Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:14]2)#[N:10]>CCO>[OH:3][NH:2][C:9](=[NH:10])[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:14]2
Reactant: CCOC(=O)CCc1cc2cc(C#N)ccc2[nH]1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1cc2cc(C(=N)NO)ccc2[nH]1
Temperature: 50 °C
Reaction time: 72 h
Yield: 96.8 %

Procedure:
Hydroxylamine hydrochloride (121 mg) and sodium bicarbonate (293 mg) was added to a solution of ethyl 3-(5-cyano-1H-indol-2-yl)propanoate (D30) (200 mg) in EtOH (15 mL), in that sequence. The reaction mixture was heated to 50° C. and stirred for 72 hours at that temperature. Another portion of hydroxylamine hydrochloride (60 mg) was added, followed by addition of sodium bicarbonate (150 mg). The resulting suspension was stirred at 50° C. for 24 hours. The inorganics was filtered off. The solid was washed with dichloromethane. The filtrate was concentrated to afford a pale yellow oil. Trituration of the residue provided ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (220 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH2:28]([Sn:32](I)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Reactant: CCCC[Sn](I)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred and cooled (−90° C.) solution of bromide 4 (206 mg, 0.66 mmol) in THF (2.5 mL) was added dropwise 1.5 M solution of tert-butyllithium in pentane (1 mL, 1.51 mmol). After 35 min additional stirring at −90° C., tri-n-butyltin iodide (0.23 mL, 0.79 mmol) was added in one portion. The mixture was stirred at −90° C. for 10 min, −78° C. for 40 min, and then allowed to warm to r.t. The mixture was partitioned between AcOEt-brine. The aqueous layer was extracted with AcOEt (3×) and the combined organic solutions were dried (MgSO4), and concentrated to afford the crude stannane 17, which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][C:17]([NH2:19])=O)[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:20][CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][C:17]#[N:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:20][CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(CC(N)=O)c(Cl)c1Cl)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCC12CCC(=O)C=C1c1c(cc(CC#N)c(Cl)c1Cl)C2
Reaction time: 0.5 h

Procedure:
(5,6-Dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)acetamide (7.03 g, 20 mMole) is dissolved in pyridine (50 ml) and 1,3-dicyclohexylcarbodiimide (4.35 g, 21.1 mMole) in pyridine (25 ml) is added with stirring at 15°-20° C. over a period of 30 minutes. The mixture is stirred at 20° C. for 3 hours and the precipitated dicyclohexylurea removed by filtration and the filtrate concentrated in vacuo to remove the pyridine. Addition of water gave the nitrile which is extracted with ether, dried over MgSO4 and the solvent evaporated to give the pure nitrile.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](=[O:37])[C:34](O)=[O:35].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:34](=[O:35])[C:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)c1cccs1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)C(=O)c3cccs3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (74 mg, 0.20 mmol) in CH2Cl2 (1 mL) at 0-5° C. was treated with a catalytic amount of 4-dimethylaminopyridine (DMAP) and 2-thiophene glyoxylic acid (37 mg, 0.24 mmol) followed by DCC (50 mg, 0.24 mmol). The reaction mixture was allowed to warm to room temperature and stir for 3 h. After this time the reaction mixture was evaporated and the residue purified by silica gel flash chromatography with 25% then 35% EtOAc/hexanes as eluant to afford the title compound as yellow foam (93 mg, 93%). LC/MS (Method B) 4.27 min, [M+1]+ 505.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:1]
Reactant: COC(=O)c1cc(CO)cc(-n2cccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.8 %

Procedure:
A mixture of methyl 3-hydroxymethyl-5-(pyrrol-1-yl)benzoate (20.0 g) and manganese dioxide (100.0 g) in dichloromethane (0.5 l) was stirred for 22 hours at room temperature. The manganese dioxide was filtered off and the filtrate was evaporated in vacuo. The residue was pulverized from diisopropyl ether and petroleum ether to give methyl 3-formyl-5-(pyrrol-1-yl)benzoate (17.6 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([N:9]([CH3:11])[CH3:10])=[N:6][NH:7][CH:8]=1.CS(O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O>CN(C=O)C>[Br:3][C:4]1[C:5]([N:9]([CH3:11])[CH3:10])=[N:6][N:7]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CN(C)c1n[nH]cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Sodium hydride (0.498 g, 60% in mineral oil) was added to a stirred solution of 4-bromo-N,N-dimethyl-1H-pyrazol-3-amine (1.97 g) dissolved in DMF (20 ml) under argon. The resulting mixture was stirred at 23° C. for 30 minutes. A solution of Tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (3.19 g) in DMF (10 ml) was added and the reaction mixture was stirred at 95° C. for 5 hours and left at 23° C. overnight. DMF was evaporated and the residue was taken up in dichloromethane, washed with H2O and sat NaCl. The organic was dried (magnesium sulphate), filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 30% ethyl acetate in petroleum ether. The solvent was evaporated to afford tert-butyl 4-(4-bromo-3-dimethylamino-pyrazol-1-yl)piperidine-1-carboxylate (1.700 g) as a clear colorless oil which crystallised on standing. NMR Spectrum: (DMSOd6) 1.40 (s, 9H), 1.65 (d, 1H), 1.71 (d, 1H), 1.89-1.87 (m, 2H), 2.74 (s, 6H), 2.85 (bs, 2H), 3.93-4.06 (m, 2H), 4.09-4.17 (m, 1H), 7.82 (s, 1H); Mass spectrum: M+H+ 373-375
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]2[N:18]([CH2:28][CH3:29])[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:16]=2[CH:15]=1.[BH4-].[Na+]>CO>[CH2:28]([N:18]1[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:16]2[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:31]=[CH:30][C:17]1=2)[CH3:29]
Reactant: O=Cc1ccncc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCNCc3ccncc3)ccc21
Temperature: 25 °C

Procedure:
4-Pyridine carbaldehyde(0.15 ml) was added to a methanol solution (10 ml) of 7-(4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.51 g). The mixture was stirred for an hour at room temperature under nitrogen atmosphere. Sodium borohydride (0.2 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound(0.38 g) as a colorless oily matter.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([NH2:31])[CH2:27][CH2:26]1.[OH-].[Na+]>C1C=CC=CC=1>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:31][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Reactant: CN1CCN(N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NN1CCN(C)CC1
Yield: 49.3 %

Procedure:
4-acetylamino-5-chloro-2-methoxy benzoyl chloride (2.70 g, 0.0103 mole) in anhydrous benzene (100 ml) in the presence of triethylamine (1.1 g) was treated with 4-methyl-1-amino piperazine (1.18 g). After 6 hours the reaction mixture was basified with dilute sodium hydroxide and extracted with hot ethyl acetate. On cooling the extracts yielded 4-acetylamino-5-chloro-2-methoxy-N-[4-methyl-1-piperazinyl]benzamide (1.72 g), m.p. 198°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=N[CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].BrC1C=CC=[C:29]([F:33])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:29]([F:33])[CH:20]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Fc1cccc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Product: Cc1ccc(Nc2cccc(F)c2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) in accordance with the general method of example 20 using 1-Bromo-3-Fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=355.3 (M+H+).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2>>[CH2:1]([NH:3][C:4]([N:12]1[C:13]2[C:9](=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)[CH2:10][C:11]1=[O:16])=[O:5])[CH3:2]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCN=C=O
Product: CCNC(=O)N1C(=O)Cc2cc(Cl)ccc21
Temperature: 138 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Ethyl isocyanate (71.37 ml, 2.5 eq) was added to a solution of 5-chlorooxindole (60.45 g, 1.0 eq) in 500 ml xylenes. The reaction mixture was heated under reflux for 2 hours (138° C.) and then cooled to room temperature and evaporated to dryness. Isopropyl ether (500 ml) was added to the reaction vessel and the mixture was heated to 60° C. and stirred about 2 hours before cooling overnight in an ice bath to promote crystallization of the product. The white crystalline product was collected by filtration, washed once with isopropyl ether and then dried under vacuum to afford 5-Chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethylamide in 90% yield (78.0 g), mp 121-122° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl.[Cu]>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Brc1nccs1
Reactant: C[C@@H](NC(=O)Cc1ccc(O)cc1)c1ccc(NCC(F)(F)F)cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)Cc1ccc(Oc2nccs2)cc1)c1ccc(NCC(F)(F)F)cn1
Yield: 24.3 %

Procedure:
To a solution of the starting 2-(4-hydroxyphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide (60.0 mg, 0.17 mmol) in 1.0 ml of dry DMF was added the 2-bromo-1,3-thiazole (30.6 mg, 0.186 mmol), Cs2CO3 (166 mg, 0.508 mmol), and copper powder (1.1 mg, 0.017 mmol). The mixture was irradiated with microwave at 100° C. for 1 h. The mixture was cooled, diluted with CH2Cl2, and washed with saturated sodium bicarbonate solution and brine. The combined aqueous washes were extracted with CH2Cl2. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. Purification by reverse phase chromatography gave 2-[4-(1,3-thiazol-2-yloxy)phenyl]-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide as a white solid (18 mg, 24%). 1H NMR (CDCl3, 400 MHz) δ 8.227 (d, J=2.75 Hz, 1H); 7.329 (m, 2H); 7.242 (m, 5H); 6.825 (d, J=2.85 Hz, 1H); 6.765 (d, J=7.14 Hz, 1H); 5.106 (quintet, J=6.84 Hz, 1H); 4.381 (dd, J=7.87, 15.93 Hz, 2H); 3.592 (s, 2H); 1.411 (d, J=6.78 Hz, 3H); MS (ES): m/z 438.1 (M+H). FLIPR alpha1I IP=46 nM.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24](=[O:27])[CH2:25]Cl)=[O:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24](=[O:27])[CH2:25][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: C1CCNC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)CCl)no1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)CN2CCCC2)no1
Temperature: 60 °C

Procedure:
A mixture of pyrrolidine (33.43 mg; 0.47 mmol) and 4-dimethylaminopyridine (2 mg; 0.016 mmol) in DMF (1 mL) is added to (S)-1-(2-Chloro-acetyl)-piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (77 mg; 0.235 mmol). The reaction mixture is heated at 60° C. for 18 hours. Purification by preparative HPLC provides the title compound, m/z 363 [M+H+].
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[C:15]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)[N:14]2[N:28]=[CH:29][N:30]=[C:13]2[N:12]=1.Cl>O1CCCC1>[Cl:23][C:22]1[C:17]([C:15]2[N:14]3[N:28]=[CH:29][N:30]=[C:13]3[N:12]=[C:11]([CH2:10][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:16]=2)=[N:18][CH:19]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:21]=1
Reactant: FC(F)(F)c1cnc(-c2cc(CBr)nc3ncnn23)c(Cl)c1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COCc1cc(-c2ncc(C(F)(F)F)cc2Cl)n2ncnc2n1
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
230 mg of 2,2,2-trifluoroethanol was added to a tetrahydrofuran (dehydrated) 8 mL solution of 33 mg of 60% sodium hydride, followed by stirring for 5 minutes, and 300 mg of 5-bromomethyl-7-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine was added at room temperature, followed by stirring for 5 minutes. After completion of the reaction, 1N hydrochloric acid was added to make it acidic, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 97 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]
Reactant: O=Cc1cccc(O)c1
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2cccc(F)c2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
A mixture of 3-fluorobenzyl chloride (0.71 g; 4.91 mmol), 3-hydroxybenzaldehyde (0.6 g; 4.91 mmol) and Cs2CO3 (1.6 g; 4.91 mmol) in anhydrous DMF (5 ml) was stirred for 4 h at ˜60° C. under N2, cooled to room temperature and poured onto H2O (15 ml). The precipitate formed was filtered off, washed with H2O and dried in vacuo to give the title compound (0.9 g; 80%), as creamy solid. 1H-NMR (CDCl3) 5.11 (s, 2H); 7.13-7.25 (m, 3H+CDCl3); 7.3-7.36 (m, 1H); 7.44-7.48 (m, 3H); 9.96 (5, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].O.[N-:19]=[N+]=[N-].[Na+]>CN(C=O)C>[NH2:19][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1nc(-c2cccnc2)sc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cccnc2)sc1N
Temperature: 75 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a round bottom flask containing ethyl 5-bromo-2-(pyridin-3-yl)thiazole-4-carboxylate (2.5 g, 7.98 mmol) in DMF (26.6 ml)/water (13.3 ml) was carefully added sodium azide (2.59 g, 39.9 mmol) and stirred overnight at 75° C. The reaction was cooled to room temperature and poured into water which was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with hexanes/water. The ethyl acetate extracts were dried (MgSO4), filtered and concentrated to dryness. The crude material was purified by silica gel column chromatography (0 to 75% ethylacetate/hexanes) to give the desired product as a white solid (0.6 g, 30%) 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 8.63 (d, 1H), 8.19 (d, 1H), 7.45-7.32 (m, 1H), 6.3 (s, 2H), 4.46 (q, 2H), 1.43 (t, 3H). ESIMS m/z 251.1 (M+2).
Reaction SMILES: CO.[CH3:3][C:4]1[N:5]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:6]2[C:11]([C:12]=1[C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[OH-].[K+]>O>[CH3:3][C:4]1[N:5]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:6]2[C:11]([C:12]=1[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccccc1
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To a mixed solution of methanol and water (4 mL), ethyl 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (300 mg, 0.98 mmol) and potassium hydroxide (546 mg, 9.76 mmol) was added. The mixture was refluxed with stirring for 4 hours. The reaction mixture was concentrated to give a residue. To the residue, water (10 mL) was added and the mixture was extracted with dichloromethane (20 mL×3). The organic phase was concentrated to give crude product 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylic acid (150 mg). LRMS (M−H)− m/z: calcd 279.13. found 279.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH:18]=[C:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:47])C=1.[OH-].[Na+].CO>ClCCl>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH:17]3[O:47][C@H:18]3[C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1[C@@H]2OC2[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 2 %

Procedure:
To a solution of 3β-benzoyloxy-4,4dimethylcholesta-5,16-diene (250 mg, 4.8 mmol) in dichloromethane (5 mL) at ice bath temperature was added mCPBA (180 mg, 5.2 mmol) and the whole stirred for 3 hours. 2N NaOH (5 mL) was added and the aqueous phase extracted with dichloromethane. Concentration under reduced pressure gave a residue which was tritured with methanol and purified by flash chromatography to give 3β-benzoyloxy-4,4-dimethyl-16α-epoxycholesta-5-ene (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:18]([C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:32])[CH:24]=1)=[S:21])[NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH:18][C:20]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:32])[CH:24]=3)=[S:21])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
From 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) and 4-hydrazinocabonothioylamino-2-chlorobenzoic acid (42.8 mg, 0.17 mmol), the desired product was obtained in the same manner as in Synthetic Example 50 as a pale yellow solid (61.1 mg, yield 68%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14].O=[C:16]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([OH:19])=[O:18].[OH-].[Na+].[Na]>O>[C:17]([CH:16]([NH:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:19])=[O:18]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: NC1CN2CCCC(C(=O)O)N2C1=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCc1ccccc1)NC1CN2CCCC(C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.4 %

Procedure:
0.51 g of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate B) was dissolved in 4 ml of water. 1.37 g of 2-oxo-4-phenylbutyric acid were added and the mixture was adjusted to pH 6 using 2N aqueous sodium hydroxide solution. 0.33 g of sodium cyanoborohydrde was then added and the mixture was left to stir at room temperature for 22 hours. The product was absorbed on to a strong acidic ion-exchange resin and eluted with water containing 2% pyridine to give 0.62 g of crude product. Crystallization from water gave 0.3 g (32%) of 2-(1-carboxy-3-phenylpropylamino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (2 racemates: racemates C and D) in the form of a white solid.