Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[CH:11][N:8]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=CCCl
Solvent: CCCCO
Product: Clc1ccc2nccn2n1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 6-chloro-pyridazinamine (5.00 g, 38 mmol) in 1-butanol (5 mL) was treated with chloroacetaldehyde (50% in water, 5.0 mL, 38 mmol) and the tan suspension was refluxed two hours and to give a dark solution. The reaction mixture was cooled to room temperature and the solid was collected by filtration and washed with methanol to afford a brown solid (3.04 g); evaporation of the filtrate gave additional product (4.60 g). The solids were combined (7.64 g) and used in the next reaction without further purification: MS [M+H]+ 154.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 10 mmol morpholine in DMF at room temperature for fourteen hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 50% ethyl acetate and 50% hexane to obtain 1-(2,4-dichlorophenyl)-2-morpholin-4-ylethan-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:4](=[O:23])[CH:3]=1.O.C(O)C.[N:28]([O-])=[O:29].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6](=[O:15])[N:5]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:4](=[O:23])[C:3]=1[N:28]=[O:29]
Reactant: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Temperature: 25 °C

Procedure:
6-Amino-1,3-bis(cyclohexylmethyl)uracil (from step (b), 25.0 g, 78.3 mmol) was dissolved in glacial acetic acid (440 mL), water (440 mL) and ethanol (440 mL) at reflux. To this solution was added sodium nitrite (5.65 g, 81.9 mequiv). The resulting mixture was stirred as it cooled slowly to ambient temperature. The lavender precipitate was filtered off, washed with 1:1 water-ethanol and dried to give 6-amino-1,3-bis(cyclohexylmethyl)-5-nitrosouracil as light purple crystals (23.46 g, 86%), m.p. 240°-243° C. dec with effervescence;
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[CH3:13][C:14](=O)[CH2:15][CH3:16].Cl>C(O)(=O)C.O>[CH3:13][C:14]1[NH:2][C:4]2[C:12]([C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7]
Reactant: NNc1ccccc1C(=O)O
Reactant: CCC(C)=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c2c(C(=O)O)cccc2c1C
Temperature: 100 °C

Procedure:
To a suspension of 2-hydrazinobenzoic acid hydrochloride (2.0 g) in acetic acid (8 ml) was added dropwise a solution of 2-butanone (0.9 ml) in acetic acid (2 ml), and the resultant mixture was heated at 80° C. for one hour. After 6N-hydrochloric acid (8 ml) was added to the reaction mixture, the mixture was heated at 100° C. for 5 hours. The mixture was diluted with water (18 ml), and allowed to cool to 40° C. The resultant precipitate was collected by filtration, washed with a small amount of diisopropyl ether and dried in vacuo to give 2,3-dimethyl-1H-indole-7-carboxylic acid (0.78 g).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH3:11].C([Li])(C)(C)C.CN([CH:20]=[O:21])C>O1CCCC1.CCOCC>[CH3:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH:20]=[O:21]
Reactant: COc1cc(C)c(Br)c(C)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C)c(C=O)c(C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To 4-bromo-3,5-dimethylanisole (20 g, 93.0 mmol) in 500 mL of tetrahydrofuran at -78° C. was added 120 mL of tert-Butyllithium (1.7M in pentane). The reaction mixture was stirred for 30 minutes at -78° C. and then DMF (136.0 g, 186.0 mmol) was added. The reaction mixture was stirred for 1 hour at -78° C. and for 1.5 hours at room temperature, diluted with 300 mL of ether, washed with 300 mL of water, acidified 1N HCl , and 5×100 mL of brine. The organic portion was dried (MgSO4), filtered, and evaporated to give the crude product, which was purified by flash column chromatography (silica gel, 90:10 hexane/ethylacetate) to yield 2,6-dimethyl-4-methoxybenzaldehyde (6), (9.50 g, 57.8 mmol, 62%) as a white solid; 1HNMR (CDCl3 δ 2.61 (s, 6H), 3.83 (s, 3H), 6.6 (s, 2H), 10.5 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][OH:20])=[O:5].C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][O:20][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:41]([Cl:42])=[C:33]([Cl:32])[CH:34]=1)=[O:5]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CO)s1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2COC(=O)c2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-3-hydroxymethyl-5-methyl[1,2,4]triazole (1.08 g) was dissolved in chloroform (50 ml). Triethylamine (0.34 g) and 3,4-dichlorobenzoyl chloride (0.69 g) were added, and the mixture was stirred at room temperature for 2 hours. Then, water was added to the solution for washing, and the mixture was dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent:ethyl acetate-methanol) and recrystallized from ethyl acetate-diisopropyl ether to give 1.10 g of (4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3,4-dichlorobenzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[CH2:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:15][CH:14]=1)[CH:10]([CH3:12])[CH3:11].C(N(CC)CC)C.O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:20](=[O:21])[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=1)[CH3:23]
Reactant: OCc1ccccn1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2ccccn2)cc1
Yield: 88.2 %

Procedure:
To a solution of 2.2 g of 2-pyridinemethanol in 20 ml of tetrahydrofuran were added 3 g of 2-(4-isobutylphenyl)propionic acid chloride and subsequently 2.7 g of triethylamine, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether. The ether extract was dehydrated and freed of ether by distillation. The oily residue thus obtained was distilled in vacuo to give 3.5 g of 2-(4-isobutylphenyl)propionic acid-2-pyridylmethyl ester as a pale yellow oil, boiling at 138°-140° C./0.15 mmHg. Mass spectrum: parent ion 297 m/e.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2F)[CH2:7][CH2:6]1.C([BH3-])#N.[Na+].[F:24]C(F)(F)C(O)=O>CO>[CH3:4][N:5]1[CH2:6][CH2:7][CH:8]([NH:11][CH2:12][CH2:17][C:16]2[CH:2]=[CH:1][CH:13]=[C:14]([Cl:18])[C:15]=2[F:24])[CH2:9][CH2:10]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC=O
Reactant: CN1CCC(Nc2cccc(Cl)c2F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(NCCc2cccc(Cl)c2F)CC1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
Add acetaldehyde (0.817 g) to a solution of 1-methyl-4-(3-chloro-2-fluorophenylamino)piperidine (Preparation 19) (0.45 g), sodium cyanoborohydride (0.123 g) and trifluoroacetic acid (0.633 g) in methanol (20 mL) and heat in a sealed tube at 80° C. for three days. Load on a SCX column (10 g), wash with methanol, elute with 2M NH3 in methanol, evaporate, and further purify on a silica gel column (35 g), using a gradient of dichloromethane-2M NH3 in methanol to give 0.50 g of the title intermediate as a colorless oil: mass spectrum (electric spray) m/z=271 (M+1); 1H NMR (CDCl3): 6.94 (m, 3H), 3.14 (q, J=7.0 Hz, 2H), 3.06 (m, 1H), 2.84 (br d, 2H), 2.22 (s, 3H), 1.93 (m, 2H), 1.74 (m, 4H), 0.95 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](Cl)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N(CC)CC)C.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:24]3[CH2:25][CH2:26][N:21]([C:18](=[O:20])[CH3:19])[CH2:22][CH2:23]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: CC(=O)N1CCNCC1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
A mixture of 1.989 (7.50 mmole) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 1.169 (9.05 mmole) of N-acetylpiperazine, and 2.0 mL of triethylamine in 20 mL of dry THF was refluxed under a nitro9en atmosphere for 16 hr. It was then poured into 5% aqueous sodium hydroxide and extracted three times with methylene chloride. The combined organic portions were dried over MgSO4, filtered and concentrated in vacuo to yield a product which was purified by flash chromatography (5% CH3OH in CHCl3) to afford 1.71g of the title compound as a glass.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.CCCCCC.C([Li])CCC.[C:30]1(=[O:35])[O:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[OH:35][CH2:30][CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:34]
Reactant: O=C1CCCO1
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCCO)Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 11.9 %

Procedure:
A solution of 1.0 g of 2-(trans-3-aminostyryl)benzothiazole dissolved in 15 ml of anhydrous tetrahydrofuran was cooled to -78° C. and 2.8 ml of a n-hexane solution (1.55M) of n-butyl lithium was added dropwise in a nitrogen gas atmosphere. After a mixture was stirred at the same temperature for 25 minutes, 375 mg of γ-butyrolactone was injected, followed by stirring for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude crystals obtained were washed with ethyl ether and dried to obtain 160 mg (yield 12%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-5-bromo-2-chloropyridine (stage 152.1.2, 3.59 mmol) and triethylamine (1 ml) in dichloromethane (20 ml) was added acetyl chloride (Aldrich, Buchs, Switzerland, 0.312 ml). The RM was stirred for 17 h at rt then was added acetyl chloride (0.3 ml), the RM was stirred for 3 h at rt. Acetyl chloride (0.1 ml) was added and the RM was stirred for 1 h at rt. The RM was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=249, 251 MS-ES)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:5]2.C[O-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C=O)C.CO>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]4)[CH2:30][CH2:31]2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: ClCCN1CCN(c2ccc(Cl)cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2cc(OCCN3CCN(c4ccc(Cl)cc4)CC3)ccc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
2.11 g of methyl 6-hydroxy-2-naphthoate and 0.84 g of sodium methoxide are stirred under N2 at 40° C. for 30 min in 50 ml of DMF. 4.6 g of 4-(p-chlorophenyl)piperazinoethyl chloride are then added and the reaction mixture is stirred at 40° C. for 8 h. It is diluted with 350 ml of methanol and the precipitate which is deposited is filtered off with suction. It is dissolved in 80 ml of DMF and 10 ml of water, and the mixture is treated with 3.8 g of KOH and stirred at 100° C. for 10 h. The DMF is largely stripped off on a rotary evaporator, the residue is poured onto water and acidified, and the resulting precipitate is filtered off with suction. 2.5 g of 6-{2-[4-(4-chlorophenyl)-1-piperazinyl]ethoxy}-2-naphthoic acid are obtained; m.p. 197-199° C.
Reaction SMILES: [NH2:1][C:2](=[N:33][OH:34])[C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH:46]([CH2:51][CH3:52])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:43]>CN(C=O)C>[NH2:1][C:2](=[N:33][O:34][C:42]([O:44][CH2:45][CH:46]([CH2:51][CH3:52])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:43])[C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C(N)=NO)ccc1O2
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCC(CC)COC(=O)ON=C(N)c1ccc2c(c1)C(O[Si](C)(C)C(C)(C)C)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6-[amino(hydroxyimino)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 80 mL of DMF were added 3.78 mL of pyridine and 8.4 mL of 2-Ethylhexyl chloroformate at 0° C., and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into ice-cold brine, and extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure to give a crude product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=[CH:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:27][CH:28]([C:31]#[N:32])[C:29]#[N:30].O>CN1C(=O)CCC1>[CH3:7][CH2:6][CH2:5][CH:10]([CH3:15])[CH3:11].[NH2:32][C:31]1[O:8][C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][C:5]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:27][C:28]=1[C:29]#[N:30]
Reactant: N#CC(N)C#N
Reactant: Cn1cnc(-c2ccccc2)c1C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCC(C)C
Product: Cn1cnc(-c2ccccc2)c1-c1nc(C#N)c(N)o1
Yield: 135.2 %

Procedure:
A suspension of 1-methyl-4-phenyl-1H-imidazole-5-carbonyl chloride (intermediate 4) (0.80 g) in anhydrous NMP (2 mL) was added to aminomalononitrile p-toluenesulfonate (0.92 g) in anhydrous NMP (10 mL). The resultant mixture was stirred for 24 hours. The mixture was poured into water (10 mL), extracted with EtOAc (3×20 mL), organics combined and further washed with water (10 mL), aqueous sodium hydrogen carbonate solution (10 mL) then brine (10 mL). Organics were dried (MgSO4) and evaporated to give a pale gum. Trituration with isohexane (5 mL) gave the title compound as a white solid (650 mg, 68%);
Reaction SMILES: [CH2:1]([NH:9][N:10]=[C:11]([CH3:17])[C:12]([O:14]CC)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].C(O)C.Cl>C(OCC)C.O>[CH2:1]([NH:9][N:10]=[C:11]([CH3:17])[C:12]([OH:14])=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)=NNCCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(=NNCCc1ccccc1)C(=O)O
Reaction time: 30 h
Yield: 47 %

Procedure:
6 g. Ethyl 2-(phenethylhydrazono)-propionate (prepared according to Example 2) are dissolved in a solution of 1.4 g. potassium hydroxide in 28 ml. 80% ethanol and saponified at ambient temperature. After stirring for 30 hours, the reaction mixture is mixed with 25 ml. water and shaken out twice with 50 ml. amounts of diethyl ether. The aqueous phase is acidified with dilute hydrochloric acid. The crystals which precipitate out are filtered off and recrystallized from toluene. There is obtained 2-(phenethylhydrazono)-propionic acid in a yield of 47% of theory; m.p. 74°-76° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:20]([CH3:22])[CH3:21])[C:10]([C@H:12]1[C@H:16]([CH3:17])[C:15](=[O:18])[NH:14][C:13]1=[O:19])=[O:11])=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[NH2:8][C@@H:9]([CH:20]([CH3:22])[CH3:21])[C:10]([C@H:12]1[C@H:16]([CH3:17])[C:15](=[O:18])[NH:14][C:13]1=[O:19])=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)[C@@H]1C(=O)NC(=O)[C@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)[C@@H]1C(=O)NC(=O)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution, cooled at 0° C., of 4.40 g (14.09 mmol) of (3R,4S)-3-[(2S)-2-(tert-butoxycarbonyl)amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedione (preparation: S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643) is admixed dropwise with 35 ml of 4N hydrochloric acid solution in 1,4-dioxane. When the addition is at an end the mixture is warmed to room temperature and stirred for 2 h, after which the mixture is concentrated under reduced pressure. The crude product can be used directly in the next stage. If desired the residue is treated with diethyl ether and the crystals precipitated are filtered off and dried under a high vacuum. Yield: 2.99 g of colorless crystals (86% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].Cl.NC[C:29]1[CH:30]=[C:31]([CH:35]([CH3:41])[C:36]([O:38]CC)=[O:37])[CH:32]=[CH:33][CH:34]=1.C[CH2:43][N:44]=C=NCCCN(C)C.Cl.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:44][CH2:43][C:34]3[CH:29]=[CH:30][C:31]([CH:35]([CH3:41])[C:36]([OH:38])=[O:37])=[CH:32][CH:33]=3)=[O:20])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: CCOC(=O)C(C)c1cccc(CN)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3ccc(C(C)C(=O)O)cc3)cn2)C1

Procedure:
2-(4-((2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)phenyl)propanoic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and ethyl 2-(3-(aminomethyl)phenyl)propanoate hydrochloride using Amidation Method 2 (EDCl) and Ester Hydrolysis Method 1 (LiOH). 2-(4-((2-((R)-3-(2-Ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)phenyl)propanoic acid was isolated by chiral SFC purification: Chiralcel-OJ-H, 5μ, 1.0×25 cm, MeOH/CO2 (20/80), T=35° C.; retention time, Example 15 diasteromer 7.056 min, other diastereomer 7.773 min. 1H NMR (500 MHz, DMSO-d6) δ 12.25 (br s, 1H), 8.84 (app t, 1H), 8.76 (s, 2H), 7.25 (m, 4H), 7.04 (m, 1H), 6.90 (m, 3H), 4.43 (d, 2H), 4.31 (m, 1H), 4.19 (dd, 1H), 3.91 (m, 4H), 3.78 (m, 1H), 3.65 (q, 1H), 2.02 (m, 1H), 1.84 (m, 2H), 1.52 (m, 1H), 1.35 (d, 3H), 1.22 (t, 3H). MS (ES+) 505.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[CH:6][CH:7]=1.O.N>C(O)C.[Pd]>[OH:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[N:4]=[N:3][CH:2]=[CH:7][CH:6]=1
Reactant: Oc1cccc(Oc2ccc(Cl)nn2)c1
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CCO
Product: Oc1cccc(Oc2cccnn2)c1

Procedure:
11.1 g of 3-chloro-6-(3-hydroxyphenoxy)pyridazine are dissolved in 100 ml of ethanol, followed by addition of 6 ml of concentrated ammonia water and 1.0 of 5% Pd-C. Then catalytic reduction is carried out at 50° C. under atmospheric pressure. The theroretical amount of hydrogen gas is almost completely absorbed in about 1 hour. The reaction mixture is filtered and the filtrate is concentrated to dryness.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C:19]([C:25](=[O:32])[NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])([CH2:23][CH3:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:23]([C:19]([OH:18])([C:25]([NH:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[O:32])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21])[CH3:24]
Reactant: CCC(O)(C(=O)O)C(=O)NCC(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A solution of 250 mg (1.12 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 256 mg (1.12 mmol) (RS)-2-hydroxy-2-(2,2,2-trifluoro-ethylcarbamoyl)-butyric acid in 24 ml tetrahydrofuran were cooled to 0° C. and 174 mg (0.94 mmol) 1-hydroxy-benzotriazole hydrate, 390 μl (2.23 mmol) diisopropylethylamine and 218 mg (1.12 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane 2/8 yielded 330 mg (68%) (R/S)-2-ethyl-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide as a colorless oil, MS (m/e): 436.1 (M+H)+.