Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:14]=[C:15]([CH3:25])[C:16]([C:21](OC)=[O:22])=[N:17][C:18]=1[O:19][CH3:20])(=[O:11])=[O:10].C([BH-](CC)CC)C.[Li+].ClCCl.C(OCC)(=O)C.C(O)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH2:21][OH:22])=[C:15]([CH3:25])[N:14]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1nc(OC)c(NS(=O)(=O)c2cccc(Cl)c2Cl)nc1C
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(CO)c(C)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 214.8 %

Procedure:
To a stirred solution of 5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-3-methylpyrazine-2-carboxylic aicd, methyl ester (Example 119) (0.19 g) in tetrahydrofuran (10 mL) under an atmosphere of nitrogen was added a solution of lithium triethylborohydride (1.7 mL of a 1M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 1 h, before quenching with aqueous ammonium chloride and extraction into dichloromethane. The organic phase was dried (MgSO4), filtered and evaporated to give the crude product as a colourless oil. Chromatography on silica gel eluting with dichloromethane/ethyl acetate/acetic acid (150:50: 1) gave the title compound as a white solid (0.38 g).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[N:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]=2[CH3:33])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1>[Zn]>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[N:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]=2[CH3:33])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](NC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c([N+](=O)[O-])cccc12)c1ccccc1
Agent: [Zn]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(C)n(-c2ccccc2)c(=O)c2c(N)cccc12)c1ccccc1
Yield: 62.3 %

Procedure:
To a stirred solution of 3-methyl-8-nitro-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (1am, 10 mg, 0.023 mmol) in tetrahydrofurane (0.15 ml) 2M aq. HCl (0.12 ml, 0.25 mmol) and Zn powder (45 mg, 0.69 mmol) was added. After 30 min the mixture was filtered and partitioned between ethyl acetate (4 ml) and sat. aq. NaHCO3 (2 ml), then brine (3 ml). The organic solution was dried (MgSO4) and evaporated to afford 5.9 mg of the title compound (70% yield). LC-MS (m/z) 412.4 (MH+); tR=1.37.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14]1.[C:19]([O:23][C:24]1[C:29]([F:30])=[CH:28][N:27]=[C:26](F)[C:25]=1[O:32][CH3:33])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]1[C:29]([F:30])=[CH:28][N:27]=[C:26]([CH:16]([CH:13]2[CH2:15][CH2:14]2)[C:17]#[N:18])[C:25]=1[O:32][CH3:33])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1c(F)ncc(F)c1OC(C)(C)C
Reactant: N#CCC1CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1c(C(C#N)C2CC2)ncc(F)c1OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
A −78° C. solution of diisopropylamine (1.3 mL, 9.0 mmol), under a nitrogen atmosphere in dry tetrahydrofuran (20 mL), was treated dropwise with 2.5 N n-butyllithium (3.6 mL, 9.0 mmol) and stirred for 10 minutes. The solution was treated dropwise with cyclopropylacetonitrile (0.8 g, 3.5 mmol) and stirred at −78° C. for 15 minutes. A solution of 4-tert-butoxy-2,5-difluoro-3-methoxypyridine (0.8 g, 3.5 mmol)[Example 7] in dry tetrahydrofuran (5 mL) was added and stirred for 1 hour at −78° C. followed by 1 hour at 0° C. The mixture was quenched with saturated ammonium chloride and extracted with diethylether. The combined extracts were washed with brine, dried over sodium sulfate, and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexanes (1:4) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 3.98 (s, 3H), 3.77 (d, 1H), 1.55-1.48 (m, 1H), 1.42 (s, 9H), 0.62-0.54 (m, 2H), 0.50-0.42 (m, 1H), 0.35-0.30 (m, 1H). MSCI: m/z=279 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][S:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][C:21]4[CH:20]=[CH:19][C:18]([NH:17][S:14]([CH3:13])(=[O:15])=[O:16])=[CH:23][CH:22]=4)[CH2:27][CH2:28]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CS(=O)(=O)Nc1ccc(CCN2CCNCC2)cc1
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(C(=O)c3ccc4[nH]ccc4c3)CC2)cc1

Procedure:
In the manner described in Example 24, indole-5-carboxylic acid (100 mg, 0.62 mmol) and 1-[2-(4-methanesulfonamidophenyl)ethyl]piperazine (180 mg, 0.64 mmol) gave, after purification by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 ; 95:5:0.5 and trituration with hexane/EtOAc, the piperazine (68 mg, 26%), mp 94°-97° C. Elemental analysis for C22H26N4O3S.0.5H2O: Calculated: C, 60.66; H, 6.26; N, 12.86%. Found: C, 61.02; H, 6.19; N, 12.51%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([N:10]=C=O)([CH3:9])[CH3:8])([CH3:3])=[CH2:2].[N-]=C=O.OC(C)(C)CC(=O)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>O>[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([NH2:10])([CH3:9])[CH3:8])([CH3:3])=[CH2:2]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: [N-]=C=O
Solvent: CC(=O)CC(C)(C)O
Solvent: O
Product: C=C(C)c1cccc(C(C)(C)N)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A flask blanketed with nitrogen was charged with 3-isopropenyl-α,α-dimethylbenzylisocyanate (m-TMI) (475.33 g) and the isocyanate was heated to about 85° C. 4-hydroxy-4-methyl-2-pentanone (274.99 g) was added from an addition funnel to the flask at a fairly rapid rate. The mixture was stirred for two hours and about 0.16 g of dibutyltin dilaurate was added to the mixture, after which the temperature was raised to about 100° C. The reaction mixture was stirred for about 1.5 hours at 100° C. and then allowed to cool and stand at room temperature for approximately 48 hours. Subsequently, about 0.14 g of additional dibutyltin laurate was added and heating at 100° C. was resumed. The reaction mixture temperature was then raised to about 125°-130° C. and the mixture was stirred overnight. Water (800 ml) was added to the cooled reaction mixture and the mixture was distilled. The remaining material in the distillation pot was extracted with toluene. The toluene extract was dried with anhydrous K2CO3, the toluene was distilled and the title product was recovered in a toluene solution.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:16])[S:13][C:14]=2[CH3:15])[CH:5]=1.[C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH3:19].[Li]>>[C:22]([O:21][C:18](=[O:20])[CH2:19][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:16])[S:13][C:14]=2[CH3:15])[CH:5]=1)=[O:17])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2nc(C)sc2C)c1
Agent: [Li]
Product: Cc1nc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)s1

Procedure:
A sample of 3-(2,5-dimethyl-thiazol-4-yl)-benzoic acid methyl ester (0.99 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give 3-[3-(2,5-dimethyl-thiazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (1.12 g) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:21]([N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1)[CH3:22].C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1>>[CH2:21]([N:23]1[CH:27]=[C:26]([NH:28][C:2]2[N:20]=[C:5]3[C:6]([C:10]4[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:25]=[N:24]1)[CH3:22]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CCn1cc(N)cn1
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Product: CCn1cc(Nc2nc3c(-c4ccc(S(C)(=O)=O)cc4)cccn3n2)cn1

Procedure:
(1-Ethyl-1H-pyrazol-4-yl)-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.125 g, 0.406 mmol) and 1-ethyl-1H-pyrazol-4-ylamine (0.058 g, 0.52 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. Product was isolated as a tan solid (0.09 g, 58%). MP=201-203° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.78 (d, J=6.48 Hz, 1H), 8.42 (d, J=8.05 Hz, 2H), 8.06 (d, J=8.09 Hz, 2H), 7.94 (d, J=7.21 Hz, 1H), 7.82 (s, 1H), 7.48 (s, 1H), 7.12 (t, J=7.08 Hz, 2H), 4.10 (q, J=7.08 Hz, 2H), 3.29 (s, 3H), 1.37 (t, J=7.16 Hz, 3H). MS=383 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10]Cl)[CH:3]=1.[C-:12]#[N:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][C:12]#[N:13])[CH:3]=1
Reactant: COc1ccc(Cl)cc1CCl
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1CC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
To a solution of (5-chloro-2-methoxy-phenyl)-methanol (17.1 g, 99.1 mmol) in methylene chloride (100 mL) was added thionyl chloride (14.5 mL, 198 mmol). The reaction was stirred at reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The crude product was dissolved in methylene chloride and washed with saturated aqueous sodium hydrogen carbonate then dried over magnesium sulfate. Concentration in vacuo gave 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g). To a solution of 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g, 96.4 mmol) in acetonitrile (100 mL) was added potassium cyanide (12.5 g, 193 mmol) and 18-crown-6 (2.54 g, 9.64 mmol). The reaction was stirred 12 hours at ambient temperature, diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by passing it through a pad of silica gel, eluting with methylene chloride to give the title compound (17.2 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=[O:9])=[CH:23][CH:22]=1
Reactant: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Reactant: O=Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cn1c(Nc2ccc(Oc3ncccc3C=O)cc2)nc2ccccc21

Procedure:
A solution of 2-chloropyridine-3-carboxaldehyde (3 g, 21 mmol), 4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenol (5 g, 21 mmol), CESIUM CARBONATE (10 g, 32 mmol) in DMSO (60 mL) was heated to 80° C. overnight. Purification by aqueous workup (water, brine) and DCM extraction then Biotage (0-10% DCM/MeOH) produced product which partially solidified.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:35]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(N5CCN(C)CC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (from Boron Molecular). LCMS calculated for C26H31N6O2 (M+H)+: m/z=459.2. Found 459.1.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[CH:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[CH:32]=[N:33][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:35][CH:36]=3)=[N:27][NH:28]2)=[CH:24][CH:23]=1.[CH3:44]O>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C@:14]12[CH2:44][C@H:21]1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[CH:32]=[N:33][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:35][CH:36]=3)=[N:27][NH:28]2)=[CH:24][CH:23]=1
Reactant: CO
Reactant: COc1ccc2c(c1)C(=Cc1ccc3c(-c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of NaH (260 mg, 6.5 mmol) in DMF (10 mL) at 0° C. was added trimethylsulfoxonium iodide (475 mg, 2.2 mmol). The resulting mixture was stirred at rt for 30 min followed by the addition of 5-methoxy-3-((3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazol-6-yl)methylene)indolin-2-one (504 mg, 1.1 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 24 h. Additional portion of NaH (130 mg, 3.3 mmol) and trimethylsulfoxonium iodide (238 mg, 1.1 mmol) were added to the reaction mixture and the reaction was stirred at rt for another 19 h. The reaction was cooled to 0° C. and quenched with saturated NH4Cl. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give a yellow viscous oil. The crude product was purified by silica gel chromatography (95:5 to 90:10 CH2Cl2/MeOH) to yield a viscous yellow oil. MeOH was added and the resulting suspension was sonicated for 5 min and the title compound was collected by vacuum filtration as a pale yellow powder (224 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 13.08 (br s, 1H), 10.44 (br s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.08 (dd, J=8.8, 2.3 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.00 (d, J=8.8, 1H), 6.96 (d, J=8.9 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.57 (dd, J=8.4, 2.4 Hz, 1H), 5.70 (d, J=2.5, 1H), 3.54 (t, J=4.6 Hz, 4H), 3.29 (s, 3H), 3.19 (t, J=8.3 Hz, 1H), 2.41 (t, J=4.9 Hz, 4H), 2.34 (dd, J=8.0, 4.8 Hz, 1H), 2.22 (s, 3H), 1.99 (dd, J=8.7, 4.7 Hz, 1H); MS ESI 481.3 [M+H]+, calcd for [C28H28N6O2+H]+ 481.23.
Reaction SMILES: N#N.C(OC(=O)[NH:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[O:17][C:18]([C:21](=[O:23])[CH3:22])=[CH:19][CH:20]=2)[S:13][CH:14]=1)(C)(C)C.[ClH:25]>C(Cl)Cl.O1CCOCC1>[ClH:25].[NH2:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[O:17][C:18]([C:21](=[O:23])[CH3:22])=[CH:19][CH:20]=2)[S:13][CH:14]=1
Reactant: CC(=O)c1ccc(Cc2nc(NC(=O)OC(C)(C)C)cs2)o1
Agent: Cl
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1ccc(Cc2nc(N)cs2)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-acetyl-furan-2-ylmethyl)-thiazol-4-yl]-carbamic acid tert-butyl ester (167 mg, 0.52 mmol) in dry CH2Cl2 (5.2 mL) was treated at 0° C. with HCl (1.3 mL of a 4M solution in dioxane, 5.18 mmol). After stirring at 0° C. for 1 h, the reaction mixture was stirred at rt for 16 h. The solvents were removed under reduced pressure to give the title compound. LC-MS-conditions 02: tR=0.65 min, [M+H]+=223.36.
Reaction SMILES: ClC(Cl)(Cl)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[CH3:14][C:15]1([CH3:28])[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=2)[CH2:18][NH:17][CH2:16]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:14][C:15]1([CH3:28])[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=2)[CH2:18][N:17]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH2:16]1
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(CC(F)(F)F)Cc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoroethyl trichloromethanesulfonate (1.8 g, 6.40 mmol) was added to a solution of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.8 g, 3.88 mmol) and sodium bicarbonate (0.66 g, 7.86 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred at 60° C. for 16 hour. The mixture was concentrated, and CH2Cl2 (70 mL) and water (70 mL) were added to the residue. After separation, the aqueous layer was extracted with CH2Cl2 again. The combined organic layers were washed with saturated aqueous NaCl (1×150 mL), dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:24](=[O:28])[C:25]([NH2:27])=[O:26])=[C:9]([CH2:22][CH3:23])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].CO.Cl>CCOC(C)=O>[NH2:27][C:25](=[O:26])[C:24]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5][CH2:4][C:3]([OH:29])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[CH2:22][CH3:23])=[O:28]
Reactant: CCc1c(C(=O)C(N)=O)c2c(NCC(=O)OC)cccc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(NCC(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A mixture of 190 mg (0.48 mmol) of [[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]amino]acetic acid methyl ester, 5 ml of 1N NaOH, and 15 ml of MeOH was refluxed 0.33 hour, cooled, and stirred at room temperature for 1 hour. EtOAc and aqueous HCl were added and the EtOAc layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was crystallized from MeOH to give 96 mg (53%) of [[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]amino]acetic acid melting at 151-157° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10]([C:13]2[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)=[CH:9][C:8]1=[O:28])=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10]([C:13]2[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)=[CH:9][C:8]1=[O:28])([OH:4])=[O:2]
Reactant: COC(=O)CCN1CCC(c2c(-c3ccccc3)nn3ccccc23)=CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCC(c2c(-c3ccccc3)nn3ccccc23)=CC1=O
Yield: 51.9 %

Procedure:
A mixture of 3-[1-(2-methoxycarbonylethyl)-2-oxo-1,2,5,6-tetrahydropyridin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine (440 mg), 1N sodium hydroxide aqueous solution (3 ml) and methanol (4 ml) was heated under reflux for 1.5 hours. Methanol was evaporated in vacuo and water (20 ml) was added to the residue. The aqueous solution was acidified with 5% hydrochloric acid and precipitates were collected by filtration, washed with water, and then with petroleum ether (5 ml). The precipitates were recrystallized from 95% ethanol to give crystals of 3-[1-(2-carboxyethyl)-2-oxo-1,2,5,6-tetrahydropyridin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine (220 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15](O)=[N:16][CH:17]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:1][CH:2]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]2)=[N:16][CH:17]=1
Reactant: COC(=O)C1CCC(O)C1
Reactant: Oc1ccc(Br)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(Oc2ccc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
A solution of methyl 3-hydroxycyclopentanecarboxylate A-11 (500.0 mg, 3.00 mmol) in anhydrous toluene (10.0 mL) was added to a solution of 5-bromopyridin-2-ol (522.0 mg, 3.00 mmol) in anhydrous toluene (10.0 mL) at room temperature. Diisopropyl azodicarboxylate (1.57 g, 6.00 mmol) was then added dropwise, and the yellow-orange solution was stirred at room temperature for 12 h. The reaction mixture was then quenched with methanol (1.0 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give methyl 3-(5-bromopyridin-2-yloxy)cyclopentane carboxylate A-12 (462.0 mg, Yield=51%). MS (ESI), [M+Na]+ 321, 323.
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=C\CCCCCCCC.OOS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CCOC(C)=O>CN(C=O)C.O=[Os](=O)(=O)=O>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCC(=O)O
Reaction time: 0.08 h
Yield: 80 %

Procedure:
Methyl oleate (50 mg) was dissolved in DMF (2 mL), and OsO4 (0.02 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (0.418 g) was added in one portion and the reaction had a final volume (2.5 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (300 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (20 mL×3) and brine (20 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. Nonanoic acid and nonanedoic acid monomethyl ester were obtained in 80% yield, 93% yield by GC, after purification by silica gel column chromatography.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[O:30]=[C:31]1[NH:36][C:35]2[N:37]=[CH:38][C:39](/[CH:41]=[CH:42]/[C:43]([OH:45])=O)=[CH:40][C:34]=2[C:33](=[O:46])[NH:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[O:30]=[C:31]1[NH:36][C:35]2[N:37]=[CH:38][C:39](/[CH:41]=[CH:42]/[C:43]([N:2]([CH3:1])[CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH3:13])[CH:5]=3)=[O:45])=[CH:40][C:34]=2[C:33](=[O:46])[NH:32]1
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Reactant: CNCc1cn(C)c2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Yield: 34 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl)acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.16 g, 34%) was prepared as a tan solid and as a mixture of amide rotamers; 1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 11.53 (s, 1H), 8.91 (s, 1H), 8.73-8.66 (m, 1H), 7.78-7.30 (m, 5H), 7.17-7.12 (m, 1H), 7.03-6.98 (m, 1H), 4.96-4.73 (m, 2H), 3.76 (s, 3H), 3.07-2.90 (m, 3H); MS (ESI) m/e 390 (M+H)+.