g of sodium hydride (50% paraffin-containing paste, purified by washing with benzene). Then 95 ml of freshly distilled dimethyl sulphate were added at 40°. The mixture was stirred at reflux for a further 7 hours, cooled to 5°, treated with 20% citric acid solution and extracted with ether. The ethereal phase was washed with bicarbonate solution and water, dried in a conventional manner and concentrated under reduced pressure. The oily residue so obtained (12.5 g) was loaded onto 125 g of silica gel and by elution with hexane there were obtained 7.65 g (74%) of 6-methoxy-1,6-dimethyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene which was then distilled in high vacuum; b.p.0.02 ca 55°; IR(film): νmax = 3090, 1640, 1450/40, 1370, 1252, 1120, 1080, 890, 835, 765/55 cm-1. The compound has a camphorous, woody odour.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CS(C)=O.ClCCl.[Cl-].[NH4+].[Cu]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Nc1ncc(I)cn1
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1cnc(N)nc1
Temperature: 80 °C

Procedure:
To the Schlank flask containing 2-amino-5-iodopyrimidine (2.210 g, 10.00 mmol) and copper powder (0.953 g, 15.0 mmol) in anhydrous DMSO (10 mL) was added ethyl bromodifluoroacetate (1.285 mL, 10.00 mmol). The reaction mixture was heated at 80° C. under nitrogen overnight. Reaction mixture was cooled to room temperature and diluted with dichloromethane (80 mL) and 2N aqueous ammonium chloride (150 mL). The mixture was extracted with dichloromethane (2×60 mL). The organic layer was washed with brine (2×50 mL), and concentrated. The residue was purified by Biotage SP1 column chromatography on silica gel [40+M], eluting with 5-60% ethyl acetate/hexanes, 24 CV; 60% ethyl acetate/hexanes, 6 column volumes. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 2H), 7.35 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][CH3:13])=[CH:6][C:5]=1[OH:15].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:24][C:20]3[C:21]([C:11]=2[CH2:12][CH3:13])=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=3[F:26])=[CH:6][C:5]=1[OH:15]
Reactant: CCCC(=O)c1ccc(C(=O)OC)c(O)c1
Reactant: NNc1cccc(Cl)c1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCc1c(-c2ccc(C(=O)OC)c(O)c2)[nH]c2c(F)c(Cl)ccc12
Temperature: 120 °C

Procedure:
A mixture of 4-butyryl-2-hydroxy-benzoic acid methyl ester (60 mg, 0.27 mmol), (3-chloro-2-fluoro-phenyl)-hydrazine (Apollo Scientific, Ltd., 54 mg, 0.27 mmol), and zinc chloride (110 mg, 0.8 mmol) in acetic acid (2 mL) is purged with nitrogen for 5 minutes and then heated in a sealed tube at 120° C. for 2 hours. The mixture is cooled to room temperature and diluted with ethyl acetate. The resulting mixture is sequentially washed with saturated aqueous Na2CO3 and saturated aqueous NaCl, and finally dried over sodium sulfate. After concentration, the crude product is purified via silica gel flash column chromatography (10% ethyl acetate in hexanes) to afford 4-(6-chloro-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxy-benzoic acid methyl ester as a light yellow solid: ESMS m/z 348.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:13](=[O:14])[C:6]2[N:7]3[CH2:12][CH2:11][CH2:10][C:8]3=[N:9][C:5]=2[C:4](=[O:15])[CH:3]=1.[CH2:16]1[NH:18][CH2:17]1.CC(C)=O.[K+].[Br-]>CO>[N:18]1([C:3]2[C:4](=[O:15])[C:5]3[N:9]=[C:8]4[CH2:10][CH2:11][CH2:12][N:7]4[C:6]=3[C:13](=[O:14])[C:2]=2[CH3:1])[CH2:16][CH2:17]1
Reactant: CC1=CC(=O)c2nc3n(c2C1=O)CCC3
Reactant: C1CN1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CC1=C(N2CC2)C(=O)c2nc3n(c2C1=O)CCC3
Reaction time: 0.5 h

Procedure:
To a solution of 35 mg (0.17 mmol) of 26 in 4 mL of dry methanol, chilled at 0° C., was added 0.5 mL of ethyleneimine. The reaction was stirred at 0° for 30 min and then at room temperature for 1 hour. The solvent was removed in vacuo and the red residue flash chromatographed on silica gel using chloroform as the eluant. The purified product was recrystallized from chloroform/hexane: 20.5 mg (48%) yield; mp 192°-194° C. dec.; TLC (acetone), Rf =0.73; IR(KBr pellet) 1674, 1632, 1575, 1518, 1377, 1338, 1315, 1137, 988 cm-1 ; 1H NMR (CDCl3) δ4.17 (2 H, t, J~7 Hz, C(1) methylene), 2.89 (2H, t, J~7 Hz, C(3) methylene), 2.65 (2 H, quintet, J~7 Hz, C(2) methylene): 2.31 (4 H, s, aziridine protons), 2.02 (3 H, s, 7-methyl): mass spectrum (EI mode) m/z 243 (P+), 228 (P+ -methyl). (Anal. Calcd for C13H13N3O2 : C, 64.18; H, 5.34; N, 17.27. Found: C, 64.02; H, 5.21; N, 16.76.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[N:12][CH:13]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Reactant: NC1CCCC1
Product: CCc1cc(-c2ccc(C(=O)NC3CCCC3)cn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and cyclopentyl amine to afford the title compound. MS: m/e=326 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[H-].[Na+].[CH2:14](I)[CH3:15]>CN(C)C=O>[CH2:14]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])[CH3:15]
Reactant: O=C1COc2ccccc2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)COc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a cooled solution of 2H-1,4-benzoxazin-3(4H)-one (11.93 g, 80 mmol) in N,N-dimethylformamide (120 ml) was added sodium hydride (60% dispersion in mineral oil, 3.2 g, 80 mmol) in portions between 0° C. and 5° C. (1 h). The mixture was stirred 1 h at 0° C. To the cooled mixture was added ethyl iodide (13.7 g, 88 mmol) dropwise. The ice bath was removed and the mixture was stirred at r.t. for 17 h. The mixture was poured on water and extracted twice with AcOEt. The organic layers were washed with brine and water, dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, heptane/AcOEt 9:1) to give the title compound (13.3 g) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([CH3:40])[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][C:33]=4[CH3:40])[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: Cc1cc(F)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1-c1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
3-Bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (600 mg, 1.31 mmol), 4-fluoro-2-methylphenyl boronic acid (271 mg, 1.98 mmol), cesium carbonate (730 mg, 2.24 mmol) and tetrakis triphenylphosphine palladium(0) (25 mg) in dioxane (10 ml) are heated to 100° C. under a nitrogen atmosphere for 16 hours. The mixture is cooled to room temperature then poured into ethyl acetate (100 ml). The organic layer is washed with water (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The residue is then purified by column chromatography on silica gel to give 4′-fluoro-2′-methyl-biphenyl-3-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide as pale purple needles (0.44 g). Mp: 95-7° C. 1H NMR 300 MHz (CDCl3) δ 8.35 (d, 1H, J=7.5 Hz), 7.85-8.1 (m, 5H), 7.75 (d, 1H, J=7.5 Hz), 7.5-7.63 (m, 4H), 7.2 (m, 1H), 6.9-7.05 (m, 2H), 6.85 (d, 1H, J=12 Hz), 4.3 (t, 2H), 3.75 (m, 4H), 2.98 (t, 2H), 2.6 (m, 4H), 2.3 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23][C:24](=[O:39])[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].C1(C)C=CC(S([N:49]=[N+:50]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[N+:49](=[C:25]([C:24](=[O:39])[CH2:23][C@@H:19]1[C@@H:18]([C:2]([CH3:1])([O:4][C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:6])[CH3:3])[C:21](=[O:22])[NH:20]1)[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)=[O:27])=[N-:50]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
To a solution of 4-nitrobenzyl 4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate (58.3 mg) in acetonitrile (1.17 ml) was added a solution of p-toluenesulfonyl azide (25.3 mg) in acetonitrile (0.228 ml) at 0° C. After stirring for 5 minutes at 0° C., a solution of triethylamine (53.7 μl) in acetonitrile (0.483 ml) was added dropwise. The stirring mixture was allowed to warm to ambient temperature during 15 minutes and kept at the same temperature for 20 minutes. The solvent was distilled off and the residue (85.9 mg) was flash chromatographed on silica gel (1 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 3:1) to give 4-nitrobenzyl 2-diazo-4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate (58.4 mg) as an amorphous solid
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[CH:10]=[CH:11][C:12]([O:14]C)=[CH:13][C:8]=3[S:7](=[O:17])(=[O:16])[NH:6][CH2:5]2)[CH2:3][CH2:2]1.B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:9]3[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=3[S:7](=[O:16])(=[O:17])[NH:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=S1(=O)NCN(C2CC2)c2ccc(O)cc21
Reaction time: 20 h

Procedure:
A solution of the compound of Example 84 (50 mg) in chloroform (3 mL) is cooled on an ice bath and then boron tribromide (0.15 mL) is added. After stirring for 20 hours, water (5 mL) is added to the mixture, which is then concentrated under reduced pressure and subsequently extracted with ethyl acetate (3×20 mL). The organic phases are collected and dried over anhydrous MgSO4. After filtration, the filtrate is evaporated to dryness and the residue is dissolved in ethyl acetate (1 mL); hexane (5 mL) is then added. The precipitate obtained is collected by filtration, washed with hexane and dried to yield the expected product in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:18][C:19](=[O:21])[CH3:20])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)(Cl)Cl.C(=O)=O>CO>[C:19]([NH:18][C:4](=[C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([O:2][CH3:1])=[O:22])(=[O:21])[CH3:20]
Reactant: COC(=O)[C@H](NC(C)=O)C(c1ccccc1)c1ccccc1
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(NC(C)=O)=C(c1ccccc1)c1ccccc1

Procedure:
(R)-2-Acetylamino-3,3-diphenylpropionic acid methyl ester, reaction time 6 h, conversion 100%. [α]D25-101.6 (c=1.02, CHCl3). ee 80.7% (SFC, 2× Chiralpak AD-H columns, 10% methanol, 3000 psi CO2, 35° C., flow rate 3 ml/minute, retention times R 5.2 minutes, S 10.1 minutes). Comparative examples have been disclosed by Boulton (Boulton, L. T., WO 2006127273).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccccc2)CC1
Yield: 22 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound, potassium carbonate (1.9 g) and 6-bromo-1-phenyl-1-hexanone (1.7 g) were reacted and treated in the same manner as in Example 172 to give 0.56 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-oxo-6-phenylhexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 150 °C
Yield: 28.9 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (80 mg, 0.216 mmol) in dioxane and water (4 mL/1 mL) was added phenylboronic acid (36 mg), Pd(PPh3)4 (25 mg) and K2CO3 (104 mg). The reaction mixture was heated to 150° C. for 20 minutes by microwave irradiation. The organic phase was separated, concentrated, and purified by HPLC to afford the title compound (23 mg).