Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=1[Cl:16])=[O:4].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:7]=2[Cl:16])=[O:4])=[CH:20][CH:19]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1
Product: NS(=O)(=O)c1ccc(NC(=O)CNc2ccc(Cl)cc2)c(Cl)c1

Procedure:
2-Chloro-N-(2-chloro-4-sulphamoylphenyl)-acetamide (7g) and p-chloroaniline (6.3 g) were heated together for 45 minutes on a water bath at 90°. The mixture was worked up as in Example 1(b) to yield the title product (4.5 g), m.p. 185° .
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([N:17]1[C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:20][C:19]([C:29]([NH2:31])=O)=[N:18]1)[CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[CH2:14]([N:17]1[C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:20][C:19]([C:29]#[N:31])=[N:18]1)[CH2:15][CH3:16]
Reactant: CCCn1nc(C(N)=O)cc1CC1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCn1nc(C#N)cc1CC1CCOCC1
Reaction time: 3 h
Yield: 106 %

Procedure:
A solution of trifluoroacetic anhydride (2.50 mL, 17.7 mmol) in dichloromethane (32 mL) was added over a period of ten minutes to a 0° C. solution of 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxamide (4.05 g, 16.1 mmol) and triethylamine (4.89 g, 48.3 mmol) in dichloromethane (32 mL). After the addition was complete, the cooling bath was removed and the solution was stirred for three hours. The solution was washed with 2 M aqueous sodium carbonate. The aqueous layer was extracted three times with tert-butyl methyl ether. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (eluting with 40% to 70% ethyl acetate in hexane) to provide 3.98 g of 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:8])=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1CCOCC1
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of 6-chloro nicotinic acid (1.11 g, 7.04 mmol) in CH2Cl2 at 0 C was added EDCI (2.70 g, 14.08 mmol) and HOBt and then the resulting mixture was stirred for 30 minutes at 0 C. After that, morpholine (2.46 ml, 28.17 mmol) was added, the ice-bath removed and the reaction was done in 15 minutes. Water was added, the mixture was extracted with CH2Cl2, dried over MgSO4 and concentrated to afford 1.55 g of product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Br:13]N1C(=O)CCC1=O.O>C(#N)C.[Fe](Cl)(Cl)Cl>[Br:13][C:5]1[CH:4]=[C:3]([C:9]([F:12])([F:10])[F:11])[C:2]([NH2:1])=[C:7]([F:8])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(F)cccc1C(F)(F)F
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CC#N
Product: Nc1c(F)cc(Br)cc1C(F)(F)F
Yield: 96.9 %

Procedure:
To a solution of 2-amino-3-fluorobenzotrifluoride (0.7 ml, 5.6 mmol) in acetonitrile (2 ml) was added N-bromosuccinimide (994 mg, 5.6 mmol), followed by iron (III) chloride (90.1 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 90 min, before addition of water (20 ml). The mixture was extracted with tert-butyl methyl ether (2×15 ml) and the combined extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (1.4 g), which was used directly.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O:19][C@@H:20]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:31][S:30][C@H:21]1[O:22][C:23]1[CH:24]=[N:25][C:26](Br)=[CH:27][CH:28]=1)(=[O:18])[CH3:17]>>[C:16]([O:19][C@@H:20]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:31][S:30][C@H:21]1[O:22][C:23]1[CH:24]=[N:25][C:26]([C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[CH:27][CH:28]=1)(=[O:18])[CH3:17]
Reactant: OB(O)c1ccc(N2CCCCC2)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(N3CCCCC3)cc2)nc1

Procedure:
By following a procedure analogous to Example 43 starting from [4-(1-piperidinyl)phenyl]boronic acid and 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, the expected compound is obtained in the form of a gray powder (yield=14%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C1COCC1>[OH:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]3[NH:2][O:1][C:27](=[O:28])[N:21]=3)=[CH:9][CH:8]=1)[CH:19]=[CH:18]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(NO)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Solvent: C1CCOC1
Product: O=c1nc(-c2ccc(-c3ccc4cc(O)ccc4n3)cc2)[nH]o1
Temperature: 65 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
N-hydroxy-4-(6-hydroxyquinolin-2-yl)benzimidamide (800 mg, 2.86 mmol) was dissolved in 25 mL of THF and CDI (557 mg, 3.44 mmol) and TEA (0.2 mL) was added. The mixture was stirred at 65° C. for 2 hours, followed by concentration in vacuo. The crude material was dissolved in 10 mL 1N NaOH and filtered through celite. The mixture was then acidified with 1N HCl to a pH of 4.5 and the solids were filtered and dried. The solids were slurried in 10 mL of EtOAc overnight at 50° C. followed by filtration to yield Compound 12 (315 mg, 36% yield). 1H NMR (DMSO-d6, 400 MHz): δ 10.19 (s, 1H), 8.42 (d, 2H), 8.28 (d, 1H), 8.14-8.11 (d, 1H), 8.00-7.94 (m, 3H), 7.39-7.35 (dd, 1H), 7.21 (s, 1H). MS (ESI): m/z 306.44 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])C=CC=CC=1.Cl>C1COCC1.C(OCC)(=O)C.O>[Br:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:18]
Reactant: O=C(Oc1ccccc1)c1ccccc1Br
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccccc1Br)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 58 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 2-Bromo-benzoic acid phenyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(2-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol) as brown solid in 58% yield.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br.Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:45][C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[O:47])[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccn3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-2-yl)ethanone hydrobromide and isolated as brown solid. MS (m/e): 402.3 (MH+).
Reaction SMILES: [OH:1][C:2]1C=CC=C[C:3]=1C(N(C(C)C)C(C)C)=O.[H-].[Na+].BrCC(OCC)=O.[C:26]([C:28]1[CH:62]=[CH:61][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([C:52]([N:54]([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:57])[CH3:56])=[O:53])=[C:43]([CH:51]=2)[O:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:30][CH:29]=1)#[N:27].[ClH:63]>CN(C)C=O.C(O)C>[ClH:63].[CH2:49]([O:48][C:46]([CH2:45][O:44][C:43]1[CH:51]=[C:39]([CH:40]=[CH:41][C:42]=1[C:52]([N:54]([CH:58]([CH3:60])[CH3:59])[CH:55]([CH3:56])[CH3:57])=[O:53])[O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][C:31]1[CH:30]=[CH:29][C:28]([C:26](=[NH:27])[O:1][CH2:2][CH3:3])=[CH:62][CH:61]=1)=[O:47])[CH3:50]
Reactant: CCOC(=O)COc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Reactant: CC(C)N(C(=O)c1ccccc1O)C(C)C
Agent: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=N)c1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(OCC(=O)OCC)c2)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A stirred solution of 4-15-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (0.5 g, 1.18 mmol) in 10.0 mL of N,N-dimethylformamide is treated with 60% sodium hydride (47 mg, 1.18 mmol) and ethyl bromoacetate (144 μL, 1.3 mmol), and heated at 70° C. for 2.5 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford yellow foam. The resulting ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxyacetate in 50 mL of anhydrous ethanol at 0° C. is treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and concentrated in vacuo. This material is purified by chromatography on silica gel with 60% ethyl acetate/hexane as the eluent to afford ethyl 4-[5-[3-ethoxycarbonylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride as colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Cl)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:12][CH2:13][CH:14]([CH2:16][OH:17])[OH:15].[OH-].[Na+]>O>[OH:15][CH:14]([CH2:16][OH:17])[CH2:13][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(OCC(O)CO)ccc1[N+](=O)[O-]
Yield: 59.6 %

Procedure:
0.1 mol (17.3 g) of 3-amino-4-nitro-chlorobenzene, which is a known compound [Bios Final Report, 1,147 (1948)], is introduced gradually, at about 120° C., whilst stirring, into 2.4 mols (225 g) of glycerol in which 8.6 g of sodium hydroxide have been dissolved beforehand at about 120° C. When the addition has ended, heating is continued for 21/2 hours and the reaction medium is then poured into 250 g of iced water. The desired product is extracted with ethyl acetate and the ethyl acetate is driven off in vacuo to give 13.6 g of crystalline product. After two recrystallisations from acetonitrile and drying in vacuo, 3-amino-4-nitrophenyl β,γ-dihydroxypropyl ether, which melts at 139° C., is collected.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1)[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Yield: 93.6 %

Procedure:
Using a method similar to Example 365, step 1, and using 3-ethoxy-4-hydroxy-benzaldehyde (3.00 g, 18.0 mmol), 6-chloro-nicotinonitrile (2.65 g, 18.0 mmol), and potassium carbonate (6.62 g, 45.2 mmol) in dimethylacetamide (90 mL), after 3 h at 100° C. (no purification) provides 4.52 g (93%) of the title compound as a yellow/white solid: mass spectrum (electrospray): m/z=269.0 (M+1); 1H NMR (CDCl3): 9.96 (s, 1H), 8.39 (d, 1H, J=2.0 Hz), 7.95 (dd, 1H, J=2.0, 8.3 Hz), 7.55-7.50 (m, 2H), 7.33 (d, 1H, J=7.8 Hz), 7.11 (d, 1H, J=9.3 Hz), 4.05 (q, 2H, J=6.8 Hz), 1.16 (t, 3H, J=6.8 Hz).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][CH:20]=[CH:19][C:18]=2[CH:22]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][C:18]=2[CH:22]=1
Reactant: Brc1ccc2sccc2c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1cc2cc(Br)ccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of diisopropylamine (15.5 mL, 110 mmol) in THF (100 mL) at 0° C. was added n-butyllithium (40 mL of 2.5M in hexanes, 100 mmol). The resultant reaction solution was stirred at 0° C. for 30 minutes and then cooled to −40° C., before it was cannulated to a solution of 5-bromobenzothiophene (10.5 g, 50.0 mmol) and chlorotrimethylsilane (12.7 mL, 100 mmol) in THF (150 mL) at −78° C. The reaction solution was stirred at −78° C. for 1 hour, and then it was quenched with aqueous ammonium chloride at −78° C. and warmed to room temperature. The resultant mixture was extracted with ethyl acetate and the organic extract obtained was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by flash column chromatography (hexanes to 98:2 hexanes/ethyl acetate) to give the desired 5-bromo-2-trimethylsilylbenzothiophene (14.1 g, 98%) as a clear colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 2.0 Hz, 1H), 7.37 (s, 1H), 0.38 (s, 9H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.C(OCC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:3]([O:6][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[C:4]#[CH:5]
Reactant: BrCCCCCCCBr
Reactant: C#CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C#CCOCCCCCCCBr
Temperature: 60 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
25% (w/w) aq. NaOH (700 ml) was added to a stirred mixture of propargyl alcohol (70 g), tetra-butyl ammonium bromide (3.5 g) and 1,7-dibromoheptane (322 g) maintaining the temperature below 30° C. The reaction mixture was heated at 60° C. for 5 hrs then allowed to cool to room temperature and stirred overnight. Diethyl ether (350 ml) and water (280 ml) were added, the mixture stirred and allowed to settle. The aqueous layer was extracted with diethyl ether (210 ml), the organic layers combined, dried (MgSO4). The solution was concentrated to give 280 g of crude material. 140 g Of the crude was purified by chromatography on Biotage (800 g) eluting with petroleum ether then petroleum ether:ethyl acetate (100:1 followed by 100:1.5) to give the title compound (49.6 g).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[NH:15]1[C:12]2[CH:13]=[CH:14][C:9]([C:1]3[CH:6]=[CH:5][C:4]4[NH:7][C:22]([C:21]5[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=5)=[N:8][C:3]=4[CH:2]=3)=[CH:10][C:11]=2[N:16]=[C:22]1[C:21]1[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: Oc1ccc(-c2nc3cc(-c4ccc5[nH]c(-c6ccc(O)cc6)nc5c4)ccc3[nH]2)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
A mixture of biphenyl-3,3′,4,4′-tetraamine (214 mg, 2.00 mmol), 4-hydroxybenzaldehyde (489 mg, 4.00 mmol) and Na2S2O5 (380 mg, 2.00 mmol) in IMS-H2O (3:1, 20 mL) was heated under microwave irradiation for 160° C. for 10 min, then 180° C. for 10 min. The mixture was filtered and washed with IMS. H2O was added to the filtrate, and the resulting white precipitate was filtered, and washed with water and Et2O. Column chromatography of the crude solid (EtOAc to 95:5 EtOAc-MeOH) afforded the product as a yellow solid (50 mg, 6%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1.[I-].[Na+].[CH2:19]([NH:23][C:24]1[C:25]([CH3:37])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]>C(#N)C>[CH2:19]([N:23]([CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1)[C:24]1[C:25]([CH3:37])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNc1cccc(-c2ccc(C)cc2)c1C
Reactant: CCOC(=O)COc1ccc(CCl)cc1C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C)cc2)c1C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
Ethyl [4-(chloromethyl)-2-methylphenoxy]acetate (35.9 g, 0.148 mols) was dissolved in dry acetonitrile (285 mL). Sodium iodide (20.1 g, 0.135 mols 1 eq) was added in one portion and mixture stirred for 5 mins. A solution of the N-butyl-N-(2,4′-dimethyl-1,1′-biphenyl-3-yl)amine (34 g. 0.135 mol) and disopropylethylamine (23.5 mL, 0.135 mol) in dry acetonitrile (285 mL) was added over 10 min and cooling applied to maintain reaction temperature at ca. 16° C. during the addition. The reaction was concentrated in vacuo and the resultant orange oil partitioned between DCM (700 mL) and water (700 mL). The aqueous was extracted with DCM (500 mL) and the combined organic extracts were cautiously washed with brine (300 mL). After drying (Na2SO4) the mixture was concentrated in vacuo to give a dark orange oil. Purification using flash chromatography on (2 kg silica column), eluting with 1:1–0:1 cyclohexane:DCM afforded the title compound as a yellow oil (48.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C@@H:9]2[CH2:19][CH2:20][C@@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[OH:22])=[N:6][CH:7]=1.[OH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:21]([OH:22])[CH2:20][CH2:19][C@@H:9]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([OH:30])[CH:36]=4)=[CH:7][N:6]=3)[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]2=[O:18])=[CH:24][CH:25]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(Br)cn2)N1c1ccccc1
Reactant: OB(O)c1cccc(O)c1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(O)c3)cn2)N1c1ccccc1
Yield: 86.6 %

Procedure:
(3R,4S)-4-(5-Bromopyridin-2-yl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (23 mg, 0.051 mmol) was coupled with 3-hydroxyphenyl boronic acid (9.2 mg, 0.067 mmol) under standard Suzuki conditions illustrated by Example 42. Purification by chromatography (4 g silica gel, 15% to 100% ethyl acetate-hexane) afforded (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)pyridin-2-yl]-1-phenylazetidin-2-one (20.7 mg, 87% yield) as a clear film; Rf 0.14 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 8.88 (d, J=2.2 Hz, 1H), 7.88 (dd, J=8.2, 2.3 Hz, 1H), 7.86-7.80 (m, 1H), 7.39-7.22 (m, 7H), 7.12-7.02 (m, 3H), 6.96 (t, J=8.7 Hz, 2H), 6.96-6.91 (m, 1H), 4.97 (d, J=2.3 Hz, 1H), 4.76-4.72 (m, 1H), 3.28-3.22 (m, 1H), 3.20 (br s, 1H), 2.17-1.90 (m, 4H), 1.80 (br s, 1H) ppm; MS [M+H]+ 469.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]>O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[CH3:13])=[O:15])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.7 g) was added to a pyridine solution of 4-chloro-3-nitroaniline (1 g) and the mixture was stirred at room temperature for 2 h. After the reaction, water was added and the precipitated solid was collected by filtration to give the title compound (2.1 g), melting point:221–225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C@H:19]([C:20]([NH:22][C@H:23]([C:42]([O:44]C)=[O:43])[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:41])[C:33]4[C:38]([Cl:39])=[CH:37][N:36]=[CH:35][C:34]=4[Cl:40])=[CH:27][CH:26]=3)=[O:21])[C:18]3[CH:17]=[N:16][N:15]([CH2:46][CH3:47])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[Li].O.Cl>CO.O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[C@H:19]([C:20]([NH:22][C@H:23]([C:42]([OH:44])=[O:43])[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:41])[C:33]4[C:38]([Cl:39])=[CH:37][N:36]=[CH:35][C:34]=4[Cl:40])=[CH:27][CH:26]=3)=[O:21])[C:18]3[CH:17]=[N:16][N:15]([CH2:46][CH3:47])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCn1ncc2c1CN(S(=O)(=O)c1cc(Cl)cc(Cl)c1)[C@@H]2C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)C(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCn1ncc2c1CN(S(=O)(=O)c1cc(Cl)cc(Cl)c1)[C@@H]2C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)C(=O)O
Reaction time: 2 h

Procedure:
A solution of 47 mg (0.063 mmol) of N-[(5-(3,5 -dichlorobenzensulfonyl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4 (S)-carbonyl]-4-(3′,5′-dichloroisonicotinoyl)amino-(L)-phenylalanine, methyl ester in 2 mL of MeOH and 0.5 mL of water was treated with 7 mg (0.167 mmol) of LiOH—H2O. After stirring for 2 hr the solution was acidified (pH 2) with 1.2 N HCl and concentrated in vacuo. The residue purified by preparative TLC on silica eluted with 94.5:5:0.5 CH2Cl2:MeOH:HOAc to yield N-[(5-(3,5-dichlorobenzensulfonyl)-1 -ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4(S)-carbonyl]-4-(3′,5′-dichloroisonicotinoyl)amino-(L)-phenylalanine (35 mg) as a solid. LC-MS: m/e 727 (M+1).