Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[NH:39]1[CH2:46][CH2:45][CH2:44][C@@H:40]1[C:41]([NH2:43])=[O:42]>>[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:23]2[C:9]([N:39]3[CH2:46][CH2:45][CH2:44][C@@H:40]3[C:41]([NH2:43])=[O:42])=[CH:10][C:11]3[NH:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:13][C:12]=3[CH:22]=2)=[CH:26][CH:27]=1)(=[O:32])=[O:33]
Reactant: NC(=O)[C@H]1CCCN1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2N2CCC[C@@H]2C(N)=O)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and D-prolinamide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C1O[C:14]([CH2:16][CH2:17][NH2:18])([CH3:15])[O:13]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:15][C:14](=[O:13])[CH2:16][CH2:17][NH:18]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: CC1(CCN)OCCO1
Reactant: Cc1cc(F)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1C1CC(=O)CCN1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
4-Fluoro-2-methyl-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluensulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41]([NH2:42])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][C@H:28]1[O:29][C@@H:30]([CH3:32])[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:39]4[CH:40]=[C:41]([NH2:42])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[N:24][N:23]=2)[CH2:27]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1N
Temperature: 80 °C
Yield: 99.3 %

Procedure:
To a solution of 6-bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (0.82 g, 1.540 mmol) in 1,4-dioxane (15 ml) and water (1.5 ml) was added 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (0.501 g, 2.002 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (0.225 g, 0.308 mmol) and potassium phosphate tribasic (0.981 g, 4.62 mmol). The mixture was heated at 80° C. for 2 hr, cooled and concentrated in vacuo and the residue partitioned between dichloromethane and water (20 ml), separated by hydrophobic frit and purified by silica (100 g) cartridge on Flashmaster 11, using a gradient of dichloromethane and methanol (1% triethylamine) to give the title compound as an orange solid (0.88 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([F:23])=[CH:25][CH:26]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cc([N+](=O)[O-])ccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cc([N+](=O)[O-])ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 8-nitro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-fluorobenzoyl chloride; MS (ES): 424 (MH+).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:24][CH2:25]CCCCCC>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:24][CH3:25]
Reactant: CCCCCCCCI
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Product: CCCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
Following a procedure similar to that used for the preparation of Intermediate 6a but using 1-iodo-n-octane as the alkylating reagent the title compound was obtained as a colorless oil (86% yield).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[F:22][C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([CH:21]=1)[O:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Reaction time: 3 h

Procedure:
10 ml of a solution of HCl in dioxane (4 M) were added to 1.19 g trans-[4-(5-fluoro-2-nitro-phenoxy)-cyclohexyl]-carbamic acid tert-butyl ester in methylene chloride. The mixture is stirred for 3 hours and 2 ml of HCl in dioxane (4 M) were added. The reaction mixture was stirred for 1 hour and concentrated in vacuo.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][CH2:25]OS(C)(=O)=O>>[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:15][C:14]=1[CH2:24][CH2:25][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc2c1CCCC2

Procedure:
In analogy to the procedures described in examples 91 a] and b] 5,6,7,8-tetrahydro-naphthalen-1-ol was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 5-methyl-2-phenyl-4-[2-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-ethyl]-oxazole. Treatment of 5-methyl-2-phenyl-4-[2-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-ethyl]-oxazole with dichloromethyl methyl ether and titanium tetrachloride then gave 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde as yellow solid.
Reaction SMILES: Cl.[Br:2][C:3]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]2[N:7]([CH3:13])[C:8]([CH2:10][CH2:11]Cl)=[N:9][C:5]=2[CH:4]=1.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:2][C:3]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]2[N:7]([CH3:13])[C:8]([CH2:10][CH2:11][N:29]3[CH2:30][CH2:31][CH:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)=[N:9][C:5]=2[CH:4]=1
Reactant: Cn1c(CCCl)nc2cc(Br)c3ccccc3c21
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Product: Cn1c(CCN2CCC(c3ccccc3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
The compound of the title is prepared by condensing 5-bromo-2-(2-chloroethyl)-1-methyl-1H-naphth[1,2-d]imidazole hydrochloride with 4-phenylpiperidine according to the method described in the foregoing example. M.p. 182°-84° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH:32]([OH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[OH:38][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: CCCCCC(O)Br
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCCO)C(C)(C)CCC2(C)C
Yield: 52 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 540 μl (4.1 mmol) of 1-bromohexanol, 850 mg (50%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)([CH3:3])[CH3:2].[C:12]1([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH:1]([CH:4]1[CH2:5][C:6](=[O:11])[CH:7]([C:22](=[O:23])[NH:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:19])=[O:20])[C:8](=[O:10])[CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CC(=O)CC(=O)C1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccccc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-isopropyl1,3-cyclohexanedione with benzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ISOPROPYL-2-(N-BENZENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 112.5°-114° C. (corr.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)#[N:19]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([O:26][C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-cyano-phenol to give 4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 328(MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.C(O)(=O)C(O)=O.[OH:26][C@H:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>C(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[N:3]=[C:2]2[N:33]1[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C@H:27]([OH:26])[CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:35][CH2:34]1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a mixture of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (200 mg, 0.72 mmol) and CH2Cl2 (7 mL) was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one oxalate (275 mg, 0.95 mmol). The reaction was complete after two hours. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 mixture of CH2Cl2:hexanes gave (R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (289 mg, 91%). LC/MS: m/z 439.30 (M+H)+ at 3.00 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.46 (m, 1H), 8.02 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.97 (m, 2H), 4.92 (d, J=7.2 Hz, 1H), 4.38 (m, 1H), 3.98 (m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.42 (m, 2H), 0.92 (q, J=3.8 Hz, 6H) ppm.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[CH2:16][CH2:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][CH:14]3[CH2:13][NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.Cl>O.[PH2](O)=O>[CH2:20]([N:18]1[CH2:17][CH2:16][N:15]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:28][C:10]=3[C:11](=[O:27])[NH:12][CH2:13][CH:14]2[CH2:19]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC1CN(Cc3ccccc3)CCN21
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: O=C1NCC2CN(Cc3ccccc3)CCN2c2ccccc21
Reaction time: 0.17 h

Procedure:
A solution of sodium nitrite (0.033 g, 0.478 mmol) in water (2.171 mL) was added to an ice bath chilled solution of Example 45H (0.14 g, 0.434 mmol) in hypophosphorous acid, solution in water (9.03 mL, 87 mmol, 9.63 M) and HCl (2.140 mL, 26.1 mmol, 12.2 M). A sample was taken out after 10 minutes, quenched with 1 M NaOH (aqueous), and the reaction was determined to be complete by LC/MS. The reaction mixture was allowed to reach room temperature and was poured into 100 mL 1 M NaOH (aqueous). Additional 1 M NaOH (aqueous) was added until the pH=14. The product was extracted with dichloromethane three times, dried over sodium sulfate, and the solvent was evaporated. The residue was then purified by reverse phase HPLC to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.03 (s, 1H), 8.19 (t, J=5.8, 1H), 7.61-7.50 (m, 5H), 7.50-7.39 (m, 2H), 7.11 (t, J=7.3, 1H), 7.04 (d, J=7.9, 1H), 4.47 (s, 2H), 3.37-3.10 (m, 6H), 3.02 (dd, J=6.5, 14.9, 1H); MS (ESI+) m/z 308.0 (M+H)+.
Reaction SMILES: [Cl:1][C@@:2]1([CH3:32])[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:31])[C@@H:12]([NH:13][C:14](=[O:30])[CH:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)NC(OC(C)(C)C)=O)[C@H:5]2[S:4][CH2:3]1.[C:33]1([C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N+]=[N-])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:1][C@@:2]1([CH3:32])[C@H:7]([C:8]([O:10][CH:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:9])[N:6]2[C:11](=[O:31])[C@@H:12]([NH:13][C:14](=[O:30])[CH2:15][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)O)c1ccccc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
To a solution of 3β-chloro-3α-methyl-7β-(α-tert. -butoxycarbonylaminophenylacetamido)cepham-4α-carboxylic acid (0.9 g) in methylene chloride (20 ml), is added a solution of diphenyldiazomethane in methylene chloride until the red color or the reaction solution does not disappear. The reaction mixture is evaporated to remove the solvent, leaving a residue of benzhydryl 3β-chloro-3α-methyl-7β-phenylacetamidocepham-4α-carboxylate (1.17 g). Yield: 96%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>>[OH:28][C:22]([C:24]([F:27])([F:26])[F:25])=[O:23].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC1CCN(Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 936 mg of ((1-benzyl)piperidin-4-yl)acetic acid, t-butyl ester (from EXAMPLE 163, Step B) in 2 mL of TFA was stirred at rt for 18 h. The solution was concentrated to afford the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[N+:12]([C:15]1[CH:16]=C(C=C[CH:22]=1)C=O)([O-:14])=[O:13].Cl>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1.C(OCC)(=O)C>[CH2:8]([C:9]1[CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=[CH:11][CH:10]=1)[CH:7]=[CH2:6]
Reactant: CCCCCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To a suspension of ethyltriphenylphosphonium bromide (22 g) in tetrahydrofuran (150 ml) at -78° C. was added dropwise a solution of n-butyllithium in hexane (59.3 mmol). The mixture was left to warm to room temperature over 30 minutes, then cooled to -78° C. and a solution of 3-nitrobenzaldehyde (7.5 g) in tetrahydrofuran (50 ml) was added dropwise. The reaction was left to warm to room temperature over 1 hour, poured into 2M hydrochloric acid (100 ml) and ethyl acetate (100 ml). The separated aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with water, saturated sodium bicarbonate (2×50 ml), brine (2×50 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product purified by column chromatography to give 3-(2-propenyl)nitrobenzene (5.72 g). δ(60 MHz, CDCl3) 1.9 (3H,2d, CH3), 5.9 (1 H, m, =CH--CH3), 6.3 (1H, 2d, AR--CH) and 7.3-8.1 (4H, m, ArH). To a solution of the above 3-(2-propenyl)-nitrobenzene (5.7 g) in ethyl acetate (20 ml) was added 10% palladium on carbon (0.57 g). This mixture was hydrogenated at 50 psi for 2 hours at room temperature, filtered through Hyflo and solvent evaporated to yield the crude product which was purified by column chromatography to give 3-propylaniline (4.7 g), δ (60 MHz, CDCl3) 0.9 (3H, t, CH3), 1.5 (2H, m, CH2CH3), 2.4 (2H, t, CH2CH2CH3), 3.4 (2H, bs, NH2) and 6.1 to 7.0 (4H, m, ArH).
Reaction SMILES: O1CCOCC1.[OH-].[Na+].[CH:9]([N:12]([C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[C:13]([NH:15]C(=O)C1C=CC=CC=1)=[S:14])([CH3:11])[CH3:10]>O>[CH:9]([N:12]([C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[C:13]([NH2:15])=[S:14])([CH3:11])[CH3:10]
Reactant: CC(C)N(C(=S)NC(=O)c1ccccc1)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N(C(N)=S)c1ccc2c(c1)OCO2
Temperature: 15 °C

Procedure:
To a stirred solution consisting of 45 ml. of dioxane and 200 ml. of water is added 27 grams of sodium hydroxide and the whole stirred until complete solution takes place. To this solution is added 17 grams of N-isopropyl-N-(3,4-methylenedioxyphenyl)-N'-benzoyl thiourea. The resulting mixture is heated to reflux for 48 hours and then cooled to 15°C. The resulting white solid is crystallized from benzene to obtain N-isopropyl-N-(3,4-methylenedioxyphenyl)-thiourea melting at 149°-151°C.
Reaction SMILES: [Cl:1][C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[C:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[N+:20]([O-:22])=[O:21])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:28].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]([F:26])([F:25])[C:3]([F:24])([F:23])[C:4]([Cl:28])=[N:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[N+:20]([O-:22])=[O:21]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)C(F)(F)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N=C(Cl)C(F)(F)C(F)(F)Cl

Procedure:
A mixture of 0.41 g (1.0 mmol) of 3-chloro-N-(2,6-dinitro-4-trifluoromethylphenyl)-2,2,3,3-tetrafluoropropionamide, 0.31 g (1.5 mmol) of phosphorous pentachloride, and 2 ml of toluene was heated under reflux for 6 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3-chloro-N-(2,6-dinitro-4-trifluoromethylphenyl)-2,2,3,3-tetrafluoropropionimidoyl chloride.
Reaction SMILES: [B:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+:12]>>[CH2:3]([O:2][BH-:1]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:4].[Na+:12]
Reactant: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Product: CCO[BH-](OCC)OCC
Temperature: 100 °C

Procedure:
The reaction of equation (10) is exothermic. For example, this reaction can be performed in a gravity bed reactor 190, as illustrated in FIG. 1. In such an apparatus, excess liquid triethyl borate can be added to solid sodium hydride in a reactor equipped with paddle stirring. The mixture can be maintained at a temperature from about 0° C. and about 100° C., preferably from about 60° to about 70° C., for about 1 to about 24 hours, preferably from about 1 to about 6 hours, with stirring to disperse the solid. The excess borane can be removed by conventional distillation, not shown, to give solid sodium triethoxyborohydride in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11](B(O)O)=[CH:10][CH:9]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:20]1[C:14]2[O:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:16]=3[C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cccc3c2oc2ccccc23)nc1
Yield: 62.2 %

Procedure:
To a 1 L round-bottom flask was added 2-bromopyridine (13.80 mL, 142 mmol), dibenzo[b,d]furan-4-ylboronic acid (25 g, 118 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.936 g, 4.72 mmol) and potassium phosphate tribasic monohydrate (81 g, 354 mmol) with toluene (350 mL) and water (35 mL). The reaction mixture was degassed with N2 for 20 minutes. Pd2(dba)3 (2.16 g, 2.35 mmol) was added and the reaction mixture was refluxed for 18 h. Completion of the reaction was confirmed by HPLC, GC and TLC. After cooling, the aqueous layer was removed and toluene was evaporated under reduced pressure. The residue was dissolved in dichloromethane and passed through one inch silica gel plug on a frit, eluting with dichloromethane. The crude product was chromatographed on silica gel with 20-25% ethyl acetate in hexane to give 18 g (62%) of the product. The product was confirmed by HPLC (99.6% purity) and GC/MS.