Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=O)[CH3:2].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:13]=1[CH:14]=O.[NH2:35][C:36]([NH2:38])=[O:37].Cl>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:14]([C:13]2[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[NH:35][C:36](=[O:37])[NH:38][C:6]=1[CH3:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(N)=O
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C1NC(=O)NC(C)=C1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of ethylacetoacetate (1.13 g, 8.6 mmol), 2-methoxy-6-pentadecyl benzaldehyde (3 g, 8.6 mmol) and urea (1.04 g, 17.3 mmol) in tetrahydrofuran (20 mL) was heated to reflux (65-70° C.) in the presence of hydrochloric acid (30%) for 7 h. The reaction mixture after being cooled to room temperature was poured into crushed ice (20 g) and stirred for 5 min. The viscous liquid was extracted with ethylacetate (40 mL) and was washed with 1N hydrochloric acid, water, sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to yield light yellow oil. This crude product was purified by flash column chromatography and recrystallised from hexane to get white crystalline solid of title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[CH:38][C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[CH:38][C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1
Reactant: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)N3CC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)N3CC[C@@H](O)[C@@H](N)C3)ccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
To a flask containing tert-butyl((3S,4R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-4-hydroxypiperidin-3-yl)carbamate (37 mg, 0.068 mmol) in dichloromethane (DCM) (1 mL) was added TFA (0.199 mL, 2.58 mmol) and the reaction was stirred for 1 h. The reaction mixture was concentrated in vacuo to afford a brown oil. This was dissolved in methanol and loaded onto an SCX cartridge (5 g). It was eluted with methanol (3 column volumes) and product eluted as free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield a yellow oil—((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (32 mg, 0.068 mmol, 100% yield). This was dissolved in dichloromethane (DCM) (1 mL) in a vial and HCl (2 M in Et2O) (0.034 mL, 0.068 mmol) was added. The resultant suspension was sonicated for 5 min and allowed to stand for 15 min. The solvent was then removed under a positive pressure of nitrogen and the product dried in vacuo to afford ((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (32 mg, 0.067 mmol, 98% yield) as a white solid.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:22][C:3]1[C:2]([NH:31][CH:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH3:30])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CC(N)c1ccccn1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)c1ccccn1
Temperature: 150 °C
Yield: 44.6 %

Procedure:
This compound (16 mg, 44% yield) as a yellow crystalline solid was prepared according the procedures described for Example 318, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (27 mg, 0.09 mmol), 1-(2-pyridyl)ethylamine (16.7 mg, 0.14 mmol) [Matrix Scientific, cat# 012223] and DIEA (24 μL, 0.13 mmol) in 2 mL of NMP (heated in a microwave at 150° C. for 30 min)1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 (1H, br.), 8.51 (1H, d, J=4.5 Hz), 7.89 (1H, d, J=7.4 Hz), 7.77 (1H, m), 7.62 (2H, m), 7.55 (1H, d, J=7.8 Hz), 7.33 (1H, m), 7.21 (1H, m), 7.00 (1H, br.), 6.90 (1H, d, J=2.0 Hz), 5.31 (1H, t, J=7.1 Hz), 3.47 (2H, m), 3.11 (2H, m), 2.70 (3H, s), 1.69 (3H, d, J=7.0 Hz). m/z (EST, +ve) 399.0 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[CH:15]([C:21]([OH:23])=[O:22])[C:16]([CH3:20])([CH2:18]Br)[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH3:20])[CH2:18][S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
6-(2-phenoxyacetamido)-2-methyl-2-bromomethylpenam-3-carboxylic acid (429 mg.) was suspended in dry benzene (10 cc), and pyridine (400 mg.) and trimethylsilychloride (5 cc) were added thereto. The mixture was stirred for 1.5 hours at room temperature and pyridine (400 mg.) was added thereto. The mixture was heated under reflux for 3 hours, mixed with ethyl acetate (30 cc). washed with dilute phosphoric acid and further with an aqueous solution saturated with sodium chloride, dried and then concentrated. A small amount of ethyl acetate was added to the residue and the precipitate was collected by filtration to yield crystals (250 mg.) of 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylic acid, m.p. 170.5°-172° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4]([NH:6][CH2:7][CH:8]([NH:14][S:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)(=[O:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5].C(N(C(C)C)CC)(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][CH2:57][CH:58]([CH2:62][CH2:63][CH:64]2[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][CH2:65]2)[C:59](F)=[O:60])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].O>ClCCl>[C:73]([O:72][C:70]([N:67]1[CH2:68][CH2:69][CH:64]([CH2:63][CH2:62][CH:58]([C:59]([NH:2][CH:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4]([NH:6][CH2:7][CH:8]([NH:14][S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])=[O:60])[CH2:57][CH2:56][CH:53]2[CH2:54][CH2:55][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH2:51][CH2:52]2)[CH2:65][CH2:66]1)=[O:71])([CH3:76])([CH3:75])[CH3:74]
Reactant: CCOC(=O)C(CNC(=O)C(N)c1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CNC(=O)C(NC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 3 h
Yield: 43.5 %

Procedure:
Ethyl 3-[(2-amino-2-phenylethanoyl)amino]-2-[(2-naphthylsulphonyl)amino]propanoate hydrochloride (1.7 g, 3 mmol) and diisopropylethylamine (0.8 g, 6.2 mmol) are added, at room temperature, to a solution of 4-[1-(tert-butoxycarbonyl)-4-piperidyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidyl]ethyl}butanoyl fluoride (ref. synthesis B-1) (1.55 g, 3 mmol) in 50 ml of dichloromethane. After stirring for 3 hours, water is added. The organic phase is washed with water, dried over sodium sulphate and evaporated to give the crude product, which is purified by flash chromatography (20/1 dichloromethane/methanol) to give 1.2 g of a white solid.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:11]([O:13][CH3:14])=[O:12].[C:22](=O)([O-])O.[Na+].C=O.Cl>O.CC(C)=O.ClCCCl>[OH2:12].[ClH:21].[CH3:14][O:13][C:11](=[O:12])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:9]1[CH2:8][CH2:7][C:3]2[S:2][CH:6]=[CH:5][C:4]=2[CH2:22]1
Reactant: O=C([O-])O
Reactant: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCCl
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Yield: 86.6 %

Procedure:
To 28.4 g (0.082 mol) of methyl [2-(2-thienyl)ethylamino](2-chlorophenyl)acetate hydrochloride, prepared according to example 9 or 10, are added 50 ml of 1,2-dichloroethane and the solution of 7.5 g (0.09 mol) of sodium hydrogen carbonate in 100 ml of water. The mixture is stirred well, the phases are separated, the aqueous phase is washed with 2×30 ml of 1,2-dichloroethane, the combined organic layer is dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residual 25 g material (acetate base) is dissolve din 90 ml of formic acid, to the solution 4 g (0.13 mol) of para formaldehyde is added and the mixture is stirred at 50° C. for 20 minutes. The majority of the formic acid is then distilled off in vacuo, the residue is dissolved in the mixture of 100 ml of water and 100 ml of 1,2-dichloroethane, the phases are separated, the aqueous phase is extracted again with 30 ml of 1,2-dichloroethane, the combined organic phase is shaken well with 100 ml of 5% sodium hdyrogen carbonate solution, the phases are separated and the organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in 45 ml of acetone and to the solution 6.5 ml (0.077 mol) of conc. hydrochloric acid is added at 5-10° C., under cooling. The product slowly crystallizes. The mixture is stirred for 1 hour at 0-10° C., then the crystals are filtered off, washed with 2×10 ml of acetone and dried. Weight: 26.7 g (theoretical: 30.8 g ) Yield: 86.6%, mp.: 138-140° C. (literature mp: 130-140° C.). The product was identified by elemental analysis, IR spectrum, 1H-NMR investigation and melting point determination.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:19][C:20](=[O:22])[CH3:21])[NH:14][C:15](=O)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>O1CCOCC1>[Cl:34][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:19][C:20](=[O:22])[CH3:21])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 80 °C
Yield: 52.6 %

Procedure:
To a suspension of N-[6-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-pyrido[3,2-d]pyrimidin-2-yl]-acetamide (0.77 g, 2.58 mmol) and DIEA (1.34 mL, 7.74 mmol) in dioxane (25 mL) was added POCl3 (0.73 mL, 7.74 mmol). The mixture was heated to 80° C. for 30 minutes. After the removal of solvent, the residue was dissolved in ethyl acetate (200 mL) and the solution was filtered through a short column with silica gel. The column was additionally washed with ethyl acetate. The filtrate and washings were combined and concentrated. The precipitate formed was isolated by filtration to give the pure title compound as a brown solid (0.43 g, yield 43%) which was characterised as follows: MS (m/z) 317.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc2ccc(Oc3cccnc3)nc2n1
Temperature: 4 °C
Yield: 8.8 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.9 g), 3-hydroxypyridine (38 g) and potassium hydroxide pellets (11,2 g; 85% purity). The product produced by precipitation in water and extraction with ethyl acetate (4.7 g) is dissolved in boiling ethyl acetate (80 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethyl ether (2×5 cc) and dried in the air at 20° C. 2-Amino-7-(3-pyridyl)oxy-1,8-naphthyridine (2.1 g) is produced, m.p. 178° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([NH2:18])[N:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:25]1([S:31]([Cl:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[ClH:34].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([NH:18][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[N:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCN(c2nc(N)cc3ccccc23)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN(c2nc(NS(=O)(=O)c3ccccc3)cc3ccccc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of 1-(4-methyl-1-piperazinyl)-3-isoquinolinylamine (commercially available; 0.26 g, 1.07 mmol) and pyridine (0.60 mL, 7.51 mmol) in CH2Cl2 (3.0 mL) was added benzenesulfonyl chloride (151 μL, 1.18 mmol) in CH2Cl2 (1 mL). The mixture was stirred at room temperature for 16 hours and left in the refrigerator for 24 hours. The precipitate was collected by filtration to give 0.255 g (57%) of the pure product as the HCl-salt: 1H NMR (DMSO-d6) δ 10.93 (s, 2H), 7.96–7.90 (m, 3H), 7.79–7.75 (m, 1H), 7.64–7.56 (m, 4H), 7.44–7.38 (m, 1H), 7.01 (s, 1 H9, 3.70–3.15 (m, partly obscured by solvent signal, 8H), 2.79 (s, 3H); MS (posEI-DIP) m/z 382 (M+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][OH:32])[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[C:33](Cl)(=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].O>C1(C)C=CC=CC=1>[C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCOC1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Reactant: CCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC1O[C@H](COC(=O)CCCCCCC)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Temperature: 92.5 °C
Yield: 70.4 %

Procedure:
9.5 g of (e) and 5 g of octanoyl chloride in 150 ml of toluene was heated under reflux at 90-95° C. for 4 h. After cooling, the reaction mixture was poured into 600 ml of water and extracted with toluene. The organic phases were combined, washed with NaHCO3 then with water. Finally, after drying and evaporating off the solvents, the crude product was purified over silica to recover 8.6 g of (f) (Yield: 70%).
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][CH:7]([CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[C:8](OCC)=[O:9])(=[O:5])[CH3:4]>C(O)C.O>[OH:9][CH2:8][CH:7]([NH:6][C:3](=[O:5])[CH3:4])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)C(Cc1cnccn1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)NC(CO)Cc1cnccn1
Temperature: 20 °C
Reaction time: 18 h
Yield: 157.3 %

Procedure:
2.8 g of sodium borohydride are added to a solution of 8.5 g of ethyl (2RS)-2-acetylamino-3-(2-pyrazinyl)propanoate in 100 cm3 of ethanol and the mixture is then stirred at a temperature in the region of 20° C. After 18 hours, the reaction medium is taken up in 50 cm3 of water and 100 cm3 of dichloromethane and the aqueous phase is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. 11 g of N-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)-ethyl]acetamide are obtained in the form of a brown paste [1H NMR spectrum (300 MHz, (CD3)2SO-d6 with addition of a few drops of CD3COOD-d4 δ in ppm): 1.71 (s: 3H); 2.81 (dd, J=14.5 and 9 Hz: 1H); 3.03 (dd, J=14.5 and 5 Hz: 1H); 3.35 (dd, J=11 and 6 Hz); 3.42 (dd, J=11 and 5 Hz: 1H); 4.11 (mt: 1H); 7.75 (residual d, J=8.5 Hz: 0.5H); 8.45 (d, J=2.5 Hz: 1H); 8.50 (broad s: 1H); 8.53 (mt: 1H)]).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10]N)[CH:7]=[CH:8][CH:9]=1.[C:12]([S:16][CH2:17][C:18](=O)[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23]C)=[O:22])([CH3:15])([CH3:14])[CH3:13].[C:28](O)(C)(C)C>>[CH3:28][CH:19]([C:18]1[NH:10][C:6]2[C:7]([C:17]=1[S:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[C:20]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C)O
Reactant: COc1cccc(NN)c1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Agent: Cl
Product: COc1ccc2c(SC(C)(C)C)c(C(C)C(C)(C)C(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4.2 g of 3-methoxyphenylhydrazine hydrochloride and 4.9 g of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in 100 mL of t-butanol was refluxed for 18 hours. The mixture was cooled to R.T., and evaporated to dryness. The residue was suspended in ether (150 ml) and stirred for 30 min. The salts were filtered and the filtrate evaporated to dryness to give a residue which was chromatographed on flash silica gel using as eluant ethyl acetate:toluene (1:99) to isolate the title compound as the most polar product; m.p. 133° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:29]=[O:30])[CH:8]=2)[S:3]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C=O)cc32)cc1
Temperature: -10 °C
Reaction time: 5 h

Procedure:
To a cold (−78° C.) solution of 2,2-dimethyl-4(tol-4-yl)-6-bromo-thiochrom-3-ene (Compound N, 280 mg, 0.81 mmol) in THF (5 mL) was added n-BuLi in hexane (1.6 M solution, 0.66 mL). The mixture was gradually warmed to −10° C. over 25 min. and recooled to −78° C. To this solution was added DMF (80 mg, 1.1 mmol) and stirred at ambient temperature for 5 hours. The reaction was quenched by adding water (10 mL), ethyl acetate (100 mL), and the organic layer was washed with brine (10 mL), dried and the solvent removed by distillation. The crude material was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].NC1C=CC=CC=1>O.O1CCOCC1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Nc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)ccc2C(=O)O)cc1
Yield: 81.3 %

Procedure:
2-Amino-4-fluorobenzoic acid (25 g 161 mmol) was added to a solution of sodium bicarbonate (54.1 g, 645 mmol) in water (2.4 L) at room temperature and was stirred until homogeneous. The resultant solution was heated to 60° C. in an oil bath. 4-tert-Butylbenzenesulfonyl chloride (45.0 g 193 mmol), dissolved in 200 mL p-dioxane, was subsequently added dropwise to the stirring aniline solution in a steady stream over a 30 min period. The reaction mixture was stirred at 60° C. overnight. The following day, upon LCMS verification of consumption of the aniline, the solution was poured in a slow stream into one liter of rapidly stirring 2 M HCl/H2O. The resultant precipitate was collected by vacuum filtration, washed thoroughly with water, and dried in vacuo to afford 46 g of 2-(4-tert-butyl-benzenesulfonylamino)-4-fluoro-benzoic acid as an off-white solid (82% yield): HPLC retention time=2.68; MS (ES) M+H expected 352.0, found 352.0.
Reaction SMILES: C(O)(=O)C.C(O)C.[NH2:8][C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:52])[C@@H:21]([CH2:38][CH2:39][CH2:40][NH:41]C(OCC2C=CC=CC=2)=O)[NH:22][C:23](=[O:37])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:14][CH:13]=1)=[O:10].C>[Pd].CO>[NH2:8][C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:52])[C@@H:21]([CH2:38][CH2:39][CH2:40][NH2:41])[NH:22][C:23](=[O:37])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:14][CH:13]=1)=[O:10]
Reactant: NC(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)NCc1ccc(CC(N)=O)cc1
Yield: 82 %

Procedure:
Prepared analogously to Example 1d) but using a mixture of glacial acetic acid and ethanol (1/1, v/v) as solvent instead of methanol, from (R)-N-[[4-(aminocarbonylmethyl)phenyl]methyl]-N2 -(diphenylacetyl)-N5 -(phenylmethoxycarbonyl)-ornithinamide by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 82% of theory. Colourless amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=CC(C2CCN(C)CC2)=CC=1.Br[C:30]1[CH:31]=[C:32]2C(=C[CH:39]=1)[C:36](=[O:40])NC(=O)[C:33]2=[CH:42][NH:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2CC(C)NC(C)C2)=[CH:46][CH:45]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:40][CH3:36].[CH3:39][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:42][N:43]1[C:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=1
Reactant: CN1CCC(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CC1CCCCN1c1ccc(N)cc1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (24), 1.17 g (62.6% yield) of yellow solid is obtained from 1.2 g (4.25 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 0.97 g (5.10 mmol) of [4-(methylpiperidin-1-yl)phenyl]amine: mp 217-218° C.; MS (ESI) m/z 440.1-442.1 (M+H)+1