Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:36][O:37][CH2:38][C:39]2[N:40]=[CH:41][N:42]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:43]=2)[C:33](O)=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:64][C@@H:65]1[C:82](=[O:83])[N:67]2[C:68]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])=[C:69]([CH2:73][Br:74])[CH2:70][S:71](=[O:72])[C@H:66]12.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C(Cl)Cl>[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:36][O:37][CH2:38][C:39]2[N:40]=[CH:41][N:42]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:43]=2)[C:33]([NH:64][C@@H:65]2[C:82](=[O:83])[N:67]3[C:68]([C:75]([O:77][C:78]([CH3:79])([CH3:80])[CH3:81])=[O:76])=[C:69]([CH2:73][Br:74])[CH2:70][S:71](=[O:72])[C@H:66]23)=[O:34])[N:31]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2[C@H](N)C(=O)N12
Reactant: O=C(O)C(=NOCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2[C@H](NC(=O)C(=NOCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
A mixture of methylene chloride and 209 mg of phosphorus pentachloride was cooled to -10° C. 752 mg of 2-(2-tritylaminothiazol-4-yl)-2-((N-tritylimidazol-4-yl)methoxyimino)acetic acid was added to the mixture and the mixture was stirred for 10 minutes at the same temperature. 0.25 ml of triethylamine was added thereto and after 5 minutes a mixture of methylene chloride, 401 mg of tertiary butyl 7β-amino-3-bromomethyl-3-cephem-4-carboxylate 1-oxide hydrochloride and 0.14 ml of triethylamine was added to the mixture. The resulting mixture was stirred for 30 minutes at the same temperature. A 5% aqueous solution of sodium bicarbonate was added to the reaction mixture and the organic solvent layer was washed with a diluted aqueous solution of citric acid and SSC and dried with sodium sulfate and then concentrated to dryness to give 1.0 g tertiary butyl 7β-(2-(2-tritylaminothiazol-4-yl)-2-((N-tritylimidazol-4-yl)methoxyimino)acetamido)-3-bromomethyl-3-cephem-4-carboxylate 1-oxide (syn isomer).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[C:12](I)[CH:11]=[CH:10][N:9]=1)=[O:7].CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[C:12]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)[CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: COC(=O)CNC(=O)c1cc(I)ccn1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CNC(=O)c1cc(-c2ccc(C)cc2)ccn1
Temperature: 70 °C
Yield: 85 %

Procedure:
To a degassed solution of [(4-iodo-pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 23, (0.150, 0.47 mmol) in 1,4-dioxane (4 mL) and MeOH (2 mL) is added K3PO4 (0.109 mg, 0.52 mmol), Pd(dppf)Cl2 (0.038 g, 0.047 mmol) and 4-methylphenyl boronic acid (0.064 g, 0.47 mmol). The reaction is heated to 70° C. in a sealed tube under N2 for 16 hours. The solvents are then removed under reduced pressure and the solid which remains is partitioned between CH2Cl2 and 1M K2CO3. The aqueous phase is removed and the organic phase washed with H2O, sat. NaCl, dried (MgSO4), filtered and concentrated under reduced pressure. The crude material is purified over silica (EtOAc:heptane gradient 1:4 to 3:7) to afford 0.113 g (85% yield) of the desired compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (1H, dd, J=5.1, 0.7 Hz), 8.55 (1H, t, J=4.8 Hz), 8.43-8.44 (1H, m), 8.43 (1H, s), 7.66 (1H, dd, J=5.1, 1.8 Hz), 7.63 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.1 Hz), 4.31 (1H, d, J=5.9 Hz), 3.81 (2H, s), 2.43 (3H, s). HPLC-MS: m/z 285 [M+H]+.
Reaction SMILES: Cl[Si:2]([CH2:10][Cl:11])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.N1C=CN=C1>CN(C)C=O.O>[Cl:11][CH2:10][Si:2]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)O
Reactant: C[Si](Cl)(CCl)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)O[Si](C)(CCl)c1ccccc1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of 15.4 g (0.075 mol) of chloro(chloromethyl)methyl(phenyl)silane, 14 ml (11.1 g, 0.15 mol) of t-butanol, 11.5 ml (8.3 g, 0.082 g) of triethylamine, and 0.5 g (0.008 mol) of imidazole in 60 ml of dimethylformamide was stirred at 80° For 2 hours. The resulting slurry was cooled, poured into 200 ml of water, and extracted with ether. The ether extracts were washed three times with water, followed by 0.1N aqueous HCl, saturated aqueous NaHCO3, and brine dried over magnesium sulfate, and evaporated to leave 14.0 g of a pale orange oil. Distillation provided 11.9 g (65%) of the title compound: bp 78°-82° (0.2 mm); nD21 1.5010; ir (neat) 3080, 3060, 2990, 2940, 1600, 1435, 1395, 1370, 1260, 1245, 1195, 1125, 1060, 1030, 815, 790, 740, 725, 705, 650 cm-1 ; nmr (CDCl3): 0.5 (3H, s), 1.3 (9H, s), 2.9 (2H, s) and 7.3-7.8 (5H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:14](O)=O>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:14]2[NH:8][C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=[CH:18][C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: COc1cc(C(=O)O)ccc1NS(C)(=O)=O
Reactant: Nc1cccnc1N
Product: COc1cc(-c2nc3ncccc3[nH]2)ccc1NS(C)(=O)=O

Procedure:
Prepared analogously to Example 14 from 2,3-diaminopyridine and 3-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[H-].[Na+].[CH3:26][CH:27]([Si:29](Cl)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH3:28]>C1COCC1>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:28])[CH3:26])[C:8]=3[N:9]=[CH:10][C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3[nH]ccc3n12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)n12
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a solution of 2-(4-(1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (1.03 g, 3.36 mmol; Example #N.1.50) in THF (32 ml) at about −20° C. was added NaH (0.148 g, 3.70 mmol). The mixture was allowed to stir at about −20° C. for about 20 min. TIPSCl (0.790 ml, 3.70 mmol) was added and the resulting solution was allowed to stir at about −20° C. for about 1 h. The mixture was treated with 15 mL of an ice cold saturated aqueous NaCl solution and the resulting mixture was partitioned between EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organic phases were washed with saturated aqueous NaCl solution (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(4-(1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (1.5 g, 96%). LC/MS (Table 2, Method h) Rt=2.28 min; MS m/z 463 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21]C(C)([O-])C.[K+].IC>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=1)([CH3:21])[C:3]([O:2][CH3:1])=[O:20]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)Cc1cccc(C(C(=O)OC)C(=O)OC)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(C(C)(C(=O)OC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
The compound of step 1 (0.353 g, 1.26 mmol) was dissolved in DMF (1.5 ml), potassium tert-butoxide (151 mg, 1.32 mmol) was added, the mixture stirred at room temperature for 10 min, and then iodomethane (0.542 g, 3.78 mmol) was added. The mixture was stirred at room temperature for 3 h and partitioned between EA and 2 N hydrochloric acid. The combined extracts were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to yield 0.128 g of the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH:16]([CH2:18]OS(C)(=O)=O)[CH2:15][CH:14]([N:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:34])[C:28]=3[C:27]3=[N:35][O:36][C:37]([CH3:38])=[C:26]3[C:25]2=[O:39])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH:14]([N:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:34])[C:28]=3[C:27]3=[N:35][O:36][C:37]([CH3:38])=[C:26]3[C:25]2=[O:39])[CH2:15][CH:16]([CH2:18][N:1]=[N+:2]=[N-:3])[CH2:17]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1onc2c1c(=O)n(C1CC(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CC(CN=[N+]=[N-])CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Temperature: 60 °C
Yield: 83.3 %

Procedure:
Add NaN3 (0.33 g, 5.1 mmol) to a solution of 3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-5-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 1.7 mmol) in DMF (20 mL). Heat 24 H at 60° C., cool to 0° C. and quench with water. Concentrate to dryness. Partition between 20% iPrOH/CHCl3 and water. Extract 3×CHCl3. Wash the combined organics 2× with brine, dry over Na2SO4, filter and concentrate to dryness to afford the title compound (0.67 g, 84%) as a white foam as a mixture of cis isomers. MS(IS) 473.2 (M+); TLC (50% EtOAc/hexanes) Rf=0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6](=[O:17])[C:7]([N+:14]([O-:16])=[O:15])=[C:8]1[NH:13][CH2:12][CH2:11][CH2:10][S:9]1.[H-].[Na+].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([N:13]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:7]([N+:14]([O-:16])=[O:15])[C:6](=[O:17])[CH2:5][O:4][C:3]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=1[Cl:1])(=[O:27])[CH3:26]
Reactant: O=C(COc1ccc(Cl)cc1Cl)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(=O)N1CCCSC1=C(C(=O)COc1ccc(Cl)cc1Cl)[N+](=O)[O-]

Procedure:
5 was prepared as a yellow solid, melting point: 120°-120.5° (with decomposition) by the treatment of 5C with sodium hydride and acetyl chloride, by the general procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([SH:11])[CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: N#Cc1ccccn1
Reactant: O=C(O)c1ccc(Cl)cc1S
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2cc(Cl)ccc12
Yield: 47.3 %

Procedure:
A mixture of 4-chloro-2-mercaptobenzoic acid (6.00 g, 31.8 mmol), 2-cyanopyridine (1.90 g, 17.7 mmol) and pyridine (50.0 ml) was refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (2.30 g, 48%).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[OH:15])=[O:6].Cl>C1COCC1>[OH:14][C:12]1[CH:11]=[CH:10][C:9]2[O:15][CH2:4][C:5](=[O:6])[NH:7][C:8]=2[CH:13]=1
Reactant: O=C(CCl)Nc1cc(O)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COc2ccc(O)cc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium hydride (60%) (1.6 g, 39.68 mmol) was added to a THF solution of compound 47 (2.5 g, 12.4 mmol) at 0° C. The reaction mixture was warmed to room temperature and left for 12 h. Excess sodium hydride was destroyed by careful addition of ice-water. The crude reaction mixture was acidified by the addition 1M HCl. The reaction mixture was extracted in EtOAc (6×50 ml). Solvent was evaporated to yield a brownish solid which was used for the next step without further purification. Yield=1.61 g. (78%). 1H NMR (dmso-d6): 10.5 (s, 1H), 9.14 (s, 1H), 6.71 (d, 1H, J=8.86 Hz), 6.34 (d, 1H, J=2.73 Hz), 6.26 (dd, 1H, J=8.83 and 2.62 Hz), 4.41 (s, 1H). 13C NMR (dmso-d6): 166.1, 153.2, 136.5, 128.5, 117.2, 109.8, 103.5, 67.5. ES-HRMS [M+H]+ 166.0500. Calcd for (C8H8NO3): 166.0478.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[CH3:45][NH:46][CH2:47][C:48]#[N:49].CN1CCOCC1>CN(C=O)C>[C:48]([CH2:47][N:46]([CH3:45])[C:13](=[O:15])[C@H:12]([N:9]1[C:8](=[O:19])[C:7]2=[CH:20][NH:21][C:5]3[C:6]2=[C:11]([C:2]([F:1])=[CH:3][N:4]=3)[CH2:10]1)[CH:16]([CH3:18])[CH3:17])#[N:49]
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: CNCC#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](C(=O)N(C)CC#N)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 2-(Methylamino)acetonitrile (5.41 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-55% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a pale yellow solid (7.8 mg, 44%). 1H NMR (500 MHz, DMSO-d6) δ 0.78 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H), 2.44-2.51 (m, 1H), 3.12 (s, 3H), 4.39 (AB q, J=84.5, 17.5 Hz, 2H), 4.89 (d, J=5.5 Hz, 2H), 5.42 (d, J=11.0 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.43 (s, 1H). [M+H] calc'd for C17H18FN5O2, 344; found, 344.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[C:17]2[C:9]([N:10]3[C:15](=[CH:16]2)[C:14](=[O:19])[NH:13][CH2:12][CH2:11]3)=[N:8][CH:7]=1.[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[C:17]2[C:9]([N:10]3[C:15](=[CH:16]2)[C:14](=[O:19])[NH:13][CH2:12][CH2:11]3)=[N:8][CH:7]=1
Reactant: O=C1NCCn2c1cc1cc(OCCCCl)cnc12
Reactant: C[C@H]1CCCN1
Product: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 2, from 7-(3-chloro-propoxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one and (S)-2-methylpyrrolidine (commercially available), to give the desired product as a colorless solid (19%).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])C.[OH-].[Na+]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:23])([CH3:22])[C:4]([OH:24])=[O:3])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C)(C)CCCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(CCCCCNS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Yield: 6.1 %

Procedure:
Ethyl-7-(4-chlorophenylsulphonamido)-2,2-dimethylheptanoate (3.5 g, 0.09 mol) was treated with sodium hydroxide by the method described in Example 5(iii) to give the title compound (1.9 g) m.p. 132°-3° C. (dichloroethane/40°-60° petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([OH:18])[CH2:16][CH3:17])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CS(C)=O.CCN(CC)CC>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:18])[CH2:16][CH3:17])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCC(O)c1ccc(-c2ccccn2)c(OC)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)c1ccc(-c2ccccn2)c(OC)c1

Procedure:
A solution of 1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-ol (134 mg, 0.55 mmol) was dissolved in CH2Cl2 (3 mL), DMSO (0.5 mL), Et3N (0.5 mL) and was treated with sulfur trioxide pyridine complex (350 mg, 2.2 mmol) at 0° C. for 12 h. The reaction mixture was diluted with water (10 mL) and the product was extracted into CH2Cl2 (3×10 mL), dried (MgSO4), concentrated and purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 1:1) to afford 1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[C:23](=[O:24])[NH:22][C:20]1=[O:21])(=O)C.[Na]>CO>[C:27]([C:25]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[N:19]([CH:26]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4])#[CH:28]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C#C[Si](C)(C)C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of stage b) (9.5 g, 24 mmol) was dissolved in methanol (200 mL) and diluted with a solution containing sodium (0.8 g) and methanol (100 mL). The reaction was stirred at room temperature for 2 hours and was then neutralized using Dowex 50W-X8 (H+ form) resin. The resin was removed by filtering and washed with methanol. The filtrate was concentrated in vacuo to give 4.85 g of a beige solid. The compound was purified on a Waters Prep 500 reverse phase C18 column which was eluted with H2O/MeOH 85:15 (v:v) to give 1.2 g of the title product (white solid). Impure fractions were re-chromatographed. An additional 1.94 g of product were obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20]>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH2:21])[CH:17]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Reactant: NC(=O)c1cccc(N)c1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cccc(C(N)=O)c1
Yield: 15.8 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 3-aminobenzamide as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(S)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1

Procedure:
A mixture of 2.5 g. 2-amino-4-chloro-1-nitrobenzene, 3.6 g. p-thiocresol, 4.2 g. potassium carbonate in 20 ml. dimethylformamide is stirred overnight at room temperature, then poured into water. The crude product, recrystallized from methanol, gives 2-amino-4-(p-methylphenylthio)-1-nitrobenzene.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][C:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:5]([CH3:6])[CH2:4]1.C[Si](C)(C)[Cl:22].C[Si](C)(C)Br>>[Cl:22][C:10]1[NH:11][C:12]2[C:19]3[C:9]=1[CH2:8][C@@H:7]1[C:17]([C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:18][C@@H:3]([CH2:2][OH:1])[CH2:4][N:5]1[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: C[Si](C)(C)Br
Product: CN1C[C@H](CO)C=C2c3cccc4[nH]c(Cl)c(c34)C[C@H]21

Procedure:
1 g of lysergol is halogenated according to the process of Example 1, except that 1.7 g of trimethylchlorosilane are used instead of trimethylbromosilane. The product is isolated as described in Example 1. The yield of the title compound is 0.73 g (0.0025347 mole, 64.4%), m.p.: 207° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][C:4]=1[O:15][CH2:16][CH:17]([OH:31])[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][C:4]=1[O:15][CH2:16][CH:17]([O:31][C:32](=[O:34])[CH3:33])[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:24]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCC(O)CN1CCN(c2ccccc2)CC1
Solvent: c1ccncc1
Product: COc1ccc(C2CNC(=O)C2)cc1OCC(CN1CCN(c2ccccc2)CC1)OC(C)=O
Yield: 86 %

Procedure:
7.5 mmol of 4-{4-methoxy- 3-[3-(4-phenylpiperazin-1-yl)-2-hydroxypropoxy]phenyl}-2-pyrrolidone is dissolved in 50 ml. of dry pyridine. After adding 15 mmol of acetic anhydride, the mixture is heated for 3 hours under reflux. After cooling, the reaction mixture is concentrated under vacuum. The residue is chromatographed over silica gel (acetone/dichloromethane 1:1) and recrystallized from isopropanol, thus obtaining in an 86% yield 4-{4-methoxy-3-[3-(4-phenylpiperazin-1-yl)-2-acetoxypropoxy]phenyl}-2-pyrrolidone, m.p. 128°-133°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([OH:28])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:28][CH:25]([C:5]1[C:6]2[N:7]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:26][CH3:27])(=[O:31])[CH3:30]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a stirred solution of 1-[10-chloro-1-(2-chloro-4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]propan-1-ol (136 mg, 0.325 mmol) in pyridine (1.0 mL) was added acetic anhydride (92.2 μL, 0.975 mmol) at room temperature. After 24 h, the reaction mixture was quenched with aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with water, hydrochloric acid (1 M) and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (125 mg, 0.270 mmol, 83%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.