Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/B1OC(C)(C)C(C)(C)O1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Br[C:53]1[S:57][C:56]([C:58]2[CH:59]=[N:60][N:61]([CH3:67])[C:62]=2[C:63]([O:65][CH3:66])=[O:64])=[N:55][C:54]=1[CH3:68].C(=O)([O-])O.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C(#N)C.O>[CH2:4]([O:3]/[CH:1]=[CH:2]/[C:53]1[S:57][C:56]([C:58]2[CH:59]=[N:60][N:61]([CH3:67])[C:62]=2[C:63]([O:65][CH3:66])=[O:64])=[N:55][C:54]=1[CH3:68])[CH3:5]
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1c(-c2nc(C)c(Br)s2)cnn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCO/C=C/c1sc(-c2cnn(C)c2C(=O)OC)nc1C
Temperature: 90 °C
Yield: 63.8 %

Procedure:
(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg), palladium acetate (7.1 mg), tripotassium phosphate (67 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (26 mg), and water (0.35 ml) were added to an acetonitrile (4.0 ml) solution of the methyl 4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (50 mg) obtained in (Example 5.11) <Step 1>, and the obtained mixture was then stirred under heating in a nitrogen atmosphere for 2 hours at 90° C. Thereafter, ethyl acetate (50 ml) and a saturated sodium hydrogen carbonate aqueous solution (30 ml) were added to the reaction solution. After extraction of organic layers, water layers were extracted with ethyl acetate (50 ml). The organic layers were combined. The combined organic layer was washed with a saturated saline, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=92:8-40:60), so as to obtain the title compound (31 mg) in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](O)=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].[NH2:18][NH2:19]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:19][N:18]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=1
Reactant: NN
Reactant: O=C(C=C(O)c1ccc(F)cc1F)C(F)(F)F
Solvent: CC(=O)O
Product: Fc1ccc(-c2cc(C(F)(F)F)n[nH]2)c(F)c1
Temperature: 95 °C
Yield: 93.1 %

Procedure:
At 24° C., 15.0 g (0.06 mole) of the product of step A was dissolved in 50 mL glacial acetic acid and treated with 2 mL (0.064 mole) anhydrous hydrazine, added over a period of 5 minutes. The reaction was heated to 95° C. for 30 minutes. The reaction was cooled and poured into 300 mL ice water. The slurry was filtered and the cake washed with water and air dried to give 13.86 g (94%) of 5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole as a white solid, mp 157°-158° C.
Reaction SMILES: C([O:4][CH:5]([CH3:32])[C:6]([NH:8][C:9]1[C:10]([I:31])=[C:11]([C:17]([I:30])=[C:18]([NH:21][C:22](=[O:29])[CH:23]([O:25]C(=O)C)[CH3:24])[C:19]=1[I:20])[CH2:12]CC([O-])=O)=[O:7])(=O)C.[OH-:33].[Na+].Cl>CO.O>[OH:4][CH:5]([CH3:32])[C:6]([NH:8][C:9]1[C:10]([I:31])=[C:11]([C:17]([I:30])=[C:18]([NH:21][C:22](=[O:29])[CH:23]([OH:25])[CH3:24])[C:19]=1[I:20])[CH2:12][OH:33])=[O:7]
Reactant: [OH-]
Reactant: CC(=O)OC(C)C(=O)Nc1c(I)c(CCC(=O)[O-])c(I)c(NC(=O)C(C)OC(C)=O)c1I
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)C(=O)Nc1c(I)c(CO)c(I)c(NC(=O)C(C)O)c1I
Reaction time: 15 h
Yield: 46 %

Procedure:
N,N′-Bis(2-acetoxypropionyl)-3,5-diamino-2,4,6-triiodobenzylacetate (0.16 g, 0.2 mmol) was dissolved in a mixture of methanol (5 ml) and water (5 ml) and the pH was adjusted to 12 using a 1 M aqueous solution of NaOH. After stirring for 15 h, the solution was neutralized with 1 M HCl and the solvents were removed by evaporation. Purification by preparative HPLC gave 61 mg (46%) of the pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][OH:14])[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].O>O1CCCC1>[CH2:15]([O:14][CH2:13][CH2:12][N:8]([CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)N(CCO)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
A solution of 2-(N-tert-butoxycarbonyl-N-isopropylamino)-ethanol (3.00 g, 14.8 mmol) and benzyl bromide (2.6 ml, 22.1 mmol) in anhydrous tetrahydrofuran (30 ml) was added to a solution of 60% sodium hydride (885 mg, 22.1 mmol) in anhydrous tetrahydrofuran (20 ml) under ice-cooling, and the mixture was stirred at 60° C. for four hours. Water (100 ml) was added to the reaction mixture under ice-cooling, the temperature was returned to room temperature, and the whole was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine (100 ml) and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained oily matter was purified by silica gel column chromatography (mobile phase:hexane/ethyl acetate=4/1) to give 1.30 g (30%) of the target compound.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:18]Br.N.CO.C(Cl)(Cl)Cl>CC(O)=O>[CH:1]1([CH2:7][N:8]2[C:12]3[C:13]([Br:18])=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrBr
Reactant: Nc1ccc2ncn(CC3CCCCC3)c2c1
Agent: N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1ccc2ncn(CC3CCCCC3)c2c1Br
Yield: 40 %

Procedure:
To a solution of 3-cyclohexylmethyl-5-aminobenzimidazole (2.0 g, 8.7 mmol) in 40 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHCl3) to provide 1.2 g (3.8 mmol, 40%) of the product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.C1C=CC(O[C:35](OC2C=CC=CC=2)=[N:36][C:37]#[N:38])=CC=1>CC(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]1[O:14][C:35]([NH:36][C:37]#[N:38])=[N:16][N:15]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nnc(NC#N)o2)c1Cl
Yield: 21.7 %

Procedure:
To a suspension of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid hydrazide (394.1 mg, 1.27 mmoles) in 20 ml of 2-propanol is added triethylamine (200 μl, 1.43 mmoles) followed by diphenyl cyanocarbonimidate (371.9 mg, 1.56 mmoles). After 1.5 hours the resultant yellow solution is concentrated in vacuo. The residue is dissolved in 10 ml of ethyl acetate and partitioned between water and a 1:1 mixture of ether and hexane. The aqueous layer is acidified with 1N hydrochloric acid, and the resultant white solid is collected by filtration to provide 99.3 mg (22%) of 5-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-1,3,4-oxadiazol-2-yl-cyanamide, mp above 215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(C(=O)Nc2ccc(C)c(-c3ccc(C(=O)NCC4CC4)cc3)c2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1, 1 ′-biphenyl-3-yl)-4-methylbenzamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 4-methylbenzoic acid using method B. NMR; ™H CDCl3 7.87,(1H, s), 7.83,(2H, d), 7.78,(2H, d), 7.60,(1H, dd), 7.49,(1H, d), 7.41,(2H, d), 7.29-7.26,(3H, m), 6.29,(1H, t), 3.35,(2H, m), 2.42,(3H, s), 2.23,(3H, s), 1.09,(1H, m), 0.58,(2H, m), 0.30,(2H, m). LCMS: retention time 3.63 min, MH+399.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7].C(N(C(C)C)CC)(C)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.O>[C:30]1([CH2:29][NH:36][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[N:11]=[CH:10][C:9]=2[N+:6]([O-:8])=[O:7])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cccnc2c1NCc1ccccc1
Temperature: 60 °C
Yield: 62.5 %

Procedure:
Phosphorus oxychloride (3.5 mL, 37.7 mmol) was reacted with N,N-dimethylformamide (15 mL) while chilling in an ice bath. This mixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.0 g, 31.4 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was warmed in an oil bath to 60° C. After 3 hours the reaction mixture was poured into ice water. The resulting precipitate was isolated by filtration and then washed with water. The wet crude 5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150 mL). Diisopropylethylamine (1.2 eq) was added followed by the slow addition of benzylamine (4.7 mL g, 40 mmol). The reaction mixture was refluxed for 2 hours and then combined with water (˜100 mL). The layers were separated and the organic layer was concentrated under vacuum to provide 5.5 g of N-phenylmethyl-3-nitro[1,5]naphthyridin-4-amine. A small sample was recrystallized from isopropanol to provide a pure sample, m.p. 127-129° C. Analysis: Calculated for C15H12N4O2: %C, 64.28; %H, 4.32; %N, 19.99; Found: %C, 63.89; %H, 4.40: %N, 20.35.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.C([O:16][C:17]([CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][C:23]=2[N:24]=1)=O)C>N1CCCCC1.C(O)(=O)C.C(O)C>[C:29]([C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([C:19]3[C:17](=[O:16])[O:1][C:2]4[CH:11]=[CH:10][C:9]5[C:4]([C:3]=4[CH:12]=3)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[N:24][C:23]=2[CH:25]=1)([OH:31])=[O:30]
Reactant: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2o1
Reactant: O=Cc1c(O)ccc2ccccc12
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(O)c1ccc2oc(-c3cc4c(ccc5ccccc54)oc3=O)nc2c1
Yield: 56 %

Procedure:
A mixture of 2-hydroxy-1-naphthaldehyde (1.72 g, 0.01 mol), 2-ethoxycarbonylmethyl-5-carboxybenzoxazole (2.49 g, 0.01 mol), ethanol (30 mL), piperidine (10 drops), and acetic acid (5 drops) is heated at reflux for 3 hours. After cooling the reaction mixture is filtered to isolate the yellow fluorescent product which is then washed with ethanol and dried in air to yield 2.0 g (56% of theory) of 2-(5-carboxy-2-benzoxazolyl)-3H-naphtho[2,1-b]pyran-3-one having the structure ##STR19##
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@@H:38]([C:52](O)=[O:53])[CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@H:38]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)[C:52]([N:4]3[CH2:3][CH2:2][N:1]([CH:7]4[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:8]4)[CH2:6][CH2:5]3)=[O:53])=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CCCN1CCC(N2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
283 mg (1.00 mmol) ethyl 4-(4-piperazin-1-yl-piperidin-1-yl)-butyrate (Example A16b) were added to a mixture of 500 mg (0.90 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 321 mg (1.00 mmol) TBTU and 0.14 mL (1.00 mmol) triethylamine in 10 mL DMF and the reaction mixture was stirred for 2 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined, evaporated down i. vac., the residue was stirred with saturated NaHCO3 solution, filtered and dried.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][C@@H:29]3[CH2:33][CH2:32][O:31][CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCC[C@@H]1CCOC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC[C@@H]1CCOC1

Procedure:
Prepared similarly to Intermediate 215 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3S)-3-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C[O:7][C:8](=O)/[CH:9]=[C:10](/[O:13][CH3:14])\[CH2:11]Cl.COC(=O)C/C=C/OCCl>O>[CH3:14][O:13][C:10]1[CH2:11][N:1]([CH2:2][C:3]([OH:5])=[O:4])[C:8](=[O:7])[CH:9]=1
Reactant: COC(=O)/C=C(\CCl)OC
Reactant: NCC(=O)O
Agent: COC(=O)C/C=C/OCCl
Solvent: O
Product: COC1=CC(=O)N(CC(=O)O)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 304.6 %

Procedure:
30 g (400 mmol) of glycine was suspended in 60 ml of H2O and heated to 70° C. 10M of NAOH was added with an autotitrator up to pH 8.5. Then, 22.4 g (136 mmol) of 4-chloro-3-methoxy-but-2E-enoic acid methyl ester was added at 70° to 75° C. The pH was kept constant at 8.5 by adding 10M of NAOH. After 1 hour, another 22.4 g (136 mmol) of 4-chloro-3-methoxy-but-2E-enoic acid methyl ester was added, and, after another hour, 22.4 g (136 mmol) of 4-chloromethoxy-but-3E-enoic acid methyl ester again was added. After the final addition, the reaction mixture was stirred for another 3.5 hours at 70° to 75° C. The consumption of 10M of NAOH was then 80.3 ml, which corresponded to 2 equivalents relative to the glycine used. The reaction mixture was cooled to room temperature and diluted with 40 ml of H2O. Then, the reaction mixture was adjusted to pH 1 with concentrated HCl. The product precipitated after a short time, was filtered off and washed with saturated NaCl solution. After drying, 70.9 g of product was obtained. 3.41 g of product was obtained from the mother liquor. The total yield was 84 percent. The crude product was recrystallized from isopropanol: 68 g was recrystallized from 450 ml of isopropanol. 47 g of product, which corresponded to an 87 percent yield, was obtained. The product contained less than 0.01 percent of Cl. Other data for the product was:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=1>C(Cl)Cl>[O:15]=[C:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([NH:2][S:29]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3cccnc3)cc2)CC1
Reaction time: 18 h
Yield: 11.6 %

Procedure:
To a stirred solution of 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) (8.76 g, 0.32 mol) in methylene chloride (100 mL) at room temperature was added triethylamine (9 mL). To this mixture was added a mixture of 3-pyridinesulfonyl chloride (7.45 g, 0.035 mol) and triethylamine (9 mL). The reaction was stirred for 18 hours. The reaction mixture was concentrated. The product was flash silica gel chromatographed eluting with 7:3 ethyl acetate/hexanes and then flash silica gel chromatographed eluting with 3% methanol in methylene chloride to give the titled compound as a yellow solid (1.34 g, 13%); 1H NMR (300 MHz, CDCl3) δ 2.54 (t, J=6 Hz, 4H), 3.56 (t, J=6 Hz, 4H), 6.79 (s, 1H), 6.85 (d, J=12 Hz, 2H), 6.98 (d, J=12 Hz, 2H), 7.40 (m, 1H), 7.97 (dd, J=3 Hz, 1H), 8.75 (dd, J=6 Hz, 1H), 8.90 (d, J=3 Hz, 1H); MS (ES) m/z: 331.9 (MH+, 100%); HRMS Calcd. for C16H17N3O3S(MH+): 332.1063. Found: 332.1063.
Reaction SMILES: [Mg].O1CCCC1.CO[CH:9]([O:19]C)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl.Cl.[C:22]1(C)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>C(Cl)CCC>[CH:9](=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:24][CH:23]=[CH:22][CH2:27][CH3:26]
Reactant: Cc1ccccc1
Reactant: COC(CCCCCCCCCl)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCl
Product: CCC=CCCCCCCCCCC=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 0.85 gm of magnesium in a thoroughly dried flask equipped with condensor and magnetic stirrer was added 5 mls of anhydrous tetrahydrofuran and 1.06 mls of butyl chloride and 5 mls of dry toluene. This mixture was heated with stirring at 70° C. for about two hours. A solution of 4.44 gms of 1,1-dimethoxy-9-chloro nonane in 50 mls of toluene was added all at once. The temperature was maintained at 75°±5° for one and one quarter hours. The Grignard reagent was decanted into another flask and 3.12 gms of a mixture (approximately 60:40) of 1-chloro-2-pentene and 3-chloro-1-pentene was added. The reaction was maintained at 75°±5° with stirring. The reaction mixture became cloudy within one-half to three-quarters of an hour indicating the initiation of the coupling reaction. This was confirmed by GLC of a hydrolysed aliquot of reaction mixture. The reaction was allowed to continue until a test for Grignard reagent was negative (approximately 2 hours). 50 mls of 3 N hydrochloric acid was then added, the reaction mixture was then stirred and heated at reflux for 1 hour. The aqueous layer was separated, washed two times with toluene. The organic layer and the toluene washes were combined and dried over sodium sulphate. The solvents were removed on the rotary evaporator and the residue was distilled. The majority of the material distilled at 95° at 0.35 torr yielding 2.48 gms of crude 11-tetradecenal. For physical constants see Example 5.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][N:6]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[N:30][CH:29]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCNc1ccccc1-2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Product: O=C(Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 12, 6,7-dihydro-5H-dibenz[b,d]azepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:6]
Reactant: Cc1ccc(-n2cnnn2)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4C)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methyl-5-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[S:12][C:13]4[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[N:20]=3)=[CH:8][C:7]=2[CH:21]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C=O.ClCCl.[Cl-].[Na+].O>[C:28]([CH:18]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[S:12][C:11]([C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][C:7]=4[CH:8]=3)=[N:20][C:19]1=2)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: COc1ccc2oc(-c3nc4c(s3)NCCCC4)cc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2oc(-c3nc4c(s3)NCCCC4C(C)=O)cc2c1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a cooled solution of 2-(5-methoxybenzofuran-2-yl)-4,5,6,7-tetrahydro-8H-thiazolo[5,4-b]azepine (1.3 g) and pyridine (0.65 ml) in N,N-dimethylformamide (20 ml), a solution of acetyl chloride (0.41 g) in dichloromethane (2 ml) was added dropwise below 10° C. After being stirred for 2 hours, the resulting mixture was poured into brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup, which was crystallized from ethanol and collected by filtration to give 8-acetyl-2-(5-methoxybenzofuran-2-yl) 4,5,6,7-tetrahydro-8H-thiazolo[5,4-b]azepine (1.07 g).