Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.O>C(OCC)C>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]([C:7]2[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[S:10][CH:11]=2)([OH:23])[CH2:19][CH2:18]1
Reactant: Brc1csc2ccccc12
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CN1CCC(O)(c2csc3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
13.5 g (0.21 mole) of n-butyllithium in 145 ml of absolute diethyl ether is precooled to -70° to -80°. To this solution there is then added dropwise within 30 minutes, at a temperature of -70°, a solution of 42.6 g of 3-bromobenzo[b]thiophene in 250 ml of absolute diethyl ether. The solution is thereupon stirred for a further 30 minutes at -70°. An addition is then made dropwise, in the course of 30 minutes, of a solution of 23.5 g of 1-methyl-4-piperidone in 100 ml of absolute diethyl ether; the reaction temperature is held by external cooling at -70°, and the reaction solution is subsequently stirred for a further 10 hours at -70°. The reaction solution is thereupon heated to -5°, and 300 ml of water is added dropwise. The organic phase is separated, and the aqueous phase is extracted twice with 400 ml of ethyl acetate. The organic phases are combined, dried with sodium sulphate, filtered off with suction and concentrated by evaporation. The residue is dissolved in 500 ml of 2N hydrochloric acid, and the acid solution is washed with ether. The aqueous solution is then adjusted be addition by 10% sodium hydroxide solution to have a pH-value of 12, and extracted with one litre of chloroform. The chloroform solution is dried with sodium sulphate, filtered off with suction and concentrated by evaporation to obtain crude 1-methyl-4-(benzo[b]thien-3-yl)-4-piperidinol. The free base melts at 150°-151° after recrystallisation from acetone.
Reaction SMILES: [C:1](OC[C@H]1OC(O)[C@@H](N)[C@@H](O)[C@@H]1O)(=[O:3])[CH3:2].[OH:16][C:17]([C:19]1([O:30][C@@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[C@H:24]([NH:25][C:26]([CH3:28])=[O:27])[C@@H:22]([OH:23])[CH2:21]1)[OH:20])=[O:18].C=CC(N)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(S)[C@@H](O)[C@H](O)CS.C([O-])(=O)C(C)=O.O>[C:1]([O:36][CH2:35][C@@H:33]([OH:34])[C@@H:31]([OH:32])[C@@H:29]1[O:30][C:19]([OH:20])([C:17](=[O:16])[OH:18])[CH2:21][C@H:22]([OH:23])[C@H:24]1[NH:25][C:26](=[O:27])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(O)[C@@H](N)[C@@H](O)[C@@H]1O
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: C=CC(N)=O
Agent: CC(=O)C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)COC(C)=O)OC(O)(C(=O)O)C[C@@H]1O
Reaction time: 192 h
Yield: 47 %

Procedure:
In a 10 mL of 0.1 M potassium phosphate buffer (pH 7.5) were dissolved 10 mM DTT, 0.5 M pyruvate, 100 mg of 6-O-acetylmannosamine, prepared as described above, and 1.5 mg NeuAc aldolase (36 U). The reaction mixture was incubated at 37° C. for 8 days followed by lyophilization. The lyophilized powder was dissolved in a small amount of water and directly applied to a Bio Gel P-2 column (3×90 cm) and eluted with a flow rate of 6 mL/40 minutes at 4° C. To remove the trace amount of contaminated NeuAc due to the hydrolysis of the product, another gel filtration was required. Compound 201 was obtained in 47 percent yield. Its physical data were consistent with the reported data.
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].C1CCN2C(=NCCC2)CC1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47][CH:48]=O)([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1>CC#N>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47]/[CH:48]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)/C=C/CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a 0° C. suspension of LiCl (55.4 mg, 1.306 mmol) in MeCN (2 mL) under N2 was added trimethyl phosphonoacetate (0.188 mL, 1.306 mmol) and DBU (0.197 mL, 1.31 mmol). The reaction was stirred at 0° C. for 30 minutes, and then 3-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (300 mg, 0.871 mmol) was added. The reaction was stirred at rt for 2 h and concentrated in vacuo. The residue was diluted with Et2O, washed with 1 N aq. HCl, satd aq. NaHCO3, brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (300 mg, 86% yield) as a white solid. LCMS, [M+NH4]+=418.2. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 1H), 7.03-6.93 (m, 3H), 5.86 (dt, J=15.7, 1.5 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.94 (ddd, J=11.3, 9.9, 3.0 Hz, 1H), 3.84 (s, 2H), 3.75 (s, 3H), 3.65-3.59 (m, 1H), 2.23-2.15 (m, 2H), 2.09-1.98 (m, 5H), 1.89-1.84 (m, 2H), 1.75-1.58 (m, 8H), 1.37-1.31 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:10]([N:11]2C(=O)C3=CC=CC=C3C2=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:22])[NH:6]2.O.NN.C(NN)(=O)C1C(=CC=CC=1)C(NN)=O>CO>[NH2:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH3:22])=[CH:4]2
Reactant: Cc1cc2c(F)c(N3C(=O)c4ccccc4C3=O)ccc2[nH]1
Agent: NN
Agent: NNC(=O)c1ccccc1C(=O)NN
Solvent: O
Solvent: CO
Product: Cc1cc2c(F)c(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
4-Fluoro-2-methyl-5-phthalimidoindole (1.2, 4 mmol) was dissolved in methanol (30 ml). Hydrazine monohydrate (260 μl, 5.3 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated off and the residue taken up in methylene chloride. The phthalhydrazide by-product was removed by filtration and the filtrate purified by flash chromatography 0.5% methanol in methylene chloride. Evaporation of the solvent gave a white solid which contained traces of phthalhydrazide. Further purification was done by dissolving it in ethyl acetate, washing the organic phase with NaOH 2N and brine, drying over MgSO4. Rotary evaporation of the solvent gave 5-amino-4-fluoro-2-methylindole (500 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:27][C:28]5([CH2:34][CH2:35][C:36]=4[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:4][C:3]=1[Cl:44].[F:45][CH2:46][C:47](=O)[CH2:48][F:49].C(O[BH3-])(=O)C.[Na+].O[Li].O.Cl>ClCCl.C(OCC)(=O)C.O1CCCC1.O.CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:27][C:28]5([CH2:34][CH2:35][C:36]=4[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32][N:31]([CH:47]([CH2:48][F:49])[CH2:46][F:45])[CH2:30][CH2:29]5)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[Cl:44]
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCNCC4)C3)CC2)cc1Oc1cnc(N)c(Cl)c1
Reactant: O=C(CF)CF
Agent: Cl
Agent: [BH3-]OC(C)=O
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ncc(Oc2cc(N3CCN(CC4=C(c5ccc(Cl)cc5)CCC5(CCN(C(CF)CF)CC5)C4)CC3)ccc2C(=O)O)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 391H (318 mg) in dichloromethane (4 mL) was added 1,3-difluoropropan-2-one (282 mg) and sodium acetoxyborohydride (318 mg). The mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with 2N aqueous NaOH and brine, and dried over Na2SO4. Filtration and concentration gave the crude product which was dissolved in tetrahydrofuran (10 mL), methanol (5 mL) and water (5 mL). LiOH.H2O (450 mg) was added and the mixture was stirred overnight. The mixture was neutralized with 2N aqueous HCl and extracted with ethyl acetate (300 mL) and dichloromethane (300 mL) respectively. The organic extracts were combined and dried over Na2SO4. Filtration and concentration provided the title compound.
Reaction SMILES: F[B-](F)(F)F.[H+].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[CH:22]1([CH2:27][C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH:24]=[CH:23]1.O>C(O)(=O)C>[O:29]1[C:28](=[O:30])[CH2:27][C@@H:22]2[CH2:26][CH:25]=[CH:24][C@H:23]12
Reactant: O=C(O)CC1C=CCC1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: O=C1C[C@@H]2CC=C[C@@H]2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrafluoroboric acid (2.50 mL, 15.9 mmol) was added to a solution of iodobenzene diacetate (5.10 g, 15.9 mmol) in acetic acid (13.2 mL). 2-Cyclopentene-1-acetic acid (955 μL, 7.93 mmol) was added and the solution was stirred at room temperature for 1 hour. The solution was then added to water and extracted with chloroform. The chloroform layer was extracted with water. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with 0-100% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CHCl3) δ 2.22-2.31 (m, 2H), 2.67-2.84 (m, 2H), 3.05-3.15 (m, 1H), 5.44-5.51 (m, 1H), 5.79-5.86 (m, 1H), 6.01-6.07 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][N:16]=[N+:17]=[N-:18])[CH:11]=[CH:12][C:13]=1[Cl:14].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=O.O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][N:16]2[C:21]([CH3:23])=[C:20]([C:19]([O:25][CH3:26])=[O:24])[N:18]=[N:17]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1C
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a suspension of milled potassium carbonate (38.7 g, 0.28 mol) in DMSO (100 mL) was added (3,4-dichlorophenyl)methyl azide (Intermediate 3) (14 g, 0.07 mol) and methyl acetoacetate (12.1 g, 0.1 mol). The mixture was stirred at 40° C. for 48 hours. The mixture was poured into a mixture of ice and water (100 mL). The water was extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by distillation to give the title compound as white solid crystals (14 g, 67%). LC/MS: m/z 301 (M+H)+, Rt: 1.97 min.
Reaction SMILES: C([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.[OH-].[Na+].O>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: NS(=O)(=O)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Ethoxybenzothiazole-2-sulfonamide (1.72 g, 6.7 mmol) was dissolved in dichloroethane (26 ml) and cooled to 20°. Aluminum chloride (4 g) was added portionwise such that the temperature remained 20°. After complete addition, the mixture was stirred at room temperature for 24 hours. Stirring was discontinued and after 0.5 hour, the supernatant was decanted from a tarry-like residue. This residue was cooled in an ice-water mixture and a cold solution of concentrated HCl (3 ml) in water (40 ml) was added as rapidly as possible with stirring. The resulting mixture was stirred for an hour and filtered. The solid was washed with water and suction dried to give 0.5-0.8 g. This material was combined with that from further working of the supernatant and dissolved in 20% NaOH solution, diluted to 100 ml with water and filtered. The filtrate was slowly acidified with concentrated hydrochloric acid (pH 3) and the resulting tan solid was filtered, washed with water and dried at 60°-80° C. under vacuum: total yield 1.3 g, m.p. 225°-228° C.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH2:20][C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)[CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:7][C:6]=1[CH2:26][N:27]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH3:28])C.Cl>O>[CH2:37]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][CH2:31][CH2:30][CH2:29][N:27]([CH2:26][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH2:20][C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)[CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)=[CH:10][C:5]=1[C:4]([OH:40])=[O:3])[CH3:28])[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1C(=O)OCC
Agent: Cl
Solvent: O
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1C(=O)O
Temperature: 80 °C
Reaction time: 19 h
Yield: 127.5 %

Procedure:
The compound (5.7 mg) obtained in Example 102-5 was suspended in distilled water (30 μl). The reaction solution was added with concentrated hydrochloric acid (100 μl) and the whole was stirred at 80° C. for 19 hours. After having been cooled to room temperature, the reaction solution was concentrated under reduced pressure, thereby obtaining the subject compound (6.9 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[CH:17][N:16]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:14])[CH:20]=2)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Product: CCOC(=O)c1cc(-c2ccnc(Cl)c2)cc(C)n1

Procedure:
The title compound, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (example 1, step 4) and 2-Chloropyridine-4-boronic acid in accordance with the general method of example 1, step 6 to yield the final compound as a light yellow oil, MS (ISP): m/e=277.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Br
Reactant: CC(C)(C)N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)(C)C)cc1Br
Reaction time: 2 h
Yield: 77 %

Procedure:
3-Bromo-4-methoxyphenylsulfonyl chloride (2.80 g, 9.8 mmol) was dissolved in dichloromethane (30 mL) and the solution was treated with triethylamine (1.76 mL, 12.6 mmol), followed by the dropwise addition of t-butylamine (1.33 mL, 12.6 mmol). The mixture was allowed to stand for 2 hours and then was poured onto a mixture of 5% citric acid solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were dried and concentrated. Crystallization of the crude solid from ethyl acetate/hexane gave 3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide (2.43 g, 77%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[N:8]=2)=[CH:5][C:4]([CH3:15])=[N:3]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[C:12]([O:13][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=[C:9]([CH3:14])[N:8]=2)=[CH:5][C:4]([CH3:15])=[N:3]1
Reactant: Cc1ccc(O)c(-c2cc(C)nn2C)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cc(C)nn3C)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 23.7 %

Procedure:
2-(2,5-Dimethyl-2H-pyrazol-3-yl)-6-methyl-pyridin-3-ol (33 mg), 4-chloro-6,7-dimethoxyquinoline (109 mg), and 4-dimethylaminopyridine (66 mg) were dissolved in dimethyl sulfoxide (5 ml) to prepare a solution. Cesium carbonate (165 mg) was added to the solution, and the mixture was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (15 mg, yield 23%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH:17]([C@H:19]1[CH2:23][CH2:22][C:21](=[O:24])[N:20]1[CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=O>COCCOC>[O:24]=[C:21]1[CH2:22][CH2:23][C@H:19](/[CH:17]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:20]1[CH2:25][CH2:26][S:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CCCSCCN1C(=O)CC[C@@H]1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of sodium hydride (95%, 14 mg, 0.58 mmol) in 3 mL of anhydrous 1,2-dimethoxyethane at 0° C. under an argon atmosphere was added dimethyl 2-oxoheptylphosphonate (ACROS, 0.13 mL, 0.61 mmol). The cooling bath was removed and the reaction was stirred for 2 hours. After this time period, the mixture was cooled to 0° C. and a solution of methyl 4-({2-[(2R)-2-formyl-5-oxopyrrolidin-1-yl]ethyl}thio)butanoate (0.55 mmol) in anhydrous 1,2-dimethoxyethane was added. The reaction was allowed to come to room temperature, stirred for 2 hours and then quenched with an aqueous solution of saturated ammonium chloride. Ethyl acetate (50 mL) was then added and the mixture was partitioned between the two phases. The organic solution was dried (brine, Na2SO4), evaporated via reduced pressure and purified with column chromatography (SiO2, EtOAc/Hexane-1/1) to yield methyl 4-[(2-{(5R)-2-oxo-5-[(1E)-3-oxooct-1-enyl]pyrrolidin-1-yl}ethyl)thio]-butanoate as an oil. This material was taken directly on to the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CCOC(C)=O.[Cu]=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cn1cc(Br)cn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cncc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1
Temperature: 150 °C

Procedure:
5-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester (0.100 g, 0.3 mmol), 4-bromo-1-methyl-1H-pyrazole (0.0966 mL, 0.9 mmol), copper(II) oxide (0.048 g, 0.6 mmol) and potassium carbonate (0.054 g, 0.39 mmol) were combined in pyridine (1 mL) in a sealed vial. The reaction was heated to 150° C. overnight then cooled, then diluted with EtOAc. The mixture was washed with HCl (1 M aq.) and brine, and the organic portion was dried and concentrated to yield the title compound as a crude mixture that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[N:7]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1nc(Cl)ccc1=O
Temperature: 25 °C

Procedure:
To a solution 6-chloropyridazin-3(2H)-one (130 mg, 1.0 mmol) in acetonitrile (3.0 mL) was added K2CO3 (437 mg, 3.16 mmol), CH3I (299 mg, 2.11 mmol), the reaction mixture was stirred at reflux for 2 h. The mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), washed with sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified with silica gel column (Petroleum ether:ethyl acetate=4:1) to obtained product: LC/MS m/z=145 (M+H)+.
Reaction SMILES: [N].N.[N+3].[N:4]([O-:6])=[O:5].[N:7]([O-:9])=[O:8].[N:10]([O-:12])=[O:11]>>[N+3:4].[N+:7]([O-:5])([O-:9])=[O:8].[N+:10]([O-:5])([O-:12])=[O:11].[N+:4]([O-:8])([O-:6])=[O:5]
Reactant: O=N[O-]
Agent: N
Agent: [N+3]
Agent: [N]
Product: O=[N+]([O-])[O-]

Procedure:
Ammonia nitrogen and nitrite nitrogen are oxidized by air and microorganisms to form nitrate nitrogen; and
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1.[Cu]Br>[CH3:22][C@@:10]12[CH2:11][C:12](=[O:20])[CH2:13][CH2:14][C@:15]1([CH3:16])[C@@H:17]1[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH2:8][CH2:9]2
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Al](C)C
Agent: [Cu]Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@@H]3[C@@]1(C)CCC(=O)C2
Temperature: 30 °C
Reaction time: 2 h

Procedure:
2.86 g (10 mmol) of androst-4-ene-3,17-dione and 143.3 mg (1 mmol) of copper(I) bromide are dissolved in 20 ml of dry dioxane. 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction for 10 minutes at room temperature under nitrogen atmosphere so that the temperature does not rise above 30° C. Then it is stirred for 2 hours more at 30° C. For hydrolysis, 0.54 ml of water dissolved in 5 ml of dioxane is added to the reaction and stirred for 10 minutes more. The solid is suctioned off on diatomaceous earth and washed again with 20 ml of dioxane. The filtrate is concentrated by evaporation and the crude product (3.0 g) is chromatographed on silica gel with hexane/ethyl acetate as eluent and an increasing part of ethyl acetate. After concentration by evaporation of the fractions, 2.3 g of 5β-methyl-androsta-3,17-dione (76% of theory) of a melting point of 135° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][N:5]3[C:6]([C:7]([F:8])([F:10])[F:9])=[C:2]([Br:1])[C:3]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[N:4]3)[CH2:28][CH2:29]2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: FC(F)(F)c1[nH]nc(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ccccc4)c(Br)c3C(F)(F)F)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Bromo-3-phenyl-5-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1, Rf=0.51) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.42–7.52 (m, 5H), 7.18–7.22 (d, 1H), 6.38–6.42 (dd, 1H), 6.46–6.48 (d, 1H), 4.94 (s, 2H), 3.88 (s, 3H), 3.5–3.78 (m, 4H), 3.18 (s, 4H).