Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13](O)=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:28]1([NH2:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:26])([CH3:27])[NH:17]2)[C:13]([NH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=NC(C(=O)O)=C2NC(C)(C)Cc3ccccc32)cc1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N=NC(C(=O)Nc2ccccc2)=C2NC(C)(C)Cc3ccccc32)cc1
Temperature: 25 °C

Procedure:
(4-acetyl-phenylazo)-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetic acid, phenylamine, HOBt (Advanced ChemTech Corp., USA) and triethylamine are dissolved in DMF, a dichloromethane solution of HBTU (Advanced ChemTech Corp., USA) is added, and then the mixture is stirred at room temperature. The mixture is washed with the saturated aqueous sodium chloride solution and a 5% aqueous sodium hydrogen carbonate solution. The reaction product is dried with anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>CO>[CH3:1][C@@H:2]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:5])=[O:4]
Reactant: CCCCC(=O)[C@H](C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(=O)[C@H](C)C(=O)O
Yield: 94.2 %

Procedure:
1 g of Ethyl [S]-2-methyl-3-oxo-heptanoate, 0.5 g of KOH and 15 MeOH were stirred at 50° C. for 4 hrs. Then MeOH was removed and the residue is mixed with water, neutralized with conc.HCl and extracted with methylene chloride. The combined organic phase was washed with water for 3–4 times and dried over MgSO4. After evaporation of solvent, 0.8 g of product was obtained (yield 95%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].[CH2:11](O)[CH3:12]>>[CH2:11]([O:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:12]
Reactant: CCO
Reactant: OCc1ncccc1O
Agent: [Na]
Product: CCOc1cccnc1CO
Reaction time: 65 h

Procedure:
3-Hydroxy-2-hydroxymethylpyridine (8.5 g) was added to a solution of sodium (1.565 g) in ethanol (100 cc) and the mixture was evaporated to dryness. Dimethylsulphoxide (180 cc) was added to the residue, and bromoethane (7.43 g) in dimethylsulphoxide (24 cc) was added over 20 minutes to the stirred mixture. The mixture was allowed to stand at room temperature for 65 hours, and was evaporated. The residue was partitioned between chloroform and water, and the chloroform extracts were evaporated to an oil which was converted into a crystalline hydrochloride m.p. 190°-191.5° by the addition of ethanolic hydrogen chloride. The hydrochloride was dissolved in water, and aqueous ammonia was added until the mixture was basic, and the mixture was extracted with chloroform. The chloroform extracts were evaporated and the residue crystallised from ethanol/diethyl ether to give 3-ethoxy-2-hydroxymethylpyridine (5.0 g) m.p. 74.5°-76°.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:15]([N:22]1[C:26]2=[C:27](Cl)[N:28]=[N:29][CH:30]=[C:25]2[CH:24]=[C:23]1[CH3:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCC1=O>[CH2:15]([N:22]1[C:26]2=[C:27]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:28]=[N:29][CH:30]=[C:25]2[CH:24]=[C:23]1[CH3:32])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc2cnnc(Cl)c2n1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Yield: 68 %

Procedure:
650 mg (6 mmol) of benzyl alcohol, 10 ml of N-methylpyrrolidone, 1.1 g (10 mmol) of potassium tert-butoxide, 50 mg (0.2 retool) of [18]crown-6 and 500 mg (1.94 retool) of 1-benzyl-7-chloro-2-methylpyrrolo[2,3-d]pyridazine are reacted at room temperature for 2 h. Purification: chromatography on silica gel (eluent: toluene/dioxane=2:1) and crystallization from diisopropyl ether. Yield: 68%, m.p.: 124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:16]4([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC2(CCCCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.110 g, 0.500 mmol), cyclohexanone (0.245 g, 2.50 mmol), p-toluenesulfonic acid monohydrate (0.105 g, 0.550 mmol) and toluene (5.0 mL) was stirred for 1 h at 90° C. The mixture was poured into aqueous sodium hydrogen carbonate (30 mL). Extraction with ethyl acetate/tetrahydrofuran (2:1, 2×30 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (12 g, silica, Combiflash, dichloromethane to 80:20 dichloromethane/methanol) to afford the title compound (0.053 g, 36%) as a yellow solid:
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].O>C1COCC1.CC(OC)(C)C>[CH2:3]([O:10][CH2:12][C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CCl
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COCc1ccccc1
Temperature: 50 °C
Yield: 70.4 %

Procedure:
To a suspension of KOH (17.84 g, 118 mmol) in THF (200 mL) was added benzyl alcohol (42 mL, 424 mmol). After 1.5 h the mixture was heated to 50° C. for 1.5 h and cooled to rt afterwards. Chloroacetic acid (10 g, 106 mmol) was added and the mixture was heated to 80° C. After 1.5 h the mixture was cooled to rt and water and MTBE was added. The layers were separated, the aqueous layer was extracted with MTBE, the pH of the aqueous layer was adjusted to pH=2 with 6N HCl and extracted with MTBE. The extracts of the acidic layer were dried and the solvent removed under reduced pressure to give 12.4 g of the crude product.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.Cl>C(O)C>[CH2:11]([O:19][C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9][C@H:8]([NH2:12])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:6][CH:5]=1)[CH3:10]
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
0.5 g (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one, 5 ml ethanol and 0.5 ml concentrated hydrochloric acid were heated at about 80-120° C. for about 24 hours. The mixture was evaporated to dryness to obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (hydrochloride salt). Spectroscopic data as reported in Example 9.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([Cl:27])=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:27][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Reactant: N#Cc1cn[nH]c1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cc(-c2ccnc3c(C#N)cnn23)ccc1Cl)S(C)(=O)=O
Yield: 70.2 %

Procedure:
A mixture of 0.042 g (0.39 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.124 g (0.39 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-methanesulfonamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 99 mg of N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 70%).
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[I-].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([Zn+])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>[Pd].[Cu]I.CC(N(C)C)=O>[F:8][C:3]1[C:2]([CH:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:21]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC([Zn+])C1
Reactant: Fc1ncccc1Br
Agent: [Cu]I
Agent: [Pd]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cccnc2F)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Into an oven-dried flask were charged 3-bromo-2-fluoropyridine (1.3 g, 7.39 mmol), Pd catalyst (0.181 g, 0.222 mmol), copper(i) iodide (0.084 g, 0.443 mmol), and DMA (10 mL). The resulting mixture was degassed with alternating vacuum/nitrogen purges. The (1-(tert-butoxycarbonyl)pyrrolidin-3-yl)zinc(II) iodide (3.75 g, 10.34 mmol) solution from previous step was filtered into the mixture. It was degassed one more time and then heated to 80° C. with stirring for 16 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and 1 N NH4Cl. The aqueous layer was back extracted with EtOAc (2×) and the combined EtOAc layer was washed once again with 1 N NH4Cl, then with brine, dried (Na2SO4) and concentrated. The crude material as chromatography through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 40% EtOAc in hexane, to provide tert-butyl 3-(2-fluoropyridin-3-yl)pyrrolidine-1-carboxylate as dark-red oil. [M−56]=211.2.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]3[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]3)=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:29])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:28][C:24]1([CH3:27])[O:23][C@@H:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:12]3[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:30])=[O:2])[C:10](=[O:29])[CH:11]=3)=[CH:16][CH:17]=2)[CH2:26][O:25]1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(C[C@H]3COC(C)(C)O3)cc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccc(C[C@H]3COC(C)(C)O3)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A solution of (S)-2-{4-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (0.198 g, 0.47 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.022 g 0.51 mmol) and stirred at room temperature for 1.5 h. The mixture was partitioned between ethyl acetate and water and the layers separated. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH=1) and extracted with ethyl acetate. The combined organic layers from extraction of the acidic aqueous layer were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was treated with dichloromethane/hexanes and the precipitate isolated by filtration to afford (S)-2-{4-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (148 mg, 77%), as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([C:24](F)(F)F)[CH:21]=[CH:20][C:19]=1[C:28]#[C:29][C:30](O)=[O:31]>ClCCl.CO>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][C:30](=[O:31])[C:29]#[C:28][C:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=2[Cl:17])=[CH:11][CH:12]=1)[CH3:16]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(CN)cc1
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(CNC(=O)C#Cc2ccc(C)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from [4-(2-diethylaminoethoxy)phenyl]methylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 60 mg (22% of theory); melting point: 135° C.-138° C.; C23H24ClF3N2O2 (M=452.90); calc.: molecular ion peak (M+H)+: 453/455; found: molecular ion peak (M+H)+: 453/455; Rf value: 0.4 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][C:3]=1[I:11].CN(C=O)C.O=S(Cl)Cl.CCN(C(C)C)C(C)C.[Cl:30][C:31]([F:41])([F:40])[O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[C:3]([I:11])=[CH:4][C:5]([C:8]([NH:37][C:36]2[CH:38]=[CH:39][C:33]([O:32][C:31]([Cl:30])([F:40])[F:41])=[CH:34][CH:35]=2)=[O:10])=[CH:6][N:7]=1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Chloro-5-iodo-3-pyridinecarboxylic acid (18 g, 62.2 mmol) was suspended in toluene (125 mL). DMF (1.446 mL, 18.67 mmol) and SOCl2 (13.63 mL, 187 mmol) were added at RT. The RM was stirred at 80° C. for 1 h, cooled to RT then the solvent was evaporated off under reduced pressure to give a residue that was dissolved in THF (125 mL) and cooled to −15° C. DIPEA (21.74 mL, 124 mmol) was added at −15° C., and the cold mixture was treated dropwise with a solution of 4-(chlorodifluoromethoxy)aniline in THF (125 mL) over 12 min. The resulting fine orange suspension was stirred for 1 h at RT. The solvent was evaporated off under reduced pressure and the residue was dissolved in TBME (500 mL), and sequentially washed with 1N HCl (2×150 mL), sat. aq. NaHCO3 solution (2×150 mL) and brine (2×150 mL). The aq. phases were extracted with TBME (400 mL). Combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure until crystallization began (around 100 mL). n-Heptane (800 mL) was then added with stirring and the light yellow suspension was stirred at RT for 30 min. The crystalline product was filtrated, washed with n-heptane (200 mL) and dried to afford the title product as a beige solid. LC-MS (Condition 3) tR 1.25 min, 459.0/460.7/462.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][S:38]([CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([CH3:30])([CH3:31])[C:32]#[N:33])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 710.4 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH:17]1([C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:23])[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)C2CCCC2)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(C1CCCC1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-cyclopentanecarbonylpiperidin-4-one (83.5 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}cyclopentylmethanone (144 mg, 81%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.42 min, m/z 415.36 (36), 413.40 (M++H, 100). HPLC tr=6.82 min (98.32%) 1H NMR (270 MHz, CDCl3) δ 1.23 (2H, m, CH2), 1.52 (2H, m, CH2), 1.60-1.90 (9H, m, 4CH2+NH), 2.66 (2H, m, CH2), 2.85 (1H, quin, J=7.9 Hz, CHCO), 3.00 (1H, m, CHNH), 3.79 (2H, m, CH2), 3.85 (1H, m, ½CH2), 4.40 (1H, m, ½CH2), 6.83 (2H, AA′BB′, ArH), 6.87 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.4, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 26.12, 30.09, 32.29, 32.24, 40.55 (CH2), 41.19 (CH), 44.04, 45.65 (CH2), 54.00 (CH), 118.93, 119.62, 124.54, 127.95, 128.70, 129.84, 130.58, 131.83, 154.34, 156.38 (ArC), and 174.37 (C═O).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:25])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:35][NH2:36]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:25])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:36][N:35]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 152.8 %

Procedure:
To (3S,6R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (260 mg, 0.58 mmol) in EtOH (10 mL) as a suspension at room temperature in a microwave vial was added hydrazine monohydrate (807 uL, 16.7 mmol, 30 equiv) in one portion. The mixture was capped and heated at 100° C. for 48 hours. A duplicate run was performed. The crude reactions from both runs were combined, and concentrated in vacuo. The residue was taken up in 10 mL of water. The resulting suspension was sonicated briefly, and filtered. The solids collected were dried under vacuum at room temperature over P2O5 for 18 hours, and then at 65° C. under vacuum for another 18 hours to afford the title compound (410 mg) as a cream-colored solid. LC-MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.16-1.32 (m, 3H), 1.29 (d, J=6.8 Hz, 3H), 1.34-1.45 (m, 2H), 1.65-1.68 (m, 1H), 1.76-1.81 (m, 5H), 1.85-1.92 (m, 2H), 1.97-2.05 (m, 1H), 2.35-2.42 (m, 1H), 2.97 (s, 3H), 3.11-3.15 (m, 1H), 3.64-3.70 (m, 1H), 4.45-4.65 (bs, 1H), 4.72-4.92 (bs, 1H), 6.45 (s, 1H), 7.52 (dd, J=8.5, 1.14 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: N.C(NN)(=O)C[CH2:4][CH2:5][CH2:6][C:7](NN)=[O:8]>O>[C:7]([O:8][CH2:7][CH2:6][CH2:5][CH3:4])(=[O:8])[CH:6]=[CH2:5]
Reactant: NNC(=O)CCCCC(=O)NN
Agent: N
Solvent: O
Product: C=CC(=O)OCCCC
Reaction time: 0.67 h

Procedure:
In addition, as a further difference, feed stream 1 was metered in at a uniform rate over 5 minutes rather than 40 minutes, and feed stream 2 was metered in at a uniform rate over 125 minutes rather than 90 minutes. The additions of the 12.0 g of deionized water each took place following the ends of feed streams 1 and 2, and the additions of the aqueous ammonia solution took place at the same distance from the beginning of the reaction as in example 3, and, furthermore, instead of 40.9 g of a 13.2% strength by weight aqueous solution of adipic dihydrazide, 36.4 g of a 2.5% strength by weight aqueous solution of adipic dihydrazide were used.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[F:13].[CH3:14][S:15]([O-:17])=[O:16].[Na+]>C(O)(C)C>[F:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CCBr)c(F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1F
Temperature: 70 °C
Yield: 70.3 %

Procedure:
To a stirred solution of 1-(2-bromoethyl)-2-fluoro-4-nitrobenzene (1 g, 4.03 mmol) in isopropanol (15 mL) was added sodium methane sulfinate (2.05 g, 20.16 mmol) at room temperature. The reaction mixture was heated to 70° C. for 10 h. The reaction mixture was cooled to room temperature and was concentrated under reduced pressure to obtain a crude compound which was filtered out and the residue was washed with water (2×5 mL) to obtain pure 2-fluoro-1-(2-(methylsulfonyl)ethyl)-4-nitrobenzene (700 mg, 70%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC=C(Cl)C=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1cccc(Cl)c1)c1cc(Br)ccc1OCc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (384 mg, 9.16 mmol) in water (20 ml) was added dropwise to a stirred solution of (3-chlorophenyl)methyl 5-bromo-2-([(3-chlorophenyl)methyl]oxy)benzoate (may be prepared as described in Description 21; 427 mg, 0.92 mmol) in THF (20 ml) over 1 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as a white solid. 200 mg.