Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:21](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:24])=[CH:28][CH:27]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1

Procedure:
This compound is prepared using Procedure C by coupling of Nα-benzyl-Nδ-Boc-Nα-methylornithine and (4-hydroxyphenyl)ethylamine.
Reaction SMILES: [N:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=O)=[C:6]([F:14])[C:5]=1[F:15])=[N+:2]=[N-:3].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.[OH-].[Na+]>CO.O>[N:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=[C:19]2[C:20](=[O:23])[C:21](=[CH:8][C:7]3[C:6]([F:14])=[C:5]([F:15])[C:4]([N:1]=[N+:2]=[N-:3])=[C:11]([F:12])[C:10]=3[F:13])[CH2:22][N:17]([CH3:16])[CH2:18]2)=[C:6]([F:14])[C:5]=1[F:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(C=O)c(F)c1F
Reactant: CN1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CC(=Cc2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)C(=O)C(=Cc2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)C1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a stirred solution of 4-azido-2,3,5,6-tetrafluorobenzaldehyde (23), 0.140 g, 0.640 mmol) and 1-methylpiperidine-4-one (0.040 mL, 0.32 mmol) in MeOH (1.5 mL), 1N aq. NaOH (0.650 mL, 0.650 mmol) was added dropwise. Yellow suspension resulted within minutes which was stirred at rt for forty-five minutes and diluted with water (3 mL). Yellow solid was collected by vacuum filtration, washed with water until the filtrate was neutral to pH paper. The yellow solid was dried further in vacuo to give 0.139 g (83%) 3,5-bis(4'-azido-2',3',5',6'-tetrafluorophenylmethylene)-1-methyl piperidine-4-one (22) as bright yellow powder; mp 153° C. (violent decomposition). 1HNMR(CDCL3 δ 2.37 (s, 3H), 3.42 (s, 4H), 7.55 (s,2H). ##STR28##
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[C@@H:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=4[CH:34]=3)[CH2:16][N:15]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C@@H:14]([CH2:45][C:46]([OH:48])=[O:47])[CH2:13]2)=[CH:8][CH:7]=1>CCOCC.CO>[CH3:3][O:47][C:46](=[O:48])[CH2:45][C@H:14]1[CH2:13][C@H:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=3[CH:34]=2)[CH2:16][N:15]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:36])=[O:37]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 3.5 h

Procedure:
4 ml of a solution of diazomethane in ether (0.2M) are added dropwise to a solution of 0.12 g of [(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (from example 25f) in 2 ml of methanol at 0° C. The reaction mixture is worked up after 3.5 hours by quenching with solid magnesium sulfate to decompose any excess diazomethane, filtering and concentrating under reduced pressure to afford the crude title compound as a pale yellow solid with was used in the next step without any further purification. Rf=0.78 (EtOAc); Rt=5.26.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:63]=[CH:62][C:15]2[NH:16][C:17]([CH2:19][CH2:20][CH:21]3[CH2:24][CH:23]([N:25]([CH2:30][C@@H:31]4[C@H:35]5[O:36]C(C)(C)[O:38][C@H:34]5[C@H:33]([N:41]5[C:45]6[N:46]=[CH:47][N:48]=[C:49]([NH:50]CC7C=CC(OC)=CC=7OC)[C:44]=6[CH:43]=[CH:42]5)[CH2:32]4)[CH2:26][CH:27]4[CH2:29][CH2:28]4)[CH2:22]3)=[N:18][C:14]=2[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:50][C:49]1[C:44]2[CH:43]=[CH:42][N:41]([C@@H:33]3[CH2:32][C@H:31]([CH2:30][N:25]([CH:23]4[CH2:22][CH:21]([CH2:20][CH2:19][C:17]5[NH:16][C:15]6[CH:62]=[CH:63][C:12]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:13][C:14]=6[N:18]=5)[CH2:24]4)[CH2:26][CH:27]4[CH2:29][CH2:28]4)[C@@H:35]([OH:36])[C@H:34]3[OH:38])[C:45]=2[N:46]=[CH:47][N:48]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC3CC3)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc2[nH]c(CCC3CC(N(CC4CC4)C[C@H]4C[C@@H](n5ccc6c(N)ncnc65)[C@H](O)[C@@H]4O)C3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Trifluoroacetic Acid (10 mL) added to a mixture of Water (1 mL) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclopropylmethyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.52 g, 0.68 mmol) at RT. The reaction was stirred overnight at RT and Triethylsilane (0.22 mL. 1.4 mmol) was added. The volatiles were removed in vacuo and resulting residue was taken up in MeOH (15 mls), 500 mgs of K2CO3 and 8 drops H2O were added and the reaction stirred at RT for 1 hour. The mixture was filtered and the filter cake washed with 10 ml MeOH. The filtrate was concentrated and the resulting residue purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to give the desired product (0.196 g) as an off white foam. MS (ESI+) for C33H45N7O2 m/z 572.6 [M+H]+; MS (ESP) for C33H45N7O2 m/z 570.3 [M−H]−; HPLC purity >90% (ret. time, 2.850 min.) 1H NMR (400 MHz, d4-MeOH) δH 7.944 (s, 1H), 7.361 (s, 1H), 7.280-7.259 (m, 1H), 7.172-7.150 (m, 1H), 7.092-7.078 (m, 1H), 6.484-6.475 (d, J=3.6 Hz, 1H), 4.222-4.185 (m, 1H), 3.815-3.779 (m, 1H), 3.329 (m, 0.5H (methine of trans isomer)), 2.961 (m, 0.5H (methine of cis isomer), 2.745-2.627 (m, 3H), 2.503-2.450 (m, 1H), 2.301-2.187 (m, 5H), 2.036-1.890 (m, 2H), 1.793-1.776 (m, 3H), 1.529-1.385 (m, 2H), 1.246 (s, 9H), 0.808-0.739 (m, 1H), 0.394-0.362 (m, 2H), 0.012-0.013 (m, 2H). Retention time: 2.850 minutes. HPLC Conditions:Agilent Zorbax Exlipse XDB-C18 column, 4.6×50 mm (1.8 urn packing), Solvent A—Water (0.1% TFA), Solvent B—Acetonitrile (0.07% TFA) 6 min gradient from 5 to 95% B; 1 min hold; then recycle.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]([CH3:31])[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH:22]([CH2:24][C:25]([O:27]C)=[O:26])[C:21](=[O:29])[NH:20][CH2:19][C:18]=2[CH:30]=1)=[O:13].O.[OH-].[Na+].FC(F)(F)C(O)=O>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]([CH3:31])[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21](=[O:29])[NH:20][CH2:19][C:18]=2[CH:30]=1)=[O:13]
Reactant: COC(=O)CC1Nc2ccc(C(=O)N(C)Cc3nc4ccccc4[nH]3)cc2CNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(Cc1nc2ccccc2[nH]1)C(=O)c1ccc2c(c1)CNC(=O)C(CC(=O)O)N2
Reaction time: 16 h

Procedure:
A solution of methyl (±)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.040 g, 0.09 mmol) in a mixture of methanol (7.0 mL), water (0.7 mL), and 1.0 M NaOH (0.7 mL) was kept 16 h at RT. Trifluoroacetic acid (0.5 mL) was added and the solvents were removed to give the crude product. Purification by semi-preparative HPLC (YMC ODS-AQ, 15:85; acetonitrile:water, 0.1% TFA) gave the title compound: MS (ES) m/e 408.2 (M+H)+ ; 1H NMR (250 MHz, DMSO-d6) δ 8.19 (br t, J=4.5 Hz, 1H), 7.72 (m, 2H), 7.38 (m, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.22 (br s, 1H), 5.05 (m, 1H), 4.95 (s, 2H), 3.74 (dd, 15.8, 7.4 Hz, 1H), 3.15 (s, 3H), 2.75 (dd, J=16.4, 8.5 Hz, 1H), 2.50 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH2:9]1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>[Pd].C(O)C>[CH3:13][C:10]1([NH:14][C:15](=[O:17])[CH3:16])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CC(=O)NC1(C)CCNC1
Yield: 54.1 %

Procedure:
A mixture of N-(1-benzyl-3-methylpyrrolidin-3-yl)-acetamide (600 mg, 2.6 mmol), palladium on carbon (400 mg, 10%) and ethanol (20 mL) was stirred at 40° C. under 50 Psi of hydrogen for 16 hours. The resulting mixture was filtrated. The filtrate was concentrated in vacuo to give 200 mg of the desired product (yield was 54%), which was used for next step without any purification.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[C:5]([NH:16][NH2:17])[N:4]=1)[CH3:2].[C:18](OCC)(OCC)(OCC)[CH2:19][CH3:20]>>[CH2:19]([C:20]1[N:4]2[C:3]([CH2:1][CH3:2])=[N:8][C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:6][C:5]2=[N:16][N:17]=1)[CH3:18]
Reactant: CCc1nc(NN)cc(N2CCN(C)CC2)n1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2cc(N3CCN(C)CC3)nc(CC)n12
Yield: 37 %

Procedure:
A mixture of 8.3 g (0.035 mole) of 2-ethyl-6-hydrazinyl-4-(4-methyl-1-piperazinyl)pyrimidine and 75 ml of triethyl orthopropionate was heated at reflux for 48 hours. After cooling the mixture was evaporated in vacuo. Diethyl ether was added to the residue and the mixture was cooled. The precipitate was collected by filtration to provide 4.5 g (37%) of 3,5-diethyl-7-(4-methyl-1-piperazinyl)-1,2,4-triazolo[4,3-c]pyrimidine. Recrystallizations from ethyl acetate-hexane and ethyl acetate-cyclohexane provided white crystalline product, m.p. 128°-131° C. Analysis for C14H22N6 : Calculated: %C, 61.3; %H, 8.1; %N, 30.6; Found: %C, 59.8; %H, 8.2; %N, 30.1. The structural assignment was confirmed by nuclear magnetic resonance and infrared spectral analyses.
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(O)=O)=C(C)C=3)C=N2)=CC=1.[CH3:24][C:25]1[CH:29]=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)[N:32]=[CH:31]2)[S:27][C:26]=1[C:47]([OH:49])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[CH3:24][C:25]1[CH:29]=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=3)[N:32]=[CH:31]2)[S:27][C:26]=1[C:47]([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=[O:49]
Reactant: NCc1cccnc1
Reactant: Cc1cc(-n2cnn(Cc3ccc(S(C)(=O)=O)cc3)c2=O)sc1C(=O)O
Agent: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(Cc3ccc(S(C)(=O)=O)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 61 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 3-methyl-5-(1-(4-(methylsulfonyl)benzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 61% yield: mp 208-210° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.64 (t, J=5.6 Hz, 1H), 8.54 (s, 1H), 8.46 (d, J=4.4 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.72 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.36 (dd, J=7.7, 4.4 Hz, 1H), 7.22 (s, 1H), 5.11 (s, 2H), 4.43 (d, J=5.6 Hz, 2H), 3.21 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.1, 150.0, 148.8, 148.0, 142.0, 140.1, 138.6, 135.0, 134.9, 134.3, 134.1, 128.4, 127.3, 125.6, 123.4, 119.4, 47.9, 43.4, 40.4, 15.6; MS (ES+) m/z 484.4 (M+1).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:63]/[O:64][CH3:65])/[C:37]([NH:39][CH:40]2[C:61](=[O:62])[N:42]3[C:43]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)=[O:50])=[C:44]([CH2:47]Cl)[CH2:45][S:46][C@H:41]23)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:63]/[O:64][CH3:65])/[C:37]([NH:39][CH:40]2[C:61](=[O:62])[N:42]3[C:43]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)=[O:50])=[C:44]([CH2:47][S:1][C:2]4[S:3][C:4]5[C:5]([N:10]=4)=[N:6][CH:7]=[CH:8][CH:9]=5)[CH2:45][S:46][C@H:41]23)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Sc1nc2ncccc2s1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CSc3nc4ncccc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 62 %

Procedure:
Using 111 mg of 2-mercaptothiazolo[4,5-b]pyridine in place of 2-mercaptothiazolo[4,5-c]pyridine and 477 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 345 mg of the title compound in a yield of 62%.
Reaction SMILES: C1(S(N2C3C(=CC=CC=3)C(Br)=C2)(=O)=O)C=CC=CC=1.COC1C=C(B(O)O)C=CC=1OC.[CH3:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][C:38]=2[S:44](Cl)(=[O:46])=[O:45].C1(S([N:57]2[C:65]3[C:60](=[CH:61][C:62]([O:66][CH3:67])=[CH:63][CH:64]=3)[C:59](Br)=[CH:58]2)(=O)=O)C=CC=CC=1.[CH:69]1([O:74][C:75]2[CH:76]=[C:77](B(O)O)[CH:78]=[CH:79][C:80]=2[O:81][CH3:82])[CH2:73][CH2:72][CH2:71][CH2:70]1>>[CH3:67][O:66][C:62]1[CH:61]=[C:60]2[C:65](=[CH:64][CH:63]=1)[N:57]([S:44]([C:38]1[CH:39]=[CH:40][CH:41]=[C:42]3[C:37]=1[N:36]=[CH:35][C:34]([CH3:33])=[CH:43]3)(=[O:46])=[O:45])[CH:58]=[C:59]2[C:77]1[CH:78]=[CH:79][C:80]([O:81][CH3:82])=[C:75]([O:74][CH:69]2[CH2:70][CH2:71][CH2:72][CH2:73]2)[CH:76]=1
Reactant: COc1ccc2c(c1)c(Br)cn2S(=O)(=O)c1ccccc1
Reactant: COc1ccc(B(O)O)cc1OC1CCCC1
Reactant: Cc1cnc2c(S(=O)(=O)Cl)cccc2c1
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Product: COc1ccc2c(c1)c(-c1ccc(OC)c(OC3CCCC3)c1)cn2S(=O)(=O)c1cccc2cc(C)cnc12

Procedure:
8-[5-Methoxy-3-(3-cyclopentyloxy-4-methoxy-phenyl)-indole-1-sulfonyl]-3-methyl-quinoline 97 was prepared using the same protocol as described in Examples 21 and 22, substituting 8-quinoline-sulfonyl chloride, 1-Benzenesulfonyl-3-bromoindole and 3,4-dimethoxyphenyl boronic acid with 3-methyl-quinoline-8-sulfonyl chloride, 1-benzenesulfonyl-3-bromo-5-methoxy-indole and 3-cyclopentyloxy-4-methoxy-phenylboronic acid respectively. MS(ESI) [M+H+]+=543.20.
Reaction SMILES: [IH+][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]([OH:23])([C:21]#[CH:22])[CH3:20]>>[NH2:17][C:13]1[N:14]=[CH:15][N:16]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:22]#[C:21][C:19]([CH3:20])([OH:23])[CH3:18])[CH:10]=3)[CH:6]=[N:7]2)[CH:12]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1cc(-n2ncc3ccc([IH+])cc32)ncn1
Product: CC(C)(O)C#Cc1ccc2cnn(-c3cc(N)ncn3)c2c1

Procedure:
The title compound was prepared by the procedure described in Example 1-b by reacting 6-(6-iodomoindazol-1-yl)pyrimidin-4-amine with 2-methylbut-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.50 (6H, s), 5.56 (1H, s), 6.95 (1H, s), 7.10 (2H, br. s.), 7.29 (1H, dd, J=8.20, 1.26 Hz), 7.86 (1H, d, J=8.20 Hz), 8.46 (2H, d, J=9.30 Hz), 8.81 (1H, s); LC-MS: m/z=+294.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:12]=[C:13]([C:15](O)=[O:16])[CH:14]=[C:9]2[C:8]([CH3:28])=[C:7]1[CH3:29].[NH:33]1[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:12]=[C:13]([C:15]([SH:36]3[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]3)=[O:16])[CH:14]=[C:9]2[C:8]([CH3:28])=[C:7]1[CH3:29]
Reactant: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc12
Reactant: C1CSCCN1
Product: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(C(=O)[SH]3CCNCC3)cc12
Product: Cl
Yield: 69 %

Procedure:
In accordance with the same procedures as in Example 756, except for using 1-(3-chlorobenzyl)-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Example 737 and thiomorpholine, the titled compound was obtained as a white solid. (Yield: 69%)
Reaction SMILES: [NH2:1][C:2](=[O:39])[CH2:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[CH2:6][CH2:7]C1C(C(F)(F)F)=CN=C(NC2C=CC(C(NC(=O)OC(C)(C)C)C)=CC=2)N=1.[Cl:40][C:41]1[N:46]=[C:45](Cl)[C:44]([Cl:48])=[CH:43][N:42]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:40][C:41]1[N:46]=[C:45]([C:7]#[C:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[CH2:3][C:2]([NH2:1])=[O:39])[C:44]([Cl:48])=[CH:43][N:42]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1Cl
Temperature: 70 °C

Procedure:
To a solution of 18 (0.75 g, 4.7 mmol) and 2,4,5-trichloropyrimidine (0.70 mL, 6.1 mmol) in 1,4-dioxane (10 mL) and Et3N (2.6 mL, 19 mmol) containing CuI (0.018 g, 0.094 mmol) was added PdCl2(PPh3)2 (0.033 g, 0.047 mmol). The reaction mixture was heated at 70° C. for 2 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was diluted with 20% diethyl ether in cyclohexane. The precipitate was filtered, washed with water and dried in vacuo to give the title compound (A138) as a light brown solid (1.22 g, 85%). LCMS-C: rt 4.88 min; m/z 306 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[I-:18].[Na+]>CC(C)=O>[C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][I:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCCCc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCCc1ccccc1

Procedure:
To 6-phenylhex-1-yl methylsulfonate (4.55 g; 17.3 mmol) dissolved in acetone (100 ml) is added sodium iodide (2.5 g; 173 mmol) and the reaction mixture is heated 2 hours at reflux. The reaction mixture is then concentrated to dryness and partitioned between ether and water. The organic phase is separated, dried, concentrated to dryness and purified with silica chromatography using 10 EtOAc/90 petroleum ether to give 6-phenyl-1-hexyl iodide as a colorless oil which is used directly in Step F.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:27])([CH3:28])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:31])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)cc1
Yield: 27.7 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 0.22 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (63 mg, 0.33 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol), methane sulfonamide (63 mg, 0.66 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (30 mg, 28%) as a light yellow solid: LC/MS m/e calcd for C28H32N2O4S (M+H)+: 493.64, observed: 493.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH2:12]/[C:13](/[CH3:19])=[CH:14]\[C:15]([O:17][CH3:18])=[O:16].[C:20]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35](=[O:40])[CH2:36][C:37]([CH3:39])=O)[CH2:30][CH2:29]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH3:18][O:17][C:15]([C:14]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:36]([C:35]([O:34][CH:31]2[CH2:32][CH2:33][N:28]([C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:29][CH2:30]2)=[O:40])=[C:37]([CH3:39])[NH:12][C:13]=1[CH3:19])=[O:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OC1CCN(C(=O)c2ccccc2)CC1
Reactant: COC(=O)/C=C(/C)N
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCN(C(=O)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 30.1 %

Procedure:
In this example, 2.74 g of m-nitrobenzaldehyde, 2.09 g of methyl β-aminocrotonate and 5.50 g of acetoacetic acid-N-benzoyl-4-piperidinyl ester obtained in Reference Example 3 (hereinafter described) were added to 10 ml of THF, and stirring was effected at reflux for 33 hours. The reaction mixture was treated similarly as in Example 1 to obtain 2.84 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(N-benzoyl-4-piperidinyl) ester-5-methyl ester [compound of the general formula (I) wherein R1 =R2 =R4 =CH3, ##STR14## wherein n=0, ##STR15## (yield: 30.2%)
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22]C(C3C=CC=CC=3)=O)[CH:16]=2)=[CH:11][CH:10]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O:34][CH2:35][CH3:36])(=O)C>>[C:35]([CH2:36][NH:22][CH2:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:34])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Reactant: CCOC(C)=O
Product: CCOC(=O)C(C)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Reaction time: 2 h

Procedure:
2.2 g (5.3 mmol) of ethyl (E)-2-methyl-3-(3′-{[(1-phenylmethanoyl)amino]methyl}biphenyl-4-yl)acrylate and 100 ml of ethyl acetate are introduced into a three-necked flask. The reaction medium is degassed, 450 mg of palladium-on-charcoal (10%) are added and the mixture is hydrogenated under atmospheric pressure for two hours. The reaction medium is filtered and evaporated, and the residue obtained is purified by chromatography on a column of silica eluded with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvents, 1.45 g (64%) of ethyl 3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-methylpropionate are collected in the form of an oil.