Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1.Cl[C:22]1[N:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[CH:24][N:23]=1.O>CN(C1C=CN=CC=1)C.CS(C)=O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[N:27][C:22]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=3)[C:8]([CH3:7])=[CH:9]2)=[N:23][CH:24]=1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: Fc1ccccc1-c1cnc(Cl)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(C)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (1.61 g, 11.6 mmol) and DMAP (0.18 g, 1.45 mmol) were added to a solution of methyl 3-methyl-1H-indole-6-carboxylate (1.1 g, 5.81 mmol) and 2-chloro-5-(2-fluorophenyl)-pyrimidine (1.21 g, 5.81 mmol) in dry DMSO (10 mL). The solution was stirred at 100° C. for 1 h, then cooled to room temperature and slowly poured into vigorously stirred water (100 mL). The precipitating solid was filtered off, washed with water and dried in vacuum. Light-brown solid. Yield: 1.89 g (80% chemical purity). HPLC-MS: m/z [M+H]+=362.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=3[CH3:49])[C:43]([OH:45])=[O:44])[CH:38]=2)[O:33][C:32]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1.C[CH2:58][O:59][C:60](C)=[O:61]>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:56][C:53]1[CH:54]=[CH:55][C:50]([C:32]2[O:33][C:34]3=[N:35][CH:36]=[C:37]([C:40]4[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=4[CH3:49])[C:43]([OH:45])=[O:44])[CH:38]=[C:39]3[C:31]=2[C:60]([O:59][CH3:58])=[O:61])=[CH:51][CH:52]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1cnc2oc(-c3ccc(F)cc3)c(Br)c2c1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)O)ccc3C)cc12
Reaction time: 8 h
Yield: 67 %

Procedure:
1,3-bis(diphenylphosphino)propane (160 mg, 0.387 mmol) was added to a stirring solution of palladium(II) acetate (44 mg, 0.19 mmol) and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (275 mg, 0.645 mmol) in MeOH (2.1 mL) and DMSO (4.3 mL) at 80° C. in a Parr bomb which was charged with 150 psi CO (g) and allowed to stir overnight. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the expected product 3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (176 mg, 0.434 mmol, 67% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (1H, br. s.), 8.42 (1H, d, J=2.01 Hz), 8.34 (1H, d, J=2.01 Hz), 8.14-8.21 (2H, m), 7.93 (1H, dd, J=8.03, 1.76 Hz), 7.84 (1H, d, J=1.76 Hz), 7.45-7.53 (3H, m), 3.89 (3H, s), 2.32 (3H, s). LC-MS retention time: 2.16 min; m/z (MH+): 406. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N+:18]2[O-])=[CH:13][CH:12]=1)=[O:10])[CH3:7].O.[OH-].[K+]>ClCCl>[Cl:3][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])=[CH:12][CH:13]=2)[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc2ccc(Cl)nc2c1
Temperature: 50 °C
Yield: 52.1 %

Procedure:
Phosphorus oxychloride (1.94 mL, 20.7 mmol) was added to a solution of 7-(ethoxycarbonyl)quinoline 1-oxide (450 mg, 2.07 mmol) in dichloromethane (15 mL). The reaction was heated to 50° C. for 3 hours. The reaction was then cooled to room temperature and was slowly poured into 200 mL of water, with stirring. The mixture was allowed to stir for 1 hour and was then neutralized with 1 N aqueous potassium hydroxide. The mixture was extracted with dichloromethane (3×). The extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography (0-20% ethyl acetate/heptanes) gave the title compound (254 mg, 52%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.70-8.79 (m, 1H), 8.13-8.18 (m, 2H), 7.87 (d, J=8.39 Hz, 1H), 7.47 (d, J=8.58 Hz, 1H), 4.44 (q, J=7.02 Hz, 2H), 1.43 (t, J=7.12 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:23])[CH2:4]2)[O:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH2:25]1[CH2:1][O:2][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:23])[CH2:4]2)[O:24]1
Reactant: C[C@H]1CC2(CC3=CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H]1CC2(CC3=CC[C@@H]4[C@H](CC[C@]5(C)C(=O)CC[C@@H]45)[C@]31C)OCCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
3.6 g of 3,3-ethylenedioxy-1α-methyl-5-androsten-17β-ol is dissolved in 100 ml of dichloromethane, combined with 5.8 g of pyridinium dichromate, and agitated for 20 hours at room temperature. The reaction solution is washed with water, dried, and evaporated under vacuum. The residue is chromatographed on silica gel, thus obtaining with hexane-ethyl acetate gradients (11-16% ethyl acetate) 2.81 g of 3,3-ethylenedioxy-1α-methyl-5-androsten-17-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccc(F)cc4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(4-fluorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([CH2:16][C:17]([NH:19][C:20]2[S:24][C:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C:22]=3[C:21]=2[C:29]([NH2:31])=[O:30])=[O:18])[N:10]=1)([CH3:8])([CH3:7])[CH3:6].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[C:5]([C:9]1[C:13]([CH2:14][NH:4][CH2:3][CH2:1][OH:2])=[CH:12][N:11]([CH2:16][C:17]([NH:19][C:20]2[S:24][C:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C:22]=3[C:21]=2[C:29]([NH2:31])=[O:30])=[O:18])[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1CNCCO
Reaction time: 1 h
Yield: 40.8 %

Procedure:
Ethanolamine (189 mg, 0.186 mL, 3.09 mmol) was added to a solution of 2-(2-(3-tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (120 mg, 0.309 mmol) and acetic acid (0.5 mL, 8.7 mmol) in DMF (3 mL) and stirred for 1 h. Sodium triacetoxyborohydride (655 mg, 3.09 mmol) was added and the mixture stirred for 17 h at ambient temperature. Water (500 μL) was added and the mixture stirred for 30 min. The mixture was filtered and purified by preparative reverse phase HPLC. The clean fractions were passed down an SCX cartridge and the free base eluted with 2M NH3 in MeOH. Volatiles were blown down under a nitrogen atmosphere to yield the title compound (54.8 mg, 0.126 mmol, 41%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[N:6][C:5]=1Cl.C[O-].[Na+].[C:17](O)(=[O:19])C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:11])=[N:6][C:5]=1[O:19][CH3:17]
Reactant: CC(=O)O
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C)cc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 6.50 g (29.5 mmol) of 2,6-dichloro-4-methyl-nicotinic acid methyl ester in 75 ml of CH2Cl2 was added at 0° C. 6.56 ml (35.4 mmol) of a sodium methoxide solution (5.4 molar in MeOH). After 16 hours, the reaction mixture was warmed up to RT and stirred again 16 hours at this temperature and subsequently poured into crashed ice; then, the pH was adjusted to 4-5 with 2N acetic acid and the reaction mixture was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 1.0 to 98:2) to give 5.79 g (91%) of the title compound as colorless solid. MS: 216.1 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=2[C:5]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:8]1[N:7]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2[C:5]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 25 °C
Yield: 34 %

Procedure:
The solution of ethyl 4-[4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate (6.8 g, 19.32 mmol) in phosphorus oxychloride (70 mL) was stirred at 100-110° C. for 2 days. After cooled to room temperature, the excess phosphorus oxychloride was removed by distillation and the residue was poured into water. The aqueous phase was extracted with ethyl acetate (100 mL×3) and the combined extracts were washed with saturated aqueous sodium bicarbonate (100 mL×2) and water (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether/ethyl acetate, 50/1) to afford the title compound (2.4 g, 34%) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=[O:39])[CH:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])C(OC(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].FC(F)(F)C(O)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14](=[O:39])[CH2:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CCCCCCCCCCCCCCCCC(C(=O)OC(C)(C)C)C(=O)c1ccc(C(=O)OC(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
335 mg of product from Example 9 was dissolved in 10 ml of methylene chloride and 10 ml of trifluroacetic acid was added. The reaction mixture was stirred at room temperature for 1.5 hours and added to 20 ml of water. The organic layer was separated and dried over sodium sulfate. The solvent was removed using a rotary evaporator to give 270 mg of the titled product.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[Cl:25])[C:5](OCC)=[O:6])(=O)[CH3:2].[NH2:26][NH:27]C(N)=S.C[O-].[Na+]>CO>[Cl:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[C:5]([OH:6])=[N:26][NH:27][C:1]=1[CH3:2]
Reactant: CCOC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Reactant: NNC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCCCCCCc2c(O)n[nH]c2C)c(Cl)c1
Yield: 55.2 %

Procedure:
A mixture of 11.1 g (0.03 m) of ethyl 2-acetyl-8-(2-chloro-4-methoxyphenoxy)octanoate, 2.73 g (0.03 m) of thiosemicarbazide and 1.62 g (0.03 m) of sodium methoxide in 15 ml of methanol was heated at reflux for 24 hours. The solid product was collected, washed with 50% aqueous ethanol and recrystallized from ethanol to give 5.6 g of 4-[6-(2-chloro-4-methoxyphenoxy)-hexyl]-5-methyl-1H-pyrazol-3-ol, m.p. 145°-146° C.; MIC=6 microg/ml (herpes 2). (During this reaction the thiocarbamyl group (CSNH2) of the thiosemicarbazide was cleaved so that the reaction product is the same as that obtained when unsubstituted hydrazine is used.)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[NH:15][CH2:14][C@H:13]([NH:16][O:17][CH2:18][CH:19]=[CH2:20])[CH:12]=[C:11]1[CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:31](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:32]>C(#N)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11]([CH3:21])=[CH:12][C@@H:13]2[CH2:14][N:15]1[C:31](=[O:32])[N:16]2[O:17][CH2:18][CH:19]=[CH2:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: -15 °C
Reaction time: 3 h
Yield: 117.9 %

Procedure:
Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (3R,6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-N-(prop-2-en-1-yloxy)-1,2,3,6-tetrahydropyridin-3-amine (Intermediate 147, 8.4 g, 26.88 mmol, 1.00 equiv) in acetonitrile (1600 mL), N,N-Diisopropylethylamine (14.2 g, 109.87 mmol, 4.00 equiv). This was followed by the addition of a solution of ditrichloromethyl carbonate (2.9 g, 9.77 mmol, 0.40 equiv) in acetonitrile (100 mL) dropwise with stirring at −15° C. in 3 hr. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 mL of ethyl acetate. The resulting mixture was washed with 2×400 mL of NH4Cl (aq.) and 2×400 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 3.9 g (43%) of the title compound as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([NH2:14])=[O:13])[C:6](=[O:15])[C:5]12SCCS1>[Ni].C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([NH2:14])=[O:13])[C:6](=[O:15])[CH2:5]2
Reactant: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2CC(N)=O
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CC(=O)N2CC(N)=O
Temperature: 25 °C

Procedure:
The Raney Nickel was prepared as an aqueous slurry after removing four fifth of water of the commercial solution. Aqueous Raney nickel (10 ml) was added to a solution of compound 15 (4.06 g, 13.8 mmol) in 40 ml of distilled THF and the mixture was further vigourously stirred at room temperature. When no starting material was detected by thin layer chromatography, the mixture was diluted with THF and filtered through a Celite pad. After removal of the solvent, the crude material was purified by silica gel chromatography (CH2Cl2/MeOH 95/5 then 90/10), and the solvent was evaporated to yield the 2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 24 as a white solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:12]3[C@@H:11]3[CH2:22][CH2:23][CH2:24][N:10]3[C:9](=[O:25])[C:8]=2[C:26]=1[F:27]>C(O)C.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:12]3[C@@H:11]3[CH2:22][CH2:23][CH2:24][N:10]3[C:9](=[O:25])[C:8]=2[C:26]=1[F:27]
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1F
Yield: 98.5 %

Procedure:
20.7 ml (82.7 mmol) of 4N sodium hydroxide solution were added dropwise to a suspension of 22.1 g (63.6 mmol) of ethyl (5)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate in 55 ml of ethanol and 90 ml of water and heated at reflux for 45 minutes. Subsequently, the ethanol was distilled off. The aqueous phase was washed twice with methylene chloride and adjusted to pH=3 with 4N hydrochloric acid. Extraction with methylene chloride (five times), drying with sodium sulfate, filtration and evaporation yielded 20 g (98%) of (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid as colourless crystals of m.p. 214.5°-215.5° (dec.).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=2[N:17]=1.C(N(CC)C(C)C)(C)C>CC#N>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: Clc1cccnc1N1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1
Reaction time: 0.33 h

Procedure:
A mixture of the hydrochloride salt from step (b) above (0.564 g, 2.4 mmol), 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.27 g, 1.22 mmol, Example 1c) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol, Aldrich) in MeCN (1 mL) was subjected to microwave irradiation at 180° C. with stirring for 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexane, to give the title compound as a white solid. M.p. 208-210° C. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:8][CH:7]=1)C.O[Li].O>>[C:25]([O:24][C:22]([NH:21][CH2:20][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C:6]([CH2:5][C:4]([OH:29])=[O:3])=[CH:7][N:8]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)Cc1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12
Agent: [Li]O
Solvent: O
Product: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 84.8 %

Procedure:
[1-(tert-Butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid ethyl ester (338 mg, 0.83 mmol) was hydrolysed with LiOH—H2O (60 mg, 1.4 mmol) according to the procedure outlined in example 1D to give [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid (265 mg, 84%). H1-NMR (DMSO): δ 8.11 (s, 1H), 7.57 (s, 1H), 7.28 (t, 3H, J=5.9 Hz), 7.24 (s, 1H), 4.67 (d, 2H), 3.93 (s, 2H), 3.90 and 3.88 (s, 3H each), 1.37 (s, 9H); MS: APCI (M+H) calc'd for C19H24N2O6+H 377.4; found 377.0.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH3:32])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), methyl iodide (0.19 mL), potassium carbonate (0.41 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 67%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][NH2:14]>>[CH3:13][NH:14][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and methylamine as starting materials to give the aimed compound.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=1[OH:12].O.NN.NN.C1(C(=CC=CC=1)O)O.[Co:31]>O>[Co+2:31].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=1[OH:12]
Reactant: [Co]
Agent: Cc1cc(O)ccc1O
Agent: NN
Agent: Oc1ccccc1O
Solvent: O
Product: [Co+2]

Procedure:
About 0.237 grams (2.15 millimoles) pyrocatechol and 0.288 grams (2.35 millimoles) methylhydroquinone are dissolved in 56 milliliters of distilled water in a 500 ml Erlenmeyer flask. Subsequent additions of 66 ml hydrazine hydrate (64% N2H4 by weight) and of 2.62 ml of an aqueous solution containing 20% CoCl2 · 6H2O (corresponding to 2.2× 10-3 g atom of Co++ion) give a clear, orange-red solution containing approximately 35% hydrazine and 0.6% of catalyst by weight (molar ratio pyrocatechol/cobalt of approximately 1.0).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[N:25][N:24]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:28]([C:26]1[S:27][C:23]([C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[Cl:13])=[N:24][N:25]=1)(=[O:30])=[O:29])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(-c2nnc(S(=O)(=O)Cl)s2)c(Cl)c1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2Cl)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(2-chloro-4-nitrophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.60 (d, 1H), 8.54 (d, 1H), 8.40 (dd, 1H) 4.05 (q, 2H), 3.27 (s, 2H), 3.19 (t, 2H), 2.67 (t, 2H), 1.16 (t, 3H).