Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][NH:5][C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7]>Cl.O1CCOCC1>[O:2]=[CH:3][CH2:4][NH:5][C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7]
Reactant: COC(CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)OC
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC=O)ccc21
Temperature: 50 °C
Yield: 91.4 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-oxo-ethyl)-amide (574 mg) was prepared starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2,2-dimethoxy-ethyl)-amide (700 mg) in 4M HCl-dioxane (3 mL). The reaction was heated to 50° C. for 5 h. The solvent was evaporated to give crude product.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]([CH3:16])([CH3:15])[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=O)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:16])([CH3:15])[CH2:8][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:17][CH:18]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)N1CCCC1
Solvent: C1CCOC1
Product: CC(C)(CN1CCCC1)Oc1ccc(Br)cc1
Yield: 74 %

Procedure:
BH3×THF (1M, 27.0 mmol, 27.0 mL) was added dropwise under argon to 2-(4-bromophenoxy)-2-methyl-1-(pyrrolidin-1-yl)propan-1-one (2.12 g, 6.8 mmol; see step (a)) in THF (40 mL) at 0° C. The reaction was quenched by careful addition of NH4Cl (aq. sat.). The reaction mixture was acidified by HCl (1M). NaOH (aq. 0.5M, 30 mL) was added to the filtrate which was then extracted with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4), concentrated and distilled under reduced pressure to yield the title compound (1.5 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]([NH2:23])=O)=[N:11][N:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]#[N:23])=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C(N)=O)c2c1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#N)c2c1
Yield: 32.7 %

Procedure:
A solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazine-1-carboxylic acid amide (1.06 g, 2.92 mmoles), prepared as described in example 109, in pyridine (80 ml) and trifluoroacetic anhydride (1.65 ml, 11.67 mmoles), under dry N2 at room temperature, was stirred for 3 hours, then dried, taken up in CH2Cl2, washed with citric acid, 5% NaOH and water. The organic phase was anhydrified and dried to give a solid which was flash chromatographed (eluent: CH2Cl2/CH3OH 99:1) to give 0.33 g of the title compound (yield: 33%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]([C:14]1([CH3:22])[CH2:19][CH2:18][CH2:17][CH:16]([NH2:20])[CH:15]1[OH:21])=[O:13].CCN(C(C)C)C(C)C>C1COCC1.CO>[CH3:10][O:11][C:12]([C:14]1([CH3:22])[CH2:19][CH2:18][CH2:17][CH:16]([NH:20][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:15]1[OH:21])=[O:13]
Reactant: COC(=O)C1(C)CCCC(N)C1O
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C)CCCC(Nc2nc(Cl)ncc2F)C1O
Yield: 87 %

Procedure:
To a solution of 2,4-dichloro-5-fluoro-pyrimidine (0.43 g, 2.58 mmol) and racemic methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate acetic acid salt, 66d, (0.58 g, 2.35 mmol) in THF (10 mL) and MeOH (8 mL) at room temperature was added iPr2NEt (1.23 mL, 7.04 mmol). After stirring the reaction overnight at room temperature, the solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100, Rf=0.7 in Hexanes/EtOAc 2/1) to provide 650 mg of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66e, as a white solid. LCMS: 318.16 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:5]([OH:7])=[O:6].[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)[CH2:18][CH:19]=[CH2:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCOCC>[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:6][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[C:2]([F:1])[CH:3]=3)=[CH:33][CH:34]=2)=[CH:23][CH:22]=1)[CH2:18][CH:19]=[CH2:20]
Reactant: CC[C@H](C)COc1ccc(C(=O)O)cc1F
Reactant: C=CCCc1ccc(CCc2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C=CCCc1ccc(CCc2ccc(OC(=O)c3ccc(OC[C@@H](C)CC)c(F)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.2 %

Procedure:
About 4.5 g (0.02 mol) of 3-fluoro-4-[(S)-2-methylbutoxy]benzoic acid (which can be prepared, for example, as described in EP-A 255 962 ), 5.0 g (0.02 mol) of 4-[4-(3-butenyl)phenylethyl]phenol, 4.1 g (0.02 mol) of dicyclohexylcarbodimide and 0.1 g of 4-dimethylaminopyridine were mixed in 40 ml of ether at room temperature. The mixture was first heated to reflux for 4 hours and then stirred at room temperature for 14 hours, and the resulting urea was filtered off. Washing was carried out first with 2N hydrochloric acid and then with NaHCO3 solution, and the ether phase was worked up. Column chromatography on Al2O3 with methyl tert-butyl ether/petroleum ether (1:2) as mobile phase resulted in 4.9 g of [4-[4-(3-butenyl)phenyl]ethylphenyl]-3-fluoro-4-[(S)-2-methylbutoxy]benzoate (yield 53.9%) which showed the following phase behavior: C 77 N* 86 I.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([O:17][CH3:18])[O:15][CH3:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH3:16][O:15][CH:14]([O:17][CH3:18])[C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1ccc(O)cc1
Reactant: COC(OC)c1cccc(-c2ccnc(Cl)n2)c1
Product: COC(OC)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Yield: 35 %

Procedure:
Intermediate 26 was coupled with tyramine following procedure F. The product was purified by flash chromatography using 99:1 CH2Cl2:MeOH as eluent. Yield: 35%. LC-MS showed the product had the expected M+H+ of 366.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([Cl:35])=[CH:37][CH:38]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.33 mmol, 55 μL) and 4-chlorobenzoyl chloride (0.15 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (31 mg) which was characterized by its mass spectrum: MS m/z (%): 497 ([M+H]+, 100).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC(OC)=CC=2)=[CH:19][C:18]=1[C:33]1[S:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][N:37]=1.C1(OC)C=CC=CC=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[C:33]1[S:34][C:35]([C:38]([F:39])([F:40])[F:41])=[N:36][N:37]=1
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(F)(F)F)s3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(F)(F)F)s2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
Trifluoroacetic acid (5.0 mL) was added to 2-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (299 mg) and anisole (0.66 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed 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 (ethyl acetate/hexane) to give the title compound (200 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2]O.C(N(C(C)C)CC)(C)C.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[N:28]=[C:27]([NH:29][C:30]([NH:32]C(OCC)=O)=S)[CH:26]=[C:25](OC)[CH:24]=3)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.[CH2:40]([OH:42])C.CO>>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[N:28]4[N:2]=[C:30]([NH2:32])[N:29]=[C:27]4[CH:26]=[CH:25][C:24]=3[O:42][CH3:40])=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: NO
Reactant: CCO
Reactant: CCOC(=O)NC(=S)Nc1cc(OC)cc(-c2ccc3c(c2)OCCO3)n1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(N)nn2c1-c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture ethanol/methanol (5 mL/5 mL), hydroxylamine hydrochloride (0.47 g, 6.8 mmol) and diisopropylethylamine (0.71 mL, 4.08 mmol) were added successively. The mixture was stirred for 1 hour and 1-[6-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4-methoxy-pyridin-2-yl]-3-carboethoxy-thiourea was added portionwise. The mixture was refluxed for 3 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure, and the resulting solid collected by filtration and washed with water followed by methanol. The solid was used without further purification (0.33 g, 80%). LCMS Method: 2: RT: 2.57 min, MI: 299 [M+1].
Reaction SMILES: [C:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].C1COCC1.Br[CH2:19][C:20]([N:22]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])=[O:21]>CN(C=O)C.CC(C)([O-])C.[K+]>[CH3:34][C:33]([CH3:36])([CH3:35])[CH2:32][N:22]([CH2:23][C:24]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[O:25])[C:20]([CH2:19][N:3]([C:1]#[N:2])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21]
Reactant: CC(C)(C)CN(CC(=O)N1CCOCC1)C(=O)CBr
Reactant: N#CNC(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)CN(CC(=O)N1CCOCC1)C(=O)CN(C#N)C(=O)Cc1ccccc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
To a stirred solution of N-cyano-2-phenyl-acetamide (35 mg, 0.2 mmol) (see Example 1) in DMF (1.25 mL), potassium tert-butoxide (0.22 mL of a 1.0 M THF solution, 0.22 mmol) was added, dropwise at 0° C., under nitrogen. Upon complete addition, the cooling bath was removed and the reaction was stirred for 0.5 h. After this time, the resulting anion was added dropwise to a stirred solution of the above 2-bromo-N-(2,2-dimethyl-propyl)-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide (88 mg, 0.24 mmol) in DMF (1.25 mL) at room temperature, under nitrogen. Upon complete addition, the reaction was stirred at room temperature for 0.5 h, then warmed to 45° C. for 15 h. The reaction was cooled to room temperature and concentrated to dryness. The remaining residue was dissolved in EtOAc and washed with 5% citric acid (aqueous). The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via reverse phase HPLC (C18 column, 20-100% CH3CN/H2O over 20 min at a flow rate of 20 mL/minute, UV detection was at 220 nm). Retention time of the product was 14.7 min. Product-containing fractions were concentrated to give 14 mg (15%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])C(Cl)(Cl)Cl)[NH:5][CH:6]=1.[NH3:13]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:13])=[O:12])[NH:5][CH:6]=1
Reactant: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Reactant: N
Solvent: CC#N
Product: NC(=O)c1cc(Br)c[nH]1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
A mixture of 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloroethanone (CombiBlocks, Inc., San Diego, Calif.; 1.50 g, 5.15 mmol) and ammonia (30 wt. % in water; 4.0 mL, 55.5 mmol) in CH3CN (62.5 mL) was stirred at 23° C. for 45 min. The reaction mixture was then concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/hexanes) furnished 4-bromo-1H-pyrrole-2-carboxamide (885 mg, 4.68 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (1H, br. s.), 7.55 (1H, br. s.), 7.08 (1H, br. s.), 6.95 (1H, dd, J=2.8, 1.7 Hz), 6.84 (1H, dd, J=2.4, 1.7 Hz). 13C NMR (100 MHz, DMSO-d6) δ ppm 161.1, 126.9, 121.2, 112.0, 94.8. m/z (ESL+ve) 188.9/190.9 (M+H)+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a 50 mL three-necked flask containing AlCl3 (4.406 g; 33.05 mmol) under N2, anisole (IVa) (4.467 g; 41.31 mmol) was added in one portion at RT. The reaction was exothermic. To this suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (6.430 g; 27.54 mmol) was added drop wise keeping temperature below 20° C. Then the resulting red suspension was stirred at RT for 3h30. The red thick solution was poured under stirring into a mixture of ice and 1N HCl (100 mL), then the resulting white solid was filtered, and washed with water. The solid was washed with pentane (3×30 mL) and dried under vacuum at RT to give a white powder (m=8.51 g). Purification was performed by crystallization from acetone (30 ml) to give the title compound as a white powder (m=6.113 g) in a 73% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CC1CC1CNC(=O)c1ccc(Cl)nn1
Product: CC1CC1CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-methylcyclopropylmethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (26% yield). 1H NMR (500 MHz, CDCl3) δ 8.06, 7.96, 7.75, 7.65, 7.58, 7.38, 7.01, 4.04-4.10, 3.86-3.93, 3.69-3.83, 3.25-3.42, 1.12, 1.05, 0.71-0.80, 0.64-0.72, 0.39-0.45, 0.25-0.30. MS (ES+) m/z 448 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO>[CH:26]1([O:25][C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([NH:16][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:15])[CH:12]=3)[CH2:7]2)=[O:30])[CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(Cl)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(Cl)cc3C2)c1OC1CCC1
Temperature: 25 °C

Procedure:
2-(2-Cyclobutoxy-3-methyl-benzoylamino)-5-chloro-indan-2-carboxylic acid ethyl ester (261) (370 mg, 0.86 mmol) is dissolved in EtOH (50 mL) and set to stir at RT. To this solution is added 5M KOH (3 ml). The reaction mixture is stirred at RT overnight. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl to pH 2. The resultant mixture is washed with EtOAc (3×100 ml). Organics are combined and washed with brine, then dried over anhydrous Na2SO4 and concentrated in vacuo. The desired product (262) is obtained as white solid (320 mg, 93%).
Reaction SMILES: [N:1]1[CH2:5][CH2:4][CH2:3][C:2]=1[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].[BH4-].[Na+]>CCO>[NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12]
Reactant: N#Cc1cccc(CCC2=NCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc(CCC2CCCN2)c1
Temperature: 0 °C
Yield: 45 %

Procedure:
A flask containing 3-[2-(4,5-Dihydro-3H-pyrrol-2-yl)-ethyl]benzonitrile (0.22 g, 1.11 mmol) and absolute EtOH (10 mL) was stirred under nitrogen at 0° C. To this was added NaBH4 (0.063 g, 1.66 mmol) in one portion and the reaction is warmed to room temperature and stirred 1 h. The reaction is concentrated and the residue diluted with H20 (15 mL). 1 N HCl (15 mL) is added and the solution is washed with ether. The aqueous phase is basified with solid sodium carbonate and extracted with EtOAc (3×25 mL). The combined organic extracts are dried over MgSO4 and concentrated to give the title compound as a yellow oil (0.10 g, 0.50 mmol). 1H NMR (CDCl3, 300 MHz) 7.55-7.30(m, 4H), 4.01, 3.82(two m, 1H), 3.66-3.22(m, 2H), 3.05-2.55(m, 2H), 2.33-1.60(m, 6H).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:13][CH2:14][CH3:15])(=O)C.[C:16]([OH:19])(=O)[CH3:17]>[Pd]>[C:1]([O:9][C@@H:6]1[CH2:7][C@H:2]2[C@H:3]([CH2:4][C:16](=[O:19])[CH2:17]2)[C@H:15]1[CH2:14][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CC(=O)O
Reactant: CCOC(C)=O
Agent: [Pd]
Product: O=C1C[C@H]2C[C@@H](OC(=O)c3ccccc3)[C@H](CO)[C@H]2C1

Procedure:
A solution of 680 mg. of the benzoate prepared according to Reference Example 1(n) in 10 ml. of ethyl acetate and 0.5 ml. of glacial acetic acid is combined with 120 mg. of palladium on charcoal (10%) and shaken for 8 hours under a hydrogen atmosphere. Filtration and evaporation of the solution under vacuum yields 600 mg. of an oily crude product, which is purified by chromatography on silica gel with pentane/ethyl acetate (1+1), and 395 mg. of the pure alcohol as a colorless oil.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]>>[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH2:7])=[O:42])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: COc1ccc(CN2CCN(c3nc(C)c(C(=O)O)s3)C2=O)cc1F
Product: COc1ccc(CN2CCN(c3nc(C)c(C(N)=O)s3)C2=O)cc1F

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 2-(3-(3-fluoro-4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 182-184° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.31 (br, 2H), 7.20-7.07 (m, 3H), 4.37 (s, 2H), 4.03-3.97 (m, 2H), 3.82 (s, 3H), 3.48-3.42 (m, 2H), 2.46 (s, 3H); MS (ES+) m/z 365.2 (M+1).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[NH2:2].[CH3:10][CH:11]([CH2:13][C:14](=O)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]>>[CH3:10][CH:11]([CH2:13][C:14](=[N:2][NH:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: CC(C)CC(=O)CC(C)C
Reactant: NNc1cc(O)ncn1
Product: CC(C)CC(CC(C)C)=NNc1cc(O)ncn1

Procedure:
10.00 g (79.3 mmol) 6-hydrazinopyrimidin-4-ol (CAS-No: 29939-37-5) were transformed in analogy to intermediate example 1c using 2,6-dimethylheptan-4-one to give after working up and purification 8.77 g (44%) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:27]([C:31]([OH:33])=[O:32])([F:30])([F:29])[F:28]>C1(C)C=CC=CC=1>[F:28][C:27]([F:30])([F:29])[C:31]([OH:33])=[O:32].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH2:7][C:6]([OH:26])=[O:5])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NCC(=O)O)cc12

Procedure:
A solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]glycine t-butyl ester (24 mg, 0.06 mmol) in CF3CO2H (0.5 ml) was stirred at 0° C. for 1.5 h. The reaction mixture was diluted with PhMe, evaporated in vacuo, azeotroping with PhMe, and the residue triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]glycine trifluoroacetate (21 mg, 0.05 mmol) as a white solid.
Reaction SMILES: [C:1]1([C:13]2[CH2:17][NH:16][C:15](=[O:18])[C:14]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[Mg].CO.Cl>CCOC(C)=O.O>[C:1]1([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH:14]2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NCC(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1NCC(c2cn3c4c(cccc24)CCC3)C1c1c[nH]c2ccccc12
Temperature: 60 °C

Procedure:
A mixture of 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-1,5-dihydro-pyrrol-2-one (95 mg, 270 μmol), magnesium turnings (1.3 g, 54 mmol) and methanol (15 mL) was heated at 60° C. for 3 h. Water was added to the reaction mixture and the pH adjusted to 1 with concentrated HCl. The mixture was extracted into EtOAc and washed with saturated sodium carbonate solution. The organics were dried (MgSO4), filtered and evaporated to yield a tan solid, which was titurated in hot EtOAc, yielding 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-pyrrolidin-2-one as a white solid (15 mg, 16%, cis/trans: 1/3.7 from 1H NMR). 1H NMR (400 MHz, CD3OD) trans-δ: 7.42 (d, J=7.2 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.06 (m, 1H), 7.00 (s, 1H), 6.95 (s, 1H), 6.93 (m, 1H), 6.82 (m, 2H), 4.14-4.05 (m, 4H), 3.85 (m, 1H), 3.71 (m, 1H), 2.90 (t, J=6.0 Hz, 2H), 2.12 (m, 2H). LCMS: m/e 356.13 [M+H].