Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][C@H:6]1[C:11]([O:12][CH3:13])=N[C@H](C(C)C)C(OC)=[N:7]1.[ClH:23].[OH-:24].[Na+]>C(#N)C>[ClH:23].[NH2:7][C@@H:6]([CH2:5][C:4]1[CH:19]=[C:20]([F:22])[CH:21]=[C:2]([Br:1])[CH:3]=1)[C:11]([O:12][CH3:13])=[O:24]
Reactant: [OH-]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](N)Cc1cc(F)cc(Br)c1
Reaction time: 2 h
Yield: 70 %

Procedure:
A stirred solution of (2S,5R)-2-(3-bromo-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.21 g, 3.27 mmol) in acetonitrile (15 mL) was treated with 0.3 N aqueous HCl (15 mL). The reaction was stirred for 2 h and then neutralized with the addition of 1N aq. NaOH. The acetonitrile was removed in vacuo and the solution was extracted with EtOAc. The organics were combined, dried over sodium sulfate, and removed in vacuo to provide (S)-methyl 2-amino-3-(3-bromo-5-fluorophenyl)propanoate hydrochloride (720 mg, 70%). MS (m/z) 276 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[BrH:14].[N:1]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH:8]=[CH:7]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Nc1cccc2ccc(=O)[nH]c12
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2cccc(N3CCNCC3)c2[nH]1
Reaction time: 10 h
Yield: 17 %

Procedure:
8-Aminocarbostyril (15.47 g, 96.6 mmols) and bis(β-bromoethyl)amine hydrobromide (33 g, 106 mmols) were suspended in DMF and the suspension was stirred at 70° to 80° C. for 10 hours. After adding 5.1 g of sodium carbonate the reaction mixture was stirred at the same temperature as above for 7 hours. After distilling off the solvent under reduced pressure, methanol was added to the residue to crystallize. The crude crystals thus obtained were recrystallized from methanol-ether to give 5.1 g of 8-(1-piperazinyl)carbostyril hydrobromide, m.p. above 300° C., colorless scales.
Reaction SMILES: Cl.[CH:2]1([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:16](=O)([O:22]C(C)(C)C)[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:18]([O:17][C:16]([N:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:9][CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C(O)CCNCCC1CCCCC1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCC(=O)O)CCC1CCCCC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Next, tetrahydrofuran (8 ml) was added to 3-[N-(2-cyclohexylethyl)amino]propionic acid hydrochloride (1.0 g, 4.2 mmol), and the mixture was stirred at room temperature. Di-t-butyl carbonate (1.1 g, 5.1 mmol) and triethylamine (1.3 ml, 9.3 mmol) were added to the mixture, the whole was stirred overnight, and then a 5% aqueous citric acid solution (10 ml) was added to the reaction mixture. The whole was extracted with chloroform (60 ml), and the organic layer was washed with saturated brine (20 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 0.79 g (62%) of 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionic acid as a colorless oily matter.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][O:7][CH2:8][C@@H:9]([C:21]([OH:23])=O)[NH:10]C(OCC1C=CC=CC=1)=O)=[NH:3].[CH3:24][S:25]([Cl:28])(=[O:27])=[O:26].[S:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>>[ClH:28].[NH:3]=[C:2]([NH:4][CH2:5][CH2:6][O:7][CH2:8][C@@H:9]([C:21]([N:31]1[CH2:32][CH2:33][S:29][CH2:30]1)=[O:23])[NH2:10])[NH:1][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: N=C(N)NCCOC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CSCN1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NC(=N)NCCOC[C@H](N)C(=O)N1CCSC1
Product: Cl

Procedure:
Starting from (S)-3-(2-{[amino-(imino)-methyl]-amino}-ethoxy)-N-(benzyloxycarbonyl)-alanine, methanesulphonyl chloride and 1,3-thiazolidine, the expected product is obtained according to the procedure described in Example 36.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.424 g. of pelargonic acid chloride as in Example 1. The 0.722 g. of yellow crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.617 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl nonanoate obtained melts at 43.2°-43.6° and has a clearing point of 74.0°. The compound is smectic up to 61.3°. UV (EtOH): ε272 = 26,900.
Reaction SMILES: SC1C=C2C(=CC=1)NC(=O)C2.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2.[Cl:23][S:24](O)(=[O:26])=[O:25]>>[Cl:23][S:24]([C:21]1[C:13]([CH3:12])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:22])[CH2:15]2)(=[O:26])=[O:25]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cccc2c1CC(=O)N2
Agent: O=C1Cc2cc(S)ccc2N1
Product: Cc1c(S(=O)(=O)Cl)ccc2c1CC(=O)N2

Procedure:
Under reaction conditions analogous to preparation of 5-mercaptooxindole, chlorosulfonylation of 4-methyloxindole 3.15 g (21.40 mmol) with neat chlorosulfonic acid 25 mL provided 4.55 g of 5-chlorosulfonyl-4-methyloxindole (86.5% Y, 95% isomeric purity by 1H-NMR, in d6-acetone) which was reduced with triphenyl phosphine 17.0 g (65 mmol) in anhydrous dichloromethane, to provide a crude thiol 2.573 g (75% Y) which was then methylated with excess of methyl iodide (1.50 mL; 24 mmol) to provide a crude methylthio intermediate 2.722 g (98% Y, 90% pure), by using conditions analogous to preparation of 5-methylsulfoxyoxindole.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19]([O-])([O-])=O.[Na+].[Na+].IC>CN(C=O)C>[CH3:19][N:5]1[C:6]2[C:11](=[CH:10][C:9]([CH3:12])=[N:8][C:7]=2[CH3:13])[C:2](=[O:1])[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]1
Reactant: CCOC(=O)c1cnc2c(C)nc(C)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2c(C)nc(C)cc2c1=O
Temperature: 25 °C
Yield: 20.6 %

Procedure:
Ethyl 4-hydroxy-6,8-dimethyl-1,7-naphthyridine-3-carboxylate (Preparation 47, 460 mg) is dissolved in DMF (30 mL) and treated with Na2CO3 (396 mg). Iodomethane (0.3 mL) is slowly added to the mixture, and it is then heated to reflux for 1 h. The reaction mixture is cooled to room temperature, quenched with water (20 mL) and extracted with CH2Cl2 (50 mL). The organic layer is separated, dried (MgSO4), and to concentrated in vacuo. The residue is purified by silica gel column chromatography (5% methanol/CH2Cl2) to give 100 mg (21%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 261 (M+H)+; 1H NMR (DMSO) δ8.61, 7.78, 4.23, 4.18, 3.00, 2.56, 1.28.
Reaction SMILES: O[Li].O.C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([Cl:25])[C:21]([Cl:24])=[C:22]([Br:23])[C:16]=3[N:15]=2)[CH:13]=1)=[O:8])C.C1COCC1>O>[Br:23][C:22]1[C:16]2[N:15]=[C:14]([N:12]3[CH:13]=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]3)[NH:18][C:17]=2[CH:19]=[C:20]([Cl:25])[C:21]=1[Cl:24]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
LiOH.H2O (0.046 g, 1.09 mmol) was added to a mixture of 1-(4-Bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.088 g, 0.22 mmol), THF (1 mL), and water (0.33 mL), and the mixture was stirred 18 h at 23° C. The solvent was evaporated, water (3 mL) was added and the mixture acidified with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (0.068 g, 83%). MS (ESI/CI): mass calcd. for C11H6BrCl2N4O2, 374.9; m/z found, 375.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.89 (s, 1H), 8.32 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[N:6][CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ncc(Cl)cc1O
Temperature: 25 °C
Yield: 74 %

Procedure:
5-Chloro-3-pyridinol (382 mmol) is dissolved in concentrated H2SO4 (375 ml). At 5° C. concentrated nitric acid (25 ml) is added. The reaction is allowed to warm to room temperature over 3 hours. The reaction solution is pored onto ice water (5000 ml). The precipitate is filtered, washed with water and dried over night at 40° C. in vacuo. 5-Chloro-2-nitro-pyridine-3-ol is obtained as yellow powder in a yield of 74%. Mp.: 97° C.; LC-MS (Method B): 1.35 min, 175.1 (MH+).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])[CH2:10][CH:9]=2)=[CH:4][C:3]=1[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.[O:34]1CCOCC1.Cl>O>[CH3:25][C:17]1([CH3:26])[O:16][C:15](=[O:27])[N:14]([CH:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:4]=[C:3]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:2](=[O:34])[NH:7][CH:6]=3)=[CH:9][CH2:10]2)[C@H:18]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)N(C2CC=C(c3cnc(F)c(-c4ncccn4)c3)CC2)[C@H]1c1ccccc1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: CC1(C)OC(=O)N(C2CC=C(c3c[nH]c(=O)c(-c4ncccn4)c3)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A resealable tube was charged with (4S)-3-(4-(6-fluoro-5-(pyrimidin-2-yl)pyridin-3-yl)cyclohex-3-en-1-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (See Step 1 in the synthesis of Examples 72 and 73)(50 mg, 0.112 mmol, 50% ee), dioxane (2.647 mL), and water (882 μL). Concentrated HCl (37%) (221 μL) was added, the system was flushed with argon, and the tube was sealed. The reaction mixture was then stirred at 100° C. for 2 hours. LC-MS indicated a clean and complete reaction. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The organic phase was concentrated under reduced pressure. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% MeOH in DCM. The resulting product was then washed with 10% ammonium hydroxide in MeOH. The solution was concentrated under reduced pressure providing (4S)-5,5-dimethyl-3-(4-(6-oxo-5-(pyrimidin-2-yl)-1,6-dihydropyridin-3-yl)cyclohex-3-en-1-yl)-4-phenyloxazolidin-2-one (44 mg, 0.099 mmol, 88% yield, 50% ee) as yellow solid. m/z (ESI) 443.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([Cl:24])[C:15]=1[N+:25]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[ClH:24].[NH2:25][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Product: Cl
Reaction time: 24 h
Yield: 75.4 %

Procedure:
2.50 g (6.33 mmol) of 4-[4-(tert-Butoxycarbonylamino)butylamino]-2-chloro-3-nitroquinoline was dissolved in 65 ml of methanol and 1 g of 10% palladium-carbon was added thereto. The mixture was stirred for one day under hydrogen atomosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1 (v/v)). Finally, the resulting product was triturated with diethyl ether and collected by filtration to obtain 1.75 g (4.77 mmol) of 3-amino-4-[4-(tert-butoxycarbonylamino)butylamino]quinoline hydrochloride shown below as a yellow solid. ##STR57## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3340, 2970, 1690, 1590, 1530, 1170.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]([NH:27][NH2:28])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[CH2:17]([O:24][C:25]([NH:27][NH:28][C:9]([C:8]1[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Reactant: NNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NNC(=O)OCc2ccccc2)cc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (2.00 g, 9.04 mmol), hydrazinecarboxylic acid benzyl ester (1.50 g, 9.04 mmol) and DIPEA (2.34 g, 18.1 mmol) in DCM (40 mL), TBTU (3.19 g, 9.94 mmol) is added. The mixture is stirred at rt for 2 h before it is diluted with EA (250 mL), washed twice with sat. aq. NaHCO3 solution (150 mL) followed by brine (100 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give N′-(2-cyclopentyl-6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g) as pale yellow oil; LC-MS**: tR=0.74 min, [M+1]+=369.69; 1H NMR (D6-DMSO): δ 1.62-1.83 (m, 6H), 1.95-2.05 (m, 2H), 3.10-3.21 (m, 1H), 3.88 (s, 3H), 5.13 (s, 2H), 6.97 (s, 1H), 7.23 (s, 1H), 7.28-7.40 (m, 5H), 9.45 (s, 1H), 10.52 (s, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][N:4]=[CH:3]1.S(Cl)([Cl:13])=O.C(OCC)C.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:13].[NH:4]1[CH2:5][CH:6]([C:8]([O:10][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:9])[CH2:7][N:2]=[CH:3]1
Reactant: O=C(O)C1CN=CNC1
Reactant: OCc1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1CN=CNC1
Temperature: 80 °C
Yield: 76 %

Procedure:
1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride (1.0 g, 6.1 mmol) was suspended in dry benzyl alcohol (20 ml). To the mixture was added thionyl chloride (0.76 g, 6.39 mmol) and the resulting mixture was heated in an oil bath at 80° C. for 24h. The clear solution was poured to anhydrous ethyl ether (100 ml) to induce precipitation. The white solids were collected and crystallized from methanol/THF to give 1.18 g (76%) of product (mp 113°-114° C.). 300 MHz nmr indicated the product. Microanalysis calc.: C 56.58, H 5.89, N 11.00; found: C 56.34, H 6.03, N 11.19.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([O:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COCCCCO
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(Cl)ncn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCCCCOc1cc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)ncn1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
50 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-(4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl)-ethanone and 53 mg 4-methoxy-1-butanol were added to 14 mg potassiumcarbonate in 2 mL n-methyl-2-pyrrolidinone. The reaction was sonicated for a few minutes and stirred 30 min at 200° C. The reaction was purified by HPLC to give 29 mg desired product. Rt: 1.82 min (method N), (M+H)+: 564
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[C:7](Cl)=[N:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30]>C(O)(C)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:8]2[C:7]([O:30][CH:25]([CH3:26])[CH3:24])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[OH:30])=[O:12])=[CH:16][CH:15]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: CC(C)O
Product: CC(C)Oc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 43, using 5-bromo-6-chloro-nicotinic acid methyl ester, 4-chlorophenyl-boronic acid (commercially available), isopropanol (commercially available), and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials. MS (ISP): 389.3, 391.4 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]([NH2:5])[CH3:4].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C([O-])(=[O:14])C.[Na+]>O>[CH3:1][CH:2]([CH3:6])[CH:3]([NH:5][C:8](=[O:7])[CH2:9][C:10](=[O:14])[CH3:11])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)C(C)N
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)CC(=O)NC(C)C(C)C
Temperature: 25 °C

Procedure:
To a mixture of 3-methylbutan-2-amine (1.00 g), 2,2,6-trimethyl-4H-1,3-didioxin-4-one (2.12 g) and tetrahydrofuran (3.0 mL) was added sodium acetate (941 mg) at room temperature. The reaction mixture was refluxed overnight, and cooled to room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.46 g).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:9]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCOCC2)C1
Yield: 62 %

Procedure:
The subtitle compound was prepared by the method of Example 5(e) with (R/S)-1-Boc-pyrrolidine-3-caboxylic acid [MacLeod et al J. Med. Chem, 33, 2052 (1990)] and morpholine. The subtitle compound (62%) was obtained as an oil. Rf 0.69 (CH2Cl2/MeOH 95/5, v/v). MS m/z 285 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH:6]=1.C([O:9][CH:10]=[C:11]([C:17]#[N:18])[C:12](OCC)=O)C>C(O)C>[C:17]([C:11]1[C:10](=[O:9])[N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[N:1][CH:12]=1)#[N:18]
Reactant: NC1=CCCN1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: N#Cc1cnc2n(c1=O)CCC2
Temperature: 25 °C
Yield: 42.5 %

Procedure:
16.8 g. of 2-amino-pyrroline are dissolved in 140 ml. of ethanol and the solution is cooled to -5° C. and under stirring added dropwise to a solution of 33.8 g. of ethyl ethoxy-methylene-cyanoacetate in 250 ml. of ethanol. The reaction mixture is allowed to warm up to room temperature, and boiled for an hour. The reaction is then allowed to crystallize under cooling below 0° C. The precipitated crystals are filtered and thus 13.7 g. (42.5%) of 3-cyano-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine are obtained, melting at 119°-121° C. after recrystallization from ethanol.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Br:33])[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:10][C:6]1[NH:29][N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:32]([Br:33])=[C:24]([Br:23])[CH:25]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(Br)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Br)c(Br)c2)[nH]1
Reaction time: 8 h

Procedure:
12.2 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 1 g of p-toluenesulphonic acid were dissolved in 200 ml of ethanol. A solution of 21.6 g of 3,4-dibromobenzylhydrazine in 50 ml of ethanol was added dropwise thereto, under nitrogen. After stirring overnight, the solvent was concentrated in vacuo and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 182°, 11 g (41%).
Reaction SMILES: N#N.Br[C:4]1[N:9]=[C:8]([C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][C:11]=2[CH3:16])[CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[CH2:22]([N:29]1[CH2:35][CH:34]2[C:36](=[O:37])[CH:31]([CH2:32][CH2:33]2)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O1CCCC1>[CH3:16][C:11]1[NH:12][C:13]([CH3:15])=[CH:14][C:10]=1[C:8]1[N:9]=[C:4]([C:40]2[CH:39]=[CH:38][C:43]([C:36]3([OH:37])[CH:34]4[CH2:33][CH2:32][CH:31]3[CH2:30][N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:35]4)=[CH:42][CH:41]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Reactant: CCCCCC
Reactant: Cc1cc(-c2cccc(Br)n2)c(C)[nH]1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(-c3ccc(C4(O)C5CCC4CN(Cc4ccccc4)C5)cc3)n2)c(C)[nH]1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a 125 mL 3-necked round-bottomed flask equipped with septum and N2 inlet were added 1.86 g (5.70 mmol) 6-bromo-2-(2,5-dimethylpyrrolyl)-pyridine and 40 mL dry tetrahydrofuran. The solution was cooled to −60° C., and 2.73 mL (6.84 mmol) of a 2.5M solution of butyl lithium in hexane was added dropwise and the solution stirred 10 min at −60° C. Then a solution of 1.47 g (6.84 mmol) 3-benyl-3-aza-bicyclo[3.2.1]octan-8-one in 15 mL dry tetrahydrofuran was added dropwise, and the reaction stirred at −60° C. for 10 minutes, and then at room temperature for 3 hours. The reaction was quenched with aqueous ammonium chloride solution and taken up in ethyl acetate. The organic layer was separated and washed with more aqueous ammonium chloride solution and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol and methylene chloride to afford 413 mg (16%) of a yellow oil which solidified, mp 58-68° C.