Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.Cl.[CH3:11][NH:12][O:13][CH3:14].CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: O=C(O)C1CCOCC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCOCC1
Temperature: 29 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
To a suspension of tetrahydro-2H-pyran-4-carboxylic acid (9.0 g, 69.2 mmol) in CH2Cl2 (300 mL) was added N,O-dimethylhydroxylamine hydrochloride (8.05 g, 83.0 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (20.0 g, 103.8 mmol) and triethylamine (17.5 g, 173.0 mmol) at 29° C. under N2. The reaction was stirred at 29° C. for 24 hrs. Then the mixture was filtered and the filtrate was washed with 1M HCl and saturated aqueous NaHCO3. The organic layer was concentrated in vacuo to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (7.1 g, 59.7%) as a yellow oil. 1H NMR (CDCl3, 400 M Hz) δ 4.02-3.98 (m, 2H), 3.69 (s, 3H), 3.47-3.41 (m, 2H), 3.17 (s, 3H), 2.90 (t, J=11.6 Hz, 3H), 1.90-1.82 (m, 2H), 1.81-1.62 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[Br:24][Si](C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])[CH:16]([Br:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(C)(C)c1cc(C(O)c2ccccc2)cc(C(C)(C)C)c1O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(C(Br)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
To a solution of 31.2 g (0.1 mole) of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-α-phenylbenzenemethanol (Example 16) in 350 mL of CCl4 is added 34.8 (0.227 mole) of bromotrimethylsilane. After 40 minutes at room temperature the reaction mixture is evaporated to dryness on a rotary evaporator with the water bath temperature at 35° C. The brown oil residue is used immediately without further purification.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:24]=[CH:25][C:26]([NH:29][C:30]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:31])=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)nc1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc(Cl)nc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=431.0 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 2-chloro-5-isocyanatopyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.ClCCl.[OH:15]O>C[Re](=O)(=O)=O.[O-2].[O-2].[Mn+4]>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-:15])=[CH:9][CH:8]=[CH:7]2
Reactant: OO
Reactant: Oc1cccc2cccnc12
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: [O-][n+]1cccc2cccc(O)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
59.74 g (411 mmol) of 8-hydroxyquinoline, 350 ml (822 mmol) of dichloromethane, 82.2 ml of 35% aqueous hydrogen peroxide solution and 0.52 g (2.5 mmol) of methylrhenium trioxide (MTO) are placed in a 1 l round-bottomed flask. The reaction mixture is stirred at ambient temperature (25° C.) for 24 h and then 80 ml of aqueous hydrogen peroxide solution and 0.32 g of manganese dioxide are successively added. The mixture is stirred for 1 h 30 and then separated by settling. The aqueous phase is extracted with dichloromethane (2×200 ml). The organic phases are combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide 64 g of 8-hydroxyquinoline N-oxide in the form of an organe-colored solid; M.p.=112° C. (Yield: 97%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][C:3]=1[O:17][CH3:18].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:20]=1.C(O)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCOC(C)=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:14])([CH3:15])[O:16]2)=[CH:4][C:3]=1[O:17][CH3:18])[CH3:20]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reaction time: 17.5 h

Procedure:
To a mixture of 4-hydroxy-3-methoxyphenylboronic acid pinacol ester (Aldrich, Buchs, Switzerland, 200 mg, 0.800 mmol), triphenylphosphine (315 mg, 1.200 mmol) and ethanol (0.056 ml, 0.960 mmol) in THF (4 ml) under Argon was added dropwise diisopropyl azodicarboxylate (0.253 ml, 1.20 mmol). The RM was stirred at it for 17.5 h. Then the RM was diluted with EtOAc and the organic layer was washed with brine (2×), before being dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by MPLC (hexane/EtOAc 0 to 30%). The fractions containing product were together evaporated to give the title compound as a white solid. (HPLC: tR 3.58 min (Method A); M+H=279 MS-ES)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N+:7]([O-])[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1.C(OC(=O)C)(=[O:20])C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH:9]([OH:20])[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: [O-][n+]1cc(OCC(F)(F)F)cc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC1CCCc2cc(OCC(F)(F)F)cnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinoline 1-oxide (530 mg, 2.1 mmol) and acetic anhydride (3 mL) was stirred at 100° C. for 2 hours. After cooling to room temperature, acetic anhydride was removed in vacuo. To the residue, methanol (5 mL) and potassium carbonate (1.77 g, 13 mmol) were added, and the mixture was stirred at room temperature for 20 hours. Then, methanol was evaporated in vacuo. To the residue was added ethyl acetate, and the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1-1:2) to give 193 mg (36% yield) of the title compound as a white solid:
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[C:51]([O:56][CH3:57])[CH:50]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.[Cl-].[Na+].O.O>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([C:49]2[CH:54]=[CH:53][C:52]([NH:55][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([Br:1])[N:10]4[N:9]=3)=[C:51]([O:56][CH3:57])[CH:50]=2)[CH2:47][CH2:48]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: Oc1ncc2ccc(Br)n2n1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
In a 10 mL sealed tube, to 7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol (150.0 mg, 0.701 mmol) and N,N-Diisopropylethylamine (0.488 mL, 2.80 mmol) in 3.8 mL of anhydrous DMF was added N-Phenylbis(trifluoromethanesulfonimide (263 mg, 0.736 mmol). After stirring at room temperature for 2 hours, 4-(4-Amino-3-methoxy-phenyl)-piperidin-1-carboxylic acid tert-butyl ester (214.7 mg, 0.701 mmol) was added. The reaction mixture was heated at 65° C. for 4 hours. The reaction was conc. in vacuo. Water and brine were added and the contents were extracted with DCM. The combined organic layers were dried with sodium sulfate, filtered, and conc. in vacuo. The reaction mixture was purified via silica gel column chromatography using 100:1 DCM:MeOH as the eluant to afford a the title compound as a red oil (52%). 1H NMR (DMSO-d6)-8.89 (s, 1H), 8.23 (d, 1H, J=8.20 Hz), 7.83 (s, 1H), 6.98-6.95 (m, 2H), 6.91 (d, 1H, J=4.72 Hz), 6.85 (d, 1H, J=8.52 Hz), 4.66-4.55 (br s, 1H), 4.16-3.99 (m, 3H), 3.89 (s, 3H), 2.87-2.75 (m, 2H), 1.78 (d, 2H, J=12.93 Hz), 1.70 (d, 1H, J=12.57 Hz), 1.42 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:15])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(CCl)cc1
Product: O=C(Cl)Cc1ccc(CCl)cc1

Procedure:
A mixture of 1 g of p-chloromethylphenylacetic acid and 6 ml of thionyl chloride is stirred at room temperature for 25 hours after which the excess thionyl chloride is removed under vacuum to yield p-chloromethylphenylacetyl chloride.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[C@H:41]3[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]3)[C:35](=[O:42])[N:34]([CH2:43][CH2:44]O)[N:33]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].[Cl:46]CCl>>[ClH:46].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[C@H:41]3[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]3)[C:35](=[O:42])[N:34]([CH2:43][CH2:44][Br:1])[N:33]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: ClCCl
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C2=NN(CCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 25 mmol of bromine in 10 ml of dichloromethane was added to a solution of 25 mmol of triphenylphosphine in 50 ml of dichloromethane at 0° C. under a flow of nitrogen, followed by the addition of 25 mmol of compound 35 in 25 ml of dichloromethane. After complete addition, the mixture was stirred for 2 h at room temperature. The reaction mixture was washed with aqueous sodium carbonate, dried over magnesium sulfate and evaporated. The compound was crystallized from methanol. M.p. 134°-136° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:25][CH:26]1[C:43](=[O:44])[N:28]2[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]3[S:36][CH:37]=[N:38][N:39]=3)[CH2:31][S:32][C@H:27]12>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:25][CH:26]2[C:43](=[O:44])[N:28]3[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]4[S:36][CH:37]=[N:38][N:39]=4)[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Yield: 86.2 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) were treated in a similar manner to that of Example 20-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.15 g.).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].[Br:8][CH2:9][C:10](=O)[C:11]([OH:13])=[O:12]>O1CCOCC1>[BrH:8].[CH:1]([NH:4][C:5]1[S:6][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[N:7]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(=O)CBr
Reactant: CC(C)NC(N)=S
Solvent: C1COCCO1
Product: Br
Product: CC(C)Nc1nc(C(=O)O)cs1
Temperature: 80 °C

Procedure:
A suspension of compound 9 (2.1 g, 18 mmol) and 3-bromopyruvic acid (3.0 g, 18 mmol) in dioxane (180 mL) was heated to 80° C. Upon reaching 80° C. the mixture became clear, and soon thereafter the product started to precipitate as a white solid. After 2 h of heating, the reaction mixture was cooled to rt and the precipitate was filtered off and collected. This yielded pure title compound (4.4 g, 94%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(C(=O)c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
3-Benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 26.3 mg, 0.072 mmol) in CHCl3 (1.5 mL) at 25° C. was treated with benzoylchloride (34.9 mg, 0.248 mmol) and triethylamine (16.8 mg, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (8.0 mg, 23.7%) as a colorless film: LC/MS 94% at 4.42 min (ESI+) 469 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:26])([CH3:25])[CH2:13][C:14]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][I:28]>ClCCl>[I-:28].[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:26])([CH3:25])[CH2:13][C:14]([O:16][CH2:17][CH2:18][N+:19]1([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)OCCN1CCCCC1)NC(=O)OCc1ccccc1
Reactant: CI
Solvent: ClCCl
Product: CC(C)(CC(=O)OCC[N+]1(C)CCCCC1)NC(=O)OCc1ccccc1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A batch of 2-(piperidin-1-yl)ethyl 3-(benzyloxycarbonylamino)-3-methylbutanoate (9.45 g, 26.1 mmol) was dissolved in a solution of dichloromethane (40 ml) and methyl iodide (16.3 ml, 262 mmole). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude material was purified by pre-HPLC to give 8.74 g (66%) of 1-(2-(3-(benzyloxycarbonylamino)-3-methylbutanoyloxy)ethyl)-1-methylpiperidinium iodide. 1H NMR (CD3OD) δ 7.39-7.27 (m, 5 H), 5.05 (s, 2 H), 4.52-4.47 (m, 2 H), 3.70-3.64 (m, 2 H), 3.44-3.37 (m, 4 H), 3.09 (s, 3 H), 2.84 (s, 2 H), 1.92-1.86 (m, 4 H), 1.73-1.59 (m, 2 H), 1.39 (s, 6 H). MS (ESI+) calculated for C21H33N2O4+: 377.24, Found: 377.2 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1Br
Yield: 97 %

Procedure:
To a solution of 2-bromo-4-methylbenzoic acid (21.5 g, 100 mmol) in MeOH (250 mL) was added thionyl chloride (10.9 mL, 150 mmol) dropwise and then the reaction mixture was refluxed for 4 h. MeOH was distilled out and water was added. It was extracted with EA and the organic layer was washed with saturated sodium bicarbonate solution, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (20:1) to give methyl 2-bromo-4-methylbenzoate (22.3 g, yield 97%) as colorless oil.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])=[CH:4][C:3]=2[O:2]1.[Cl:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:18]1>>[ClH:15].[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][CH2:24][CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([CH2:16][N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:12]5[O:13][CH2:1][O:2][C:3]=5[CH:4]=4)[C:9]3=[O:14])[CH2:18]2)[CH:27]=1
Reactant: O=C1NCCc2cc3c(cc21)OCO3
Reactant: ClCC1CCCN(CCCc2cccnc2)C1
Product: Cl
Product: O=C1c2cc3c(cc2CCN1CC1CCCN(CCCc2cccnc2)C1)OCO3

Procedure:
Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(pyrid-3-yl)-propyl]-piperidine analogously to Example 2.
Reaction SMILES: CN(C=O)C.Cl[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1.O.[SH2:17].[Na].C[O-].[Na+].Br[C:23]1[S:27][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:25][CH:24]=1>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:28][C:26]1[S:27][C:23]([S:17][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=2)=[CH:24][N:25]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: S
Reactant: Brc1cnc(Nc2ccccn2)s1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A DMF (3 mL) suspension of 4-chloropicolinic acid (0.160 g, 1.01 mmol) and sodium hydrogensulfide hydrate (0.225 g, 3.03 mmol, 3 eq) was heated to 100° C. After 3 h, the suspension was diluted with methanol (10 mL), 5-bromo-N-(pyridine-2-yl)thiazol-2-amine (0.256 g, 1.0 mmol, 1 eq, described in the synthesis of thiazoles Example A) was added followed by a solution of sodium methoxide 25% (2 mL). The resulting mixture was heated at 80° C. for 15 min., concentrated to remove most of the methanol, diluted with DMF and acidified with acetic acid. The resulting solution was purified on preparative HPLC (ammonium acetate/water/acetonitrile) and freeze dried to give the title compound as a solid (0.094 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00 (1H, dd, J=6.69, 5.68 Hz), 7.12 (1H, d, J=8.34 Hz), 7.34 (1H, dd, J=5.31, 1.77 Hz), 7.68 (1H, d, J=1.52 Hz), 7.73-7.83 (2H, m), 8.31 (1H, d, J=4.04 Hz), 8.48 (1H, d, J=5.31 Hz), 11.80 (1H, s). LC/MS (M+H)+: 331, (M−H)−: 329.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=O)C.[S:35]1(=[O:41])(=[O:40])[CH2:39][CH2:38][CH2:37][NH:36]1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:10]4[CH:11]=[CH:12][C:13]([N:36]5[CH2:37][CH2:38][CH2:39][S:35]5(=[O:41])=[O:40])=[CH:14][C:9]=4[N:6]4[CH2:7][CH2:8][NH:4][C:5]4=[O:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: O=S1(=O)CCCN1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCNC2=O)CC1
Yield: 28.4 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (152 mg) described in Preparation Example 236 and isothiazolidine 1,1-dioxide (57 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (47 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C@@H:13]([NH2:14])[C:11](=[O:12])[S:10][CH2:9]1.Cl.[CH:16](=O)[CH:17]([CH3:19])[CH3:18].[BH3-]C#N.[Na+]>CO>[CH2:16]([NH:14][CH:13]1[CH2:8][CH2:9][S:10][C:11]1=[O:12])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C=O
Reactant: N[C@@H]1CCSC1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)CNC1CCSC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.6 mmol of triethylamine are added at 0° C., under an inert atmosphere, to a solution of 4.23 mmol of D-homocysteine thiolactone hydrochloride and 8.46 mmol of isobutyraldehyde in 20 ml of methanol. After stirring for 4 hours at ambient temperature, the reaction mixture is cooled to 0° C. and 8.8 mmol of NaCNBH3 are slowly added in the course of 40 minutes. After stirring for 30 minutes at 0° C., the reaction mixture is hydrolysed and then extracted with ether. The combined organic phases are then washed with a saturated NaCl solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 99/1) allows the expected product to be isolated in the form of syrup.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[O:20][C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=1)([CH3:6])[CH3:5].[OH-].[Na+]>C(O)C>[C:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:25]([C:19]2[O:20][C:21]([CH2:22][CH2:23][CH3:24])=[C:17]([CH2:16][CH2:15][O:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:37])=[O:2])=[CH:9][CH:10]=3)[N:18]=2)=[CH:30][CH:29]=1
Reactant: CCCc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A sample of 2-{4-[2-(2-biphenyl-4-yl-5-propyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid methyl ester (484 mg, 0.97 mmol) was dissolved in ethanol (5 mL) followed by addition of 5.0 N NaOH (2 mL). The mixture was warmed with magnetic stirring at 50° C. for two hours. The reaction mixture was then allowed to cool to room temperature then partitioned between 50 mL of methylene chloride and 15 mL of 1.0 N HCl. The organic phase was separated, dried over sodium chloride and concentrated in vacuo to yield 384 mg (82%) of a glassy solid. HPLC RT1=6.37 min; 1H NMR (400 MHz, CDCl3) δ8.01 (d, J=8.3 Hz, 2H), 7.63-7.58 (m, 4H), 7.43-7.33 (m, 3H), 6.86 (d, J=9.3 Hz, 2H), 6.73 (d, J=9.3 Hz, 2H), 4.13 (t, J=6.3 Hz, 2H), 2.97 (t, J=6.3 Hz, 2H), 2.66 (t, J=7.3 Hz, 2H), 1.73-1.68 (m, 2H), 1.49 (s, 6H), 0.98 (t, J=7.3 Hz, 3H); MS (EI) 486.33 (M+H)+, 484.37 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:9](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccnc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86.7 %

Procedure:
To a solution of 2-nitro-1H-imidazole (500 mg, 4.4 mmol) in DMF (50 mL) is added cesium carbonate (1.7 g, 5.3 mmol) and the mixture is heated to 50° C. for 30 minutes. The resulting suspension is cooled to room temperature and MeI (0.33 mL, 5.3 mmol) is added. The reaction is heated to 50° C. for 2 hours is then cooled to room temperature and filtered through a bed of Celite. The filtrate is poured over ice water and extracted ethyl acetate. The organic layer is washed with water, brine, dried (Na2SO4) and concentrated to afford the title compound (485 mg, 86%) as a yellow solid.