Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
First, 50 g (0.29 mol) of 2-chloro-4-fluorobenzoic acid was dissolved in 150 ml of hydrochloric acid at room temperature, to which a mixed acid of 28 ml (0.31 mol) of fuming nitric acid and 56 ml of concentrated sulfuric acid was added dropwise at 35° to 45° C. Then, the solution was stirred at 40° C. for 1 hour and poured into 250 ml of ice-water. The precipitated crystals were collected by filtration and recrystallized from a mixed solution of hexane and ethyl acetate, which afforded 55 g (0.25 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid. Then, 55 g (0.25 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid was dissolved in 50 ml of ethyl acetate, to which 33 g (0.28 mol) of thionyl chloride was added, and the mixture was heated under reflux for 3 hours and then allowed to stand for cooling to room temperature. Then, 20 ml of ethanol and 30 g of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled out, and the residue was purified by silica gel chromatography, which afforded 57 g (0.23 mol) of ethyl 2-chloro-4-fluoro-5-nitrobenzoate. ##STR64##
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH:3]=[CH2:4].Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1.ClCCl>CO>[CH2:2]([O:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)[CH:3]=[CH2:4]
Reactant: C=CCO
Reactant: COc1ccc2nccc(Br)c2c1
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: C=CCOc1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
Sodium (1.22 g, 52.9 mmol, 2.1 eq) is added portionwise at 0° C. to a stirred solution of allyl alcohol (117.1 g, 201.6 mmol, 80.0 eq). After 30 minutes stirring at 0° C., 4-bromo-6-methoxy-quinoline (6.0 g, 25.2 mmol, 1.0 eq) is added to the reaction mixture that is heated under reflux for 5 hours. The reaction mixture is then cooled down to room temperature, and filtered. The filtrate is evaporated under reduced pressure to give a residue that is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 60:1, v/v) to afford 4-allyloxy-6-methoxy-quinoline as a white solid (4.0 g, 74% yield).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].O.C(=O)(O)[O-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>ClCCl>[OH:4][CH2:3][C:2]([NH:1][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
3.0 g of 2-amino-2-methylpropan-1-ol was dissolved in 100 mL of dichloromethane, and 100 mL of water and 8.4 g of sodium bicarbonate were then added. To this solution, 5.7 g of benzyl chloroformate was added dropwise, and the mixture was stirred at room temperature for 16 hours. After extraction with dichloromethane (100 mL×3), the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 7.6 g of the compound of interest as a colorless oil (86%).
Reaction SMILES: CCO.[C:4]([NH:7][C@H:8]([CH2:24][O:25][CH3:26])[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=1)=[O:10])(=[O:6])[CH3:5].CCOC(C)=O>O=[Pt]=O.CS(C)=O>[C:4]([NH:7][C@H:8]([CH2:24][O:25][CH3:26])[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:17][CH:18]=1)=[O:10])(=[O:6])[CH3:5]
Reactant: COCC#Cc1ccc(CNC(=O)[C@@H](COC)NC(C)=O)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CS(C)=O
Product: COCCCc1ccc(CNC(=O)[C@@H](COC)NC(C)=O)cc1

Procedure:
An EtOH solution (30 mL) of (R)-2-acetamido-3-methoxy-N-(4-(3-methoxyprop-1-ynyl)benzyl)propanamide ((R)-6) (1.00 g, 3.1 mmol) was treated with H2 (1 atm) in the presence of 10% PtO2 (50 mg) at room temperature (16 h). The mixture was carefully filtered through a bed of Celite®. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel with EtOAc as the eluant to obtain (R)-7 (510 mg, 51%) as a white solid: Rf=0.27 (EtOAc); mp 105-107° C.; [α]25D +3.0° (c 0.5, DMSO); IR (nujol) 3283, 3085, 1638, 1550, 1457, 1379, 1299, 1122, 979, 725, 605 cm−1; 1H NMR (CDCl3) 1.81-1.92 (m, CH2), 2.03 (s, CH3CO), 2.67 (t, J=7.8 Hz, CH2Ph), 3.33-3.46 (m, CHH′O, CH2O and 2 OCH3), 3.80 (dd, J=4.0, 9.1 Hz, CHH′O), 4.44 (d, J=5.7 Hz, CH2N), 4.50-4.57 (m, CH), 6.45 (br d, J=6.6 Hz, NHC(O)CH3), 6.70-6.75 (br t, CH2NH), 7.15-7.20 (m, 4 ArH); 13C NMR (CDCl3) 23.2 (CH3CO), 31.2, 31.9 (2 CH2), 43.3 (CH2N), 52.4 (CHCH2), 58.6, 59.1 (2 OCH3), 71.7, 71.9 (2 CH2OMe), 127.5, 128.8, 135.3, 141.4 (C6H4), 169.9, 170.2 (2C(O)); HRMS (M+Na+) (ESI+) 317.1784 [M+Na+] (calcd for C17H26N2O4Na+ 345.1790); Anal. Calcd. for C17H26N2O4: C, 63.33; H, 8.13; N, 8.69. Found: C, 63.12; H, 8.13; N, 8.64.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]([NH:64][CH2:65][CH2:66][S:67]([NH2:70])(=[O:69])=[O:68])([CH3:63])[CH3:62]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:64]([CH:61]([CH3:63])[CH3:62])[CH2:65][CH2:66][S:67](=[O:69])(=[O:68])[NH2:70])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC(C)NCCS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCS(N)(=O)=O)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.030 g) and HATU® (0.058 g) in DMF (0.4 ml) was added DIPEA (0.040 ml) followed by a solution of 2-isopropylamino-ethanesulfonic acid amide (0.058 g) in DMF (0.6 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.012 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[C:16]([F:27])[CH:15]=2)[CH2:9]1)=O)CCC.[NH3:28]>CO>[F:27][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][C@H:8]([C:6]([NH2:28])=[O:5])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:20]1[S:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=1
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
3-[3-Fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester (Step 6, 0.300 g, 0.758 mmol) is dissolved in 2M ammonia in methanol solution (8 ml) and stirred overnight at room temperature. The reaction is concentrated under vacuum and purified by PTLC (10% methanol/CH2Cl2) to give the title compound as a white solid (0.22 g, 87%), mp 249–251° C.; 1H NMR (300 Mhz, CDCl3) δ 3.59 (s, 2H), 4.04 (dd, 1H), 4.30 (t, 1H), 5.05 (dd, 1H), 7.49–7.72 (m, 4H), 7.88 (br s, 1H), 11.63 (s, 1H); MS (m/z) for C13H11FN4O4S: [M+H]+=339.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=2[F:32])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]4[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=4[F:32])[CH2:24][CH2:25]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 128 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.42–7.38 (m, 1H), 7.27–7.17 (m, 4H), 7.12–7.09 (m, 1H), 6.87 (t, 1H, J=8.6 Hz), 6.49 (t, 1H, J=5.4 Hz), 3.19 (q, 2H, J=5.8 Hz), 2.85–2.79 (m, 2H), 2.73–2.64 (m, 1H), 2.50–2.35 (m, 3H), 2.23 (t, 2H, J=6.6 Hz), 1.92–1.85 (m, 4H), 1.75–1.48 (m, 10H), 1.17 (d, 6H, J=6.7 Hz); ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[NH2:13][OH:14].Cl.C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:12][C:5]1[CH:4]=[C:3]([C:1](=[NH:2])[NH:13][OH:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: NO
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(C(=O)O)c(F)c1
Yield: 64.2 %

Procedure:
To a solution of 4-Cyano-2-fluorobenzoic acid (1 g, 6.06 mmol) in EtOH (10.09 mL) was added NH2OH.HCl (0.884 g, 12.72 mmol) previously dissolved in water (5 mL) and aqueous solution K2CO3 (1.339 g, 9.69 mmol) in water (15 mL). Then 8-hydroxyquinone (0.011 g, 0.079 mmol) was added. The resulting solution was stirred at reflux for 4 h. EtOH was evaporated from the reaction mixture, then acidified to pH 3 with aqueous HCl (2 N) solution. The precipitate was filtered, washed with water and dried to yield 2-fluoro-4-(N-hydroxycarbamimidoyl)-benzoic acid (786.3 mg, 3.89 mmol, 64.2% yield) as yellowish solid. The crude was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.21 (m, 1 H), 10.01 (s, 1 H), 7.85 (t, J=7.95 Hz, 1 H), 7.44-7.69 (m, 2 H), 5.99 (br. s., 2 H).
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]/C.[CH2:45]1COCC1>>[CH3:45][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1)=[CH:13][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]/[CH:35]=[CH:34]/[CH3:33]
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C/C=C/CCCCCCCC=O
Reactant: C1CCOC1
Agent: [Br-]
Product: C/C=C/CCCCCCCC=C(C)c1ccc2ccccc2c1
Yield: 53 %

Procedure:
Starting from (1-(2-naphthyl)ethyltriphenylphosphonium bromide (49.7 g, 100 mmol, 1.0 equiv.) in THF (400 mL), KtBuO (110 mL, 110 mmol, 1.1 equiv., 1M in THF) and (E)-undec-9-enal (16.8 g, 120 mmol, 1.2 equiv.) in THF (100 mL), 16.6 g (53%) of the title compound was obtained after purification by flash chromatography on SiO2 (hexane) as a light yellow oil.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22]CCC[O:18]2)[C:7](=[O:23])[C:6]=1[N+:24]([O-])=O>CC(O)=O.O.[Zn]>[C:17]([O:16][CH2:15][CH2:14][CH2:13][N:8]1[C:7](=[O:23])[C:6]2[NH:24][CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9]1=[O:12])(=[O:18])[CH3:22]
Reactant: CN(C)C=Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCCn1c(=O)c2[nH]ccc2n(C)c1=O
Temperature: 100 °C
Yield: 56.5 %

Procedure:
To a solution of 6-(2-(dimethylamino)vinyl)-1-methyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrimidine-2,4(1H,3H)-dione (530 mg, 1.4 mmol) in HOAc (5 mL) was added Zn dust (910 mg, 14 mmol). The reaction was heated at 100° C. for 2 h, cooled to RT, diluted with water (10 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (1:1) to give 3-(1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (210 mg, 56% yield) as a white solid. LCMS: MH+ 266 and TR=0.646 min.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:40])[CH2:4][C:5]([NH:7][CH:8]1[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:12](/[CH:15]=[CH:16]\[C:17]3[N:18]=[N:19][S:20][CH:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[N:41]([O-])=[O:42].[Na+].NC(N)=O>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:2][C:3](=[O:40])[C:4](=[N:41][OH:42])[C:5]([NH:7][CH:8]1[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:12](/[CH:15]=[CH:16]\[C:17]3[N:18]=[N:19][S:20][CH:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\c3csnn3)CS[C@H]12
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\c3csnn3)CS[C@H]12
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A methylene chloride-acetic acid (20 ml-10 ml) solution of diphenylmethyl 7-(4-bromoacetoacetamido)-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (2.22 g, 3.4 mmol) was cooled from -7° C. to -5° C. and an aqueous solution (2 ml) of sodium nitrite (0.32 g, 4.6 mmol) was added in portions. After its dropwise addition the mixture was stirred for 30 minutes, then urea (0.3 g) was added and the temperature of the reaction solution was returned to toom temperature. The reaction mixture was extracted with methylene chloride, then washed with water (40 ml×2) and then dried over magnesium sulfate. When the solvent was distilled off, diphenylmethyl 7-(4-bromo-2-hydroxyiminoacetoacetamido)-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (1.85 g) was obtained as a light yellow powder compound.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:6])C.C(=O)=O.[CH2:10](N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>CCOCC>[CH3:17][S:18]([O:6][CH2:4][CH2:3][CH2:2][C:1]#[CH:10])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCC(C)O
Reactant: CCN(CC)CC
Agent: O=C=O
Solvent: CCOCC
Product: C#CCCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To pentyne-4-ol (Farchan Chemical Co) (42.0 g: 0.5 mols) in 500 mL ether at -5° C. (dry ice bath) is added in a rapid dropwise fashion triethylamine (104.8 mL; 0.75 mols) diluted with 100 mL ether. While maintaining the temperature at or below 15° C. throughout, methane sulfonyl chloride, (94.2 mL; 0.70 mols) diluted with 100 mL ether, is added dropwise over 45 minutes. The thick suspension is stirred an additional 30 minutes, after which the precipitate is filtered. The filter cake is washed with ether and the combined ether layers washed twice with water, then once with brine. The ether layer is then dried over anhydrous magnesium sulfate and solvent removed under reduced pressure to yield the product as a pale yellow oil; yield 64 g (79%), which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:17])=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]2=[O:18].O.[O:21]1CC[CH2:23][CH2:22]1>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:22]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9]([OH:17])=[C:8]1[C:3]([C:4](=[O:19])[CH:5]=[CH:6][C:7]1=[O:18])=[C:2]2[Cl:1])(=[O:21])[CH3:23]
Reactant: O=C1C=CC(=O)c2c1c(Cl)c1cccc(O)c1c2O
Reactant: C1CCOC1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2c(Cl)c3c(c(O)c12)C(=O)C=CC3=O
Reaction time: 48 h

Procedure:
10-Chloro-8,9-dihydroxy-1,4-anthracenedione (compound 3) (180 mg) was dissolved with stirring in dry tetrahydrofuran (15 ml) at room temperature. Acetic anhydride (20 drops) and pyridine (15 drops) were added to the solution which was then stirred for 48 h. Acidified water was added and the suspension was extracted with dichloromethane. The combined organic layers were dried and evaporated, and the residue was column chromatographed on silica gel 60 (100 g) with chloroform/acetone mixture as the eluant. The major red band gave the product (compound 4) as a red solid (177 mg, 85%).
Reaction SMILES: OC[C:3]1([C:10]2[CH:15]=[N:14]C=CN=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH:16]1(N)CC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]1[C@@H:15]([NH2:14])[C@@H:10]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC1
Reactant: O=C1CCC(CO)(c2cnccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
A solution of 4-(hydroxymethyl)-4-(pyrazin-2-yl)cyclohexanone (360 mg, 2.0 mmol, 1.0 equiv) in acetonitrile (4 mL) was treated with cyclopropylamine (280 μL, 4.0 mmol, 2.0 equiv), acetic acid (0.1 mL) and NaBH(OAc)3 (848 mg, 4.0 mmol, 2.0 equiv) successively. After being stirred at 25° C. for 12 h, the reaction mixture was carefully diluted (sat.NaHCO3) and extracted (10% MeOH/CH2Cl2). The organics were washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, EtOAc containing 2.5% NH4OH then EtOAc/5% MeOH containing 2.5% NH4OH, the second spot was collected) to provide 180 mg of trans amine as a white solid (0.70 mmol, 42%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:11]([CH3:12])=[CH:10][NH:9][CH:8]=1)=[O:6].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.O>CN(C)C=O>[C:14]1([N:9]2[CH:10]=[C:11]([CH3:12])[C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1nccc2ccccc12
Reactant: COC(=O)c1c[nH]cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2nccc3ccccc23)cc1C
Temperature: 40 °C
Reaction time: 0.3 h

Procedure:
0.208 g (6.5 mmol) of sodium hydride, at 75% by weight in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 0.903 g (6.5 mmol) of 3-methoxycarbonyl-4-methyl-1H-pyrrole in 20 mL of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.3 hour, 1.07 g (6.5 mmol) of 1-chloroisoquinoline and 10 mL of dimethylformamide are added. After stirring at a temperature in the region of 120° C. for 4 hours, the reaction mixture is poured into 200 mL of salt water and then extracted with 100 mL of ethyl acetate. The organic phase is partially concentrated under reduced pressure. 100 mL of salt water are added to the residue, which is then extracted with 50 mL of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give a solid which is purified by silica gel chromatography [eluent: cyclohexane/dichloromethane/ethyl acetate (60/36/4 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.5 g of 1-(isoquinol-1-yl)-3-methoxycarbonyl-4-methyl-1H-pyrrole are obtained. Mass spectrum (EI): m/e 266 (M+.), m/e 235.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH:24]([CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[NH2:54][CH2:55][C@@H:56]([NH:60][S:61]([C:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=1)(=[O:63])=[O:62])[C:57]([OH:59])=[O:58]>C1COCC1.O>[C:43]([O:42][C:40]([N:37]1[CH2:36][CH2:35][CH:34]([CH2:33][CH2:32][CH:24]([CH2:23][CH2:22][CH:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)[C:25]([NH:27][CH2:28][C:29]([NH:54][CH2:55][C@@H:56]([NH:60][S:61]([C:64]2[CH:73]=[CH:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[CH:65]=2)(=[O:63])=[O:62])[C:57]([OH:59])=[O:58])=[O:30])=[O:26])[CH2:39][CH2:38]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Reactant: NC[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)NC[C@@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)O)CC1
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
Isobutyl chloroformate (3.3 g, 24.2 mmol) is added, at room temperature, to a solution of 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl)amino]acetic acid (compound 4) (10.8 g, 20 mmol) in 200 ml of THF and N-methylmorpholine (5 g, 49.5 mmol). A suspension is obtained. After stirring for 20 minutes, a mixture of (2R)-3-amino-2-[(2-naphthylsulphonyl)amino]propanoic acid (8 g, 25 mmol) and water (80 ml) is added, at 0° C. Stirring is continued at 0˜5° C. for 30 minutes and then at room temperature for 18 hours. The THF is evaporated off and the aqueous solution is acidified to pH 2 with 1N hydrochloric acid. The mixture is extracted with ether. The extracts are washed with water, dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (10/0.5/0.5 dichloromethane/methanol/acetic acid) to give 8.3 g of a beige-coloured solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].O>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[OH:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: Cc1ccccn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(C(O)Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 79 %

Procedure:
A stainless steel bomb containing p-nitrobenzaldehyde (300 g, 1.99 moles), α-picoline (650 ml, 6.59 moles) and distilled water (100 ml, 5.56 moles) was sealed and held in an oil bath at 140°-160° C. for 19 hours. It was cooled to room temperature and opened to the atmosphere. The contents of the reactor, a mass of crystals and some dark liquid, were added to one liter of a 60:40 methanol-water mixture and the resulting mixture stirred for two hours. The solid was recovered by filtration, washed with one liter of the same solvent mixture and dried under vacuum at 50° C. to give 383-396 g (79%-82% yield) of ##STR29## 4-nitrophenyl-(α-picolyl)carbinol.