Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:48])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:47])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:46])[NH:31][C@H:32]4[CH2:35][C@@H:34]([C:36]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:45])[CH3:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH3:44][C:33]1([CH3:45])[C@H:34]([C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[CH2:35][C@@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:47])([CH2:12][CH2:13]2)[C@@:10]2([CH3:48])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:46]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1S,3R)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 7, 0.380 g, 0.55 mmol) in MeOH:THF (2:1) (6 ml) NaOH (2N, 2 ml) was added at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the volatiles was evaporated and the aqueous layer was extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.320 g: Yield: 89.6%; 1H NMR (300 MHz, CDCl3): δ 5.88 (d, 1H, J=8.1 Hz), 4.73 (s, 1H), 4.58 (s, 1H), 4.18-4.07 (m, 1H), 3.80-3.41 (m, 7H), 3.21-3.08 (m, 2H), 2.91-2.83 (m, 1H), 2.50-2.29 (m, 3H), 1.98-1.87 (m, 2H), 1.80-1.10 (m, 26H), 0.95-0.92 (s, 12H), 0.99-0.68 (s, 9H); Mass: [M+1]+ 651 (100%), [M+Na]+ 673 (70%); IR (KBr, cm−1): 3367, 2856, 2926, 1714, 1634, 1493, 1463, 1375, 1270, 1241, 1115, 1040, 983, 884, 756, 665; M.R: 262.5° C.-267.8° C.; HPLC: 90.7%.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7]C=[CH:5][C:3]=1N.[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[NH2:19])=[CH:13][CH:12]=1.BrC(Br)(CC)CC>C(N(CC)CC)C>[CH3:9][S:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]2[CH2:7][CH2:8][CH2:2][CH2:3][CH2:5]2)=[CH:15][CH:16]=1
Reactant: Nc1ccccc1Br
Reactant: CSc1ccc(-c2ccccc2N)cc1
Agent: CCC(Br)(Br)CC
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2ccccc2N2CCCCC2)cc1

Procedure:
Compounds of Formula I wherein X is a single bond and R1 is 1-piperidinyl or 1-pyrrolyl can be prepared from 2-bromoaniline as shown in Scheme 15. Suzuki coupling of 2-bromoaniline with 4-thiomethylphenylboronic acid using the method described above followed by condensation of the resulting 2-(4-methylthiophenyl)aniline with dibromopentane in the presence of an amine base, such as triethylamine, affords the corresponding 1-[2-(4-methylthiophenyl)phenyl]piperidine. Oxidation if the methylthio to the methylsulfonyl using methods described above provides compounds of Formula I wherein R1 is 1-piperidinyl. Alternately the starting 2-bromoaniline can be converted to the 1-[(2-bromophenyl)phenyl]pyrrole by treatment with 2,5-dimethoxytetrahydrofuran in glacial acetic acid. Suzuki coupling of the resulting intermediate with 4-methylthiophenylboronic acid followed by oxidation, as described above, gives the 1-[2-(4-methylsulfonylphenyl)phenyl]pyrrole. ##STR26##
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24]Br>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(F)cc(F)c2)c(=O)[nH]c1=O
Yield: 50.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (195 mg, yield: 50.5%).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CCCCCC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C[Si](C)(C)O[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH2:42][CH2:41][CH2:40][CH2:39]2.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1.CC1C=CC(O)=CC=1>>[CH3:32][C:31]1[CH:26]=[CH:27][C:28]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:29][CH:30]=1
Reactant: CCCCCCCCCCCCC
Reactant: C[Si](C)(C)Oc1ccc2c(c1)CCCC2
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1ccc(O)cc1
Agent: Cc1ccccc1-c1ccccc1C
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (36.6 mg, 0.0530 mmol), PCy3 (35.0 mg, 0.125 mmol), tridecane (166.7 mg, 0.904 mmol, as an internal standard), and 6-trimethylsiloxy-1,2,3,4-tetrahydronaphthalene (211.4 mg, 0.957 mmol). The solvent in the Grignard reagent (1 M in ether, 3.0 mmol) was exchanged with t-AmOMe (6.0 mL) and this solution added to the above catalyst mixture under a nitrogen atmosphere at room temperature. The resulting solution was stirred for several minutes at room temperature and then warmed to 60° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M). The resulting aqueous solution was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (0.637 mmol, 67% yield) and bitoluene (0.407 mmol) and p-methylphenol (0.223 mmol) in the reaction mixture.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:30]=[CH:29][C:19]2[S:20][CH:21]=[C:22]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:18]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:15][C:16]1[CH:30]=[CH:29][C:19]2[S:20][CH:21]=[C:22]([C:23]3[CH2:24][CH2:25][N:26]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH:28]=3)[C:18]=2[CH:17]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2scc(C3=CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2csc3ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.053 g, 0.028 mmol) and the hydrochloride salt of 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.081 g, 0.028 mmol) using ethanol as reaction solvent and 1.1 equivalents of potassium carbonate (0.043 g, 0.031 mmol). Yield 0.103 g (83%) of a tan foam. mp 93°-97° C. FDMS m/e=438 (M+ of free base). α[D]589 =+7.5 (c=1.06, dimethylsufoxide)
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C:11](=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl-].[Mg+2].[Cl-]>CC(O)C>[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:13][CH2:14]2)[C@H:11]([OH:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CN(Cc2ccccc2)CCC12CC2
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC(C)O
Product: O[C@@H]1CN(Cc2ccccc2)CCC12CC2
Temperature: 35 °C
Reaction time: 96 h

Procedure:
A mixture of 300 mg of 6-benzyl-6-aza-spiro[2.5]octan-4-one hydrochloride (1.19 mmol, 1 eq.), 1.5 ml of 2-propanol and 28 ml of 30 mM aq. TRIS-HCl buffer (pH 8.1) was heated to 35° C. The pH was re-adjusted to 8.0. The reaction was started by adding 8-NAD (1 mg; free acid; Roche Diagnostics Cat. No. 10 004 626) and ketoreductase KRED-NADH-117 (29.3 mg; Codexis [ex. Biocatalytics]). The suspension was stirred at 35° C. keeping the pH constant at 8.0 by the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution. After roughly 80 area % conversion and 1d, further 2-propanol (0.3 ml), 8-NAD (3 mg; free acid; Roche Diagnostics Cat. No. 10 004 626), ketoreductase KRED-NADH-117 (30 mg; Codexis [ex. Biocatalytics]) and magnesium chloride (12.7 mg) were added. After 4 d, 98.5 area % conversion and 5.9 ml consumption of 1.0 M aq. sodium hydroxide solution the reaction mixture was stopped by the addition of sodium chloride (9 g), ethyl acetate (30 ml) and filter aid (1 g Dicalite Speedex). The mixture was stirred 30 min. and filtered. The filtrate was extracted 3 times with 30 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product in over 99.9% e.e. Purification by flash chromatography provided the titled compound as a colorless oil.
Reaction SMILES: CN([CH2:4][CH:5]=[N:6][C:7](=O)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.O.[NH2:18][NH2:19]>C(O)(=O)C>[CH3:4][C:5]1[N:6]=[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:19][N:18]=1
Reactant: CN(C)CC=NC(=O)C=Cc1ccccc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c(/C=C/c2ccccc2)n1
Temperature: 90 °C
Yield: 96 %

Procedure:
N-[(Dimethylamino)ethylidene]-cinnamamide (2.0 g, 9.0 mmol) was added to a solution of hydrazine hydrate (0.59 mL, 10 mmol) and acetic acid (25 mL). The mixture was heated to 90° C. for 3 h, cooled, and concentrated in vacuo. The resulting material was basified (pH 8) with solid K2CO3, and partitioned between ethyl acetate and water. The organics were dried over Na2SO4 and concentrated in vacuo. The resultant material was purified by flash column chromatography on silica eluting with 1:2 hexane-ethyl acetate to afford 3-methyl-5-[(E)-2-phenylethenyl]-1H-1,2,4-triazole (1.6 g, 96% yield) as a white powder. M.p. 131–134° C. 1H NMR (CDCl3,300 MHz) δ 7.68 (d, J=16 Hz, 0.3H), 7.59 (d, J=16 Hz, 0.7H), 7.49 (m, 2H), 7.32 (m, 3H), 7.05 (d, J=16 Hz, 1H), 6.49 (d, J=16 Hz, 0.4H), 6.21 (br s, 0.3H), 5.88 (br s, 0.3H), 2.53 (s, 3H). MS (EI ionization) 184 (M+−H).
Reaction SMILES: B(F)(F)F.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>CO>[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: FB(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
BF3 etherate (30.5 g; 2 equiv.) was first added dropwise to a solution of methyl quinoline-7-carboxylate (20.1 g; 1 equiv.) in 200 ml of methanol. Sodium cyanoboro-hydride (13.5 g; 2 equiv.) was then added in portions. The resulting reaction mixture was stirred for 20 minutes at room temperature and heated overnight at reflux (70-80° C.). When the conversion was complete, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure and the residue was taken up in 300 ml of water and extracted 3× with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure, and the crude product was recrystallised from isopropanol. Methyl 1,2,3,4-tetrahydro-quinoline-7-carboxylate (14 g; 67.3%) was obtained in the form of a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[S:21]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])(=[O:24])(=[O:23])[NH2:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 84.7 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and m-sulfamoylaniline (100 mg, 0.58 mmol) to give 209 mg of the title compound (85%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.33 (s, 1H), 8.13 (s, 1H), 7.70~7.78 (m, 1H), 7.45~7.55 (m,2H), 7.24 (bs, 1H), 7.15 (bs, 1H), 5.15~5.28 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.65 (dd, 1H, J=18, 13.5 Hz), 2.58 (dd, 1H, J=18, 5.4 Hz), 2.12 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:22])=[C:11]([CH2:18][C:19](=O)[CH3:20])[C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>[Ni].CO>[CH2:1]([O:8][C:9]1[C:10]([F:22])=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:19]([CH3:20])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: [Ni]
Agent: NN
Solvent: CO
Product: Cc1cc2c(F)c(OCc3ccccc3)ccc2[nH]1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (9.09 g, 30 mmol) and Raney nickel (˜5 g) in methanol (100 mL) was heated to 40° C. and then a solution of hydrazine in methanol (15 mL) was added dropwise with vigorous stirring over a period of 30 min. After refluxing for 1 h, the reaction mixture was cooled to room temperature, filtered through Celite and concentrated. The crude material was passed through a pad of silica gel eluting with dichloromethane and concentrated in vacuo to provide 5-benzyloxy-4-fluoro-2-methyl-1H-indole (6.1 g, 80%) as a yellowish oil. LC/MS; (M+H)+=256.3+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Clc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(Cl)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-5-chloropyridine (289 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (367 mg, 68%) as a light yellow oily substance.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.Cl.[CH3:20][NH:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>>[CH3:20][N:21]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[OH:22]
Reactant: CNO
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CN(O)C(=O)CCCCCCCCCCBr

Procedure:
According to the procedure shown in Example 11, 2.65 g (10 mmol) of 11-bromoundecanoic acid (IV5) was treated with 1 ml of thionyl chloride and the resulting product was treated with 850 mg (10.2 mmol) of methylhydroxylamine hydrochloride and 1.5 g (10.9 mmol) of potassium carbonate to give N-methyl-11-bromoundecanohydroxamic acid (V6), which was recrystallized from a mixture of ether-n-hexane to give 2.46 g of the compound (V6) as colorless prismatic crystals in 83.6% yield. mp. 49° C. to 51° C. To a solution of 2.11 g (7.2 mmol) of the compound (V6) was allowed to react with 1.71 g (7.2 mmol) of 3,5-di-tert-butyl-4-hydroxythiophenol under the condition shown in Example 11. The prepared product was chromatographed and eluted with a mixture of ether-ethyl acetate (2:1) to give 3.12 g of the aimed compound (I13) as a pale yellow in 96.3% yield.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].ClB1OCCO1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(N(CC)CC)C>[CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH:13][C:31]([CH2:30][C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[O:32])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cc1cccs1
Agent: ClB1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: -40 °C
Yield: 70.7 %

Procedure:
2.72 g 7-ACA were suspended in 60 ml methylene chloride, then adding 2.2 g triethylamine. After cooling to -40° C., 21 ml of a 1,1 molar solution of ethylene chloroboronate in methylene chloride was poured into the mixture. The mixture was heated to -10° C. and 1.9 g of 2-thienylacetic acid chloride were poured into the mixture. Stirring was maintained for 2 hours at 0° C. 40 ml water were poured therein and after unmixing, the organic phase was added with a solution of sodium bicarbonate to constant pH 7.5. The phases were separated and the aqueous phase was washed with 50 ml methylene chloride. The aqueous phase was treated with decolouring carbon and dicalite. The product was filtered and after addition of 65 ml acetone the filtrate was acidified to pH 2. The product was allowed to crystallize at +5° C. for 2 hours, then filtered, washing with water and acetone. After vacuum drying at 40° C. 2.8 g 7-(2-thienylacetamido) cephalosporanic acid were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19](C(O)=O)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:24])[CH:17]=2)[N:12]=1)=[O:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:24][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[CH:20]=[CH:19]2
Reactant: COC(=O)c1ccccc1-c1cc(C(=O)O)c2cc(C)ccc2n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1ccccc1-c1ccc2cc(C)ccc2n1
Temperature: 225 °C
Yield: 66.8 %

Procedure:
267 mg (0.831 mmol) of 2-(2-methoxycarbonylphenyl)-6-methyl-4-quinolinecarboxylic acid obtained in Example 4 was dissolved in 4.0 ml of diphenyl ether and heated at 225° C. for 10 minutes. After allowing the mixture to cool to room temperature, purification was carried out by flash silica gel chromatography using a mixed solvent of hexane and ethyl acetate (10/1) to obtain 154 mg of methyl 2-(6-methylquinolin-2-yl)benzoate. NMR (270 MHz, CDCl3):
Reaction SMILES: [NH2:1][NH2:2].F[C:4]1[C:9]([CH:10]=O)=[C:8]([I:12])[CH:7]=[CH:6][N:5]=1>O1CCCC1>[I:12][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:1][N:2]=[CH:10][C:9]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: NN
Solvent: C1CCOC1
Product: Ic1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1M solution of hydrazine in tetrahydrofuran (150 mL) was added slowly to 2-fluoro-4-iodopyridine-3-carboxaldehyde (10 g, 39.84 mmol) to give a clear solution. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the remaining solid was triturated with DCM to give the title compound as a pale yellow solid (8 g). The DCM filtrate was also washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude material was purified by trituration with DCM to give additional 4-iodo-1H-pyrazolo[3,4-b]pyridine as a yellow solid. MS (ESI, pos. ion) m/z: 245.9 (M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2COC2C(C(OCC)=O)=NC=CC=2)=[O:10])[CH2:5][CH2:4]1.CO[C:33]1[CH:34]=[C:35]([O:44][CH2:45][C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)[C:36]([C:39]([O:41]CC)=[O:40])=[N:37][CH:38]=1>>[F:30][C:2]([F:1])([F:29])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:45][O:44][C:35]3[C:36]([C:39]([OH:41])=[O:40])=[N:37][CH:38]=[CH:33][CH:34]=3)[CH2:15]2)=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCOC(=O)c1ncccc1OCC1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: O=C(O)c1ncccc1OCC1CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 31 using ethyl 3-((1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinate (EXAMPLE 92 Step 3) in stead of ethyl 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]([CH3:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C1COCC1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]([CH3:21])[CH2:14][CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(N(C)CC2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N(C)CC2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-methoxy-N7-methyl-N7-(tetrahydro-pyran-4-ylmethyl)-benzothiazole-2,7-diamine with 4-fluorobenzoic acid, HATU and N-ethyldiisopropylamine in THF. ES-MS m/e (%): 430 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[S:24][C:14]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.