Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCc1cccs1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1c(NCCc2cccs2)ccnc1Cl

Procedure:
A mixture of 2,4-dichloro-3-nitropyridine (1.5 g), 2-aminoethylthiophene (1 g) and triethylamine (5 ml) is heated to reflux in EtOH (60 ml). The reaction mixture is cooled, the solvent evaporated and the residue chromatographed on silica gel (10% hexane/CH2Cl2) to yield the desired addition product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[N:12]=[C:11]2[CH2:13][N:14]([C@@H:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH2:18]O)[C:15](=[O:16])[C:10]2=[CH:9][CH:8]=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[N:12]=[C:11]2[CH2:13][N:14]([C@@H:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH2:18][N:33]3[C:29](=[O:39])[C:30]4[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:32]3=[O:34])[C:15](=[O:16])[C:10]2=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1ncc(Cl)c1-c1ccc2c(n1)CN([C@H](CO)Cc1cccc(F)c1)C2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1ccc2c(n1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
To a solution of 2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-6-[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (0.065 g, 0.16 mmol) and phthalimide (0.029 g, 0.19 mmol) in tetrahydrofuran (5 mL) at 25° C. was added diethyl azodicarboxylate (0.096 mL, 0.24 mmol) and triphenylphosphine (0.055 g, 0.21 mmol). The reaction mixture was stirred at room temperature for 2 hr. After concentration, the residue was purified by pH=2 Prep.—HPLC to give 0.020 g (23% yield) of the desired product as white powder. LC/MS found: 530.1 (M+H)+.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[C:13](=[O:14])[CH2:12][C:11]2[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:10]=2[CH:9]=[CH:8]1)C.C(O)C>S(=O)(=O)(O)O>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:11]2[CH2:12][C:13](=[O:14])[N:7]([CH2:6][CH2:5][CH:4]=[O:3])[CH:8]=[CH:9][C:10]=2[CH:18]=1
Reactant: CCOC(CCN1C=Cc2cc(OC)c(OC)cc2CC1=O)OCC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(=O)N(CCC=O)C=C2

Procedure:
First, 3-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-propionaldehyde diethyl acetal (3.5 g, 0.01 mol) is heated in 2N sulphuric acid (50 ml) and ethanol (50 ml) to 40° C. for 2 hours. The alcohol is then distilled off in vacuo, the residue is made alkaline with saturated potassium carbonate solution with cooling and extracted several times with ethyl acetate. The ethyl acetate extract is extracted twice with sodium hydrogensulphite solution. The bisulphite extract is acidified with concentrated hydrochloric acid and heated for half an hour to 40° C. in vacuo in order to eliminate the sulphur dioxide. Then, saturated potassium carbonate solution is added and the mixture is extracted several times with methylene chloride, dried over magnesium sulphate and evaporated. Yield: 1.7 g. Mp: 95°-96° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH:66](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(OCC)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4nc[nH]n4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS(=O)[C@H]23)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4nc[nH]n4)CS(=O)[C@H]23)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(trityl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (11.3 g) in acetone (60 ml) under ice cooling is added toluene-p-sulfonic acid monohydrate (1.68 g: 8.83 mMol.), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with aqueous 5% sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=1:1-1:2) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (2.84 g) as brown foam. Yield: 31%.
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[CH2:25]([NH2:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>COCCOC.CCOCC.CCCCCCCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:25]([NH:31][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CCCCCCCCCCCC
Solvent: COCCOC
Product: CCCCCCNc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 2.7 %

Procedure:
A solution of Pd2(dba)3 [92 mg, 0.1 mmol (4.6 mg, 0.005 mmol, 2 mol % Pd per reaction)], ligand 1 (see FIG. 1) [168 mg, 0.4 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [40 mg, 0.4 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 10 mL DME (anhy). After 10 minutes, 0.5 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) K3PO4 (148 mg, 0.7 mmol), 2-chloronitrobenzene (79 mg, 0.5 mmol), and hexylamine (79 μL, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard. The reaction mixture was purified by preparatory TLC (EtOAc/hexanes as the eluent) to yield 3 mg of the desired product (which was used for calibration with the internal standard). The GC yield was calculated to be 19%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=2)=[O:13])=[CH:5][CH:4]=1.[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17]([N:24]3[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]3)=[CH:18][CH:19]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCNC(=O)c2ccc(Cl)nn2)cc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: COc1ccc(CCNC(=O)c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)cc1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(4-methoxyphenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (12% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.93, 7.74, 7.63, 7.56, 7.36, 7.12, 6.92, 6.81, 4.08-3.46, 3.33, 2.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH3:24])[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[S:56]1[C:60]2[CH:61]=[CH:62][C:63]([NH2:65])=[CH:64][C:59]=2[N:58]=[CH:57]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>ClC(Cl)C>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:21]([NH:65][C:63]4[CH:62]=[CH:61][C:60]5[S:56][CH:57]=[N:58][C:59]=5[CH:64]=4)=[N:20][CH:19]=[C:18]([CH:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH3:24])[CH:17]=3)[N:10]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Reactant: Nc1ccc2scnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCNCC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Temperature: 80 °C
Yield: 26.4 %

Procedure:
A glass microwave reaction vessel (80 mL) was charged with tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (3.65 g, 5.55 mmol) and trifluoroacetic acid (6.41 mL, 83 mmol) in dichloroethane (30 mL). The reaction mixture was stirred and heated in a CEM Voyager Model (Large-Scale Unit) Microwave at 80° C. for 5 min (100 watts, Powermax feature on). The mixture was added to a round bottom flask and concentrated in vacuo. The crude residue was diluted with THF (10 mL), then benzo[d]thiazol-5-amine (0.539 g, 3.59 mmol) was added to the reaction mixture with stirring. The mixture was chilled to 0° C. in an ice bath, then sodium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 5.74 mL, 5.74 mmol) was added slowly via syringe into the mixture. After the addition, the ice bath was removed and the mixture allowed to stir under inert atmosphere for 1 h. The reaction mixture was diluted with sat. sodium bicarbonate (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (80 g) eluting with a 20% mixture of 10:1 methanol and ammonium hydroxide/dichloromethane to give N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.651 g, 0.946 mmol, 66.0% yield) as a tan oil. 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H) 8.96 (s, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.63 (d, J=1.96 Hz, 1H) 8.31 (d, J=2.35 Hz, 1H) 8.12 (d, J=1.76 Hz, 1H) 7.78 (td, J=8.12, 2.35 Hz, 1H) 7.60 (dd, J=8.61, 1.96 Hz, 1H) 7.14-7.28 (m, 4H) 6.80-6.91 (m, 4H) 4.76-4.91 (m, 4H) 3.72-3.82 (m, 6H) 3.37-3.51 (m, 1H) 2.86 (dt, J=12.67, 4.72 Hz, 4H) 2.40-2.55 (m, 4H) 2.62 (s, 3H) 2.32-2.40 (m, 1H). m/z (ESI, +ve ion) 688.2 (M+H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][C@@H:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][C@@H:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: C[C@@H]1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Product: C[C@@H]1Cc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
(-)-8,9-difluoro-2-(R)-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (Compound (b)) and N-methylpiperazine were used, and treated in a manner analogous to Example 7, to give the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:8])[CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH3:9][SiH:10]([Cl:12])[Cl:11]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][CH2:3][Si:10]([CH3:9])([Cl:12])[Cl:11])(=[O:8])[CH:6]=[CH2:7]
Reactant: C[SiH](Cl)Cl
Reactant: C=CCOC(=O)C=C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)OCCC[Si](C)(Cl)Cl
Temperature: 65 °C
Yield: 68.3 %

Procedure:
To a three-necked flask equipped as in Example 1 there was added 260 grams allylacrylate (2.32 moles), 0.5 grams catalyst prepared in accordance with U.S. Pat. No. 3,814,730 (2.6 weight percent Pt) and 1.04 grams phenothiazine. The mixture was heated with stirring to 65° C. and, using the vent of the condenser, purged with nitrogen. The heat source was then turned off and 237 grams (2.32 moles) CH3SiHCl2 was added dropwise, the temperature of the reaction mass being maintained at about 70° C. Upon completion of the addition of methyldichlorosilane the crude product was cooled to room temperature. One gram phenothiazine and 0.05 gram triphenyl phosphine were added to the product prior to distillation. Acryloxypropylmethyldichlorosilane (360 grams, 68% yield) was distilled at 109°-112° C./10 mm Hg.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4].[Br:15]Br>O1CCOCC1>[Br:15][C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=2)[NH:12][N:13]=1
Reactant: O=[N+]([O-])c1cnc2[nH]ncc2c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc2[nH]nc(Br)c2c1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
4N NaOH (5.12 mL, 20.5 mmol) was added to a cold (0° C.) solution of 5-nitro-1H-pyrazolo[3,4-b]pyridine (0.84 g, 5.12 mmol) in dioxane (30 mL), followed by bromine (1.05 mL, 20.5 mmol). The cold bath was removed, and the reaction mixture was left at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and quenched with saturated Na2S2O3 (50 mL) The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1) to give 3-bromo-5-nitro-1H-pyrazolo[3,4-b]pyridine (1.10 g, 88%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[S:16][CH:17]=1)[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[S:16][CH:17]=1
Reactant: COc1cc(C=O)ccc1OCc1csc(N2CCCCC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccc1OCc1csc(N2CCCCC2)n1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde (1.20 g) in tetrahydrofuran (10 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.14 g) at room temperature. After stirring the reaction mixture for 2 hrs, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as a colorless oil (1.18 g, yield 98%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][NH:5][CH:6]=1.OP([O-])([O-])=O.[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[N:4]1
Reactant: Cc1c[nH]nn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)nn1
Temperature: 85 °C
Reaction time: 60 h
Yield: 23.9 %

Procedure:
A mixture of 4-methyl-[1,2,3]-triazole (60 g, 0.72 mol), K2HPO4 (250 g, 1.44 mol) and 3,4-difluoronitrobenzene (80 ml, 0.723 mol) in DMF (3.4 litres) was stirred at 85° C. under N2 for 2.5 days. After removal of DMF in vacuo, the residue was chromatographed on silica gel with 0-5% ethyl acetate in dichloromethane to give the title compound as a light yellow solid (38.3 g, 24%). The other two isomers were also isolated.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][CH3:23])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH2:22]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][N:16]1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)[CH:13]=1)[CH3:23]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1CCCCN1c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 60 °C

Procedure:
To a solution of 2-[5-(2-ethyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester (12 mg, 0.03 mmol) in MeOH (1 mL) was added 3N NaOH (0.200 mL) and heated to 60° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 2-[5-(2-ethyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid. 1H-NMR (CDCl3): δ 0.80 (t, 3H), 0.92 (d, 6H), 1.44 (m, 1H), 1.50 (q, 1H), 1.58-1.69 (m, 3H), 1.89 (m, 1H), 2.02 (m, 2H), 2.14-2.26 (m, 2H), 3.29 (m, 2H), 3.68-3.81 (m, 2H), 7.59-7.73 (m, 7H); Calcd for C26H32F3NO2 (M+H) 448.53, Found 448.34
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[CH:21]1([CH2:24][NH:25][CH2:26][C:27]2[NH:36][C:35](=[O:37])[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[N:28]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][N:25]([CH2:26][C:27]2[NH:36][C:35](=[O:37])[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[N:28]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:23][CH2:22]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1CCCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)CCCC4)CC3CC3)CC2)cc1
Yield: 1 %

Procedure:
The title compound (26 mg, 1% yield) was prepared following the general procedure of Example 7 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid and 2-[(cyclopropylmethyl-amino)-methyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one. 1H NMR (400 MHz, CD3OD) δ 7.75-7.83 (m, J=9.1 Hz, 2H), 6.77-6.88 (m, J=9.1 Hz, 2H), 4.48 (s, 1H), 4.26-4.44 (m, 1H), 4.04-4.26 (m, 2H), 3.67 (s, 3H), 3.37-3.59 (m, 2H), 2.93-3.19 (m, 5H), 2.39 (t, J=5.6 Hz, 2H), 2.22 (t, J=5.8 Hz, 2H), 1.91 (br. s., 3H), 1.75-1.86 (m, 1H), 1.47-1.75 (m, 4H), 0.65-0.90 (m, 1H), 0.40 (q, J=6.1 Hz, 1H), 0.16-0.32 (m, 1H), 0.06-0.16 (m, 1H), −0.13-0.06 (m, 1H). HRMS calculated for C28H36N4O4 493.2815. found (ESI, [M+H]+), 493.2826. Retention time=3.50 min.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[O:26][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:28][N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[O:26][C:27]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)=[N:28][N:29]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nnc(N2CCOCC2)o1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nnc(N4CCOCC4)o3)(CC1)CC2
Yield: 13.7 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(2-amino-1,3,4-oxadiazole-5-yl)morpholine (57.9 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[5-(4-morpholinyl)-1,3,4-oxadiazol-2-yl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (10.1 mg).
Reaction SMILES: C(OC([N:11]1[CH2:17][C@H:16]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@:13]12[CH2:14][C@@H:15]([CH3:18])[C@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@@H]1C[C@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@]2(NC(=O)OC(C)(C)C)CNC[C@H]12
Yield: 85.4 %

Procedure:
(1R,5S,6R)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (180 mg, 0.59 mmol) was dissolved in a methanol (5 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for one hour. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 114 mg (85%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1(C([O-])=O)[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[C:21]([C:30]([F:33])([F:32])[F:31])[CH:20]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7][CH2:6]1)([O-:3])=[O:2].[Na+].[Na+].[Cl-].[NH4+]>O>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]3[CH:13]=[CH:12][C:11]4[NH:10][C:9]5[CH:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:6][CH2:7][C:8]=5[C:16]=4[CH:15]=3)=[CH:20][C:21]=2[C:30]([F:33])([F:31])[F:32])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C([O-])CC1(C(=O)[O-])CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 92 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred solution of sodium 3-(carboxylatomethyl)-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indole-3-carboxylate (16.5 g, 30.2 mmol) in water at 40° C. was added ammonium chloride solution (9.71%, 100 mL). The reaction was heated at 92° C. (bath) for 4.4 h. The mixture was refrigerated overnight, decanted and triturated with ice cold 6N HCl (100 mL). The solid was collected by filtration, washed with diluted HCl (100 mL) and dried overnight in a vacuum oven at 40° C. to give the title compound (8.5 g). LCMS m/z=458.3 [M+H]+.