Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][CH3:24])[C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:31][CH2:32][CH2:33]CCC>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][CH3:24])[C:16]2[C:21]([NH:22][CH:32]([CH3:33])[CH3:31])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1N
Reactant: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1NC(C)C

Procedure:
Following the general procedure of EXAMPLE 201 and making non-critical variations, but using 1-benzyll-4-[N-ethyl-N-(3-amino-2-pyridinyl)amino]methylpiperidine (EXAMPLE 177, 8.78 g, 27.06 mmol), and chromatographing the crude product (silica gel; ethyl acetate/hexane (50/50)) gives the title compound, NMR (300 MHz, CD3OD) 7.52, 7.21, 6.93, 3.56, 3.42, 2.90, 2.81, 1.86, 1.64, 1.33, 1.22, 1.+w and 0.95δ.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[CH3:22][Si:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]#[C:27][CH2:28]O>C(Cl)Cl.CCCCC>[Br:20][CH2:28][C:27]#[C:26][CH2:25][CH2:24][Si:23]([CH3:31])([CH3:30])[CH3:22]
Reactant: C[Si](C)(C)CCC#CCO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCC#CCBr
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a flame dried flask was added PPh3 (1.76 g, 6.73 mmol) followed by dry CH2Cl2 (60 mL). The mixture was placed in an ice bath and bromine (0.34 mL, 6.41 mmol) was added dropwise. A small amount of PPh3 was added until the reaction went from yellow to clear in color. After 0.5 h at 0° C., 5-trimethylsilanylpent-2-yn-1-ol (1.0 g, 6.41 mmol) was dissolved in CH2Cl2 (5 mL) and added dropwise. After 4 h at 0° C., the reaction mixture was poured into a separatory funnel, diluted with pentane (250 mL) and extracted with H2O (100 mL) and sat. NaHCO3 (100 mL). The organic layer was dried (MgSO4), filtered and reduced in volume to 50 mL. The crude solution was chromatographed on a pad of silica gel with pentane (500 mL). After evaporation of the pentane, (5-bromopent-3-ynyl)trimethylsilane (1.2 g 87%) was obtained as a clear oil: IR (neat, cm-1) 2953, 2922, 2899, 2230, 1431, 1317, 1248, 1208, 852; 1H NMR (300 MHz, CDCl3) δ0.03 (s, 9H), 0.79 (t, J=8 Hz, 2H), 2.28 (tt, J1 =8 Hz, J2 =2 Hz, 2H), 3.92 (t, J=2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ1.7, 13.6, 15.7, 15.8, 74.6, 90.2; HRMS (EI) m/z calcd for C7H12BrSi (M-CH3) 202.9892, found 202.9889 LRMS (EI) m/z 203 (M-CH3), 137, 73, 66.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C=O)C.O.C(#N)C.O>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Ic1ccnc2c[nH]nc12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(Cn2cc3nccc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (1 g, 4.08 mmol) and sodium hydride (0.196 g, 8.16 mmol) were combined in DMF (15 mL) at room temperature. The mixture was stirred at room temperature for 10 minutes and 1-(chloromethyl)-4-methoxybenzene (0.554 ml, 4.08 mmol) was added. The mixture was stirred at room temperature for 1 hour the quenched with ice water and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-90% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water to give the 7-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine (300 mg, 20.1% yield) as a white powder. MS [M+H] found 366.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[N:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[OH:15][CH2:14][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([CH3:7])[CH:13]=1
Reactant: COC(=O)c1cncc(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cncc(CO)c1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Lithium aluminum hydride (552 mg, 14.5 mmol) was suspended in tetrahydrofuran (10 mL). To this, a tetrahydrofuran solution (10 mL) of methyl 5-methyl nicotinate (1.00 g, 14.5 mmol) was slowly added at 0° C. and the mixture was stirred at the same temperature for 30 minutes. The reaction was stopped by successive addition of water (0.552 mL), a 15% aqueous sodium hydroxide solution (0.552 mL) and water (1.66 mL) to the reaction mixture. The mixture was stirred at room temperature for 30 minutes and then filtered through Celite. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give 3-hydroxymethyl-5-methylpyridine (972 mg, yield: 100%).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[N+:15]([C:18]1[CH:24]=[C:23]([CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])[CH:22]=[CH:21][C:19]=1[NH2:20])([O-])=O>O.CO>[N:28]1([C:26]([CH2:25][C:23]2[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([NH2:15])[CH:24]=2)=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccc(CC(=O)N2CCCC2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(CC(=O)N2CCCC2)cc1N

Procedure:
A mixture of sodium dithionite (245 g) and sodium carbonate (196 g) in water (1129 ml) and methanol (1029 ml) was stirred and 2-nitro-4-pyrrolidin-1-ylcarbonylmethylaniline (30.5 g) was added over a period of five minutes. A further portion of water (1468 ml) was added and the solution was heated under reflux for 65 minutes. The volume was reduced in vacuo in several stages with any solid material removed by filtration between each stage. Any solid so removed was washed with methanol and the washings combined with the final filtrate. The resulting solution was evaporated to dryness and the residue dried by azeotropic distillation with toluene and then ethanol. The dried residue was extracted with boiling ethanol and the solution filtered to give a solution which yielded 4-pyrrolidin-1-ylcarbonylmethyl-o-phenylenediamine (m.p. 105°-108° C.) on evaporation.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:6][C:7]=1[C:8](OCC)=[O:9])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[S:4][C:5]([CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2]
Reactant: CCOC(=O)c1cc(C(CC)CC)sc1CC
Agent: [Mn+4]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1sc(C(CC)CC)cc1C=O
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution (40 mL) of ethyl 2-ethyl-5-(1-ethylpropyl)thiophene-3-carboxylate (1.98 g) synthesized above in tetrahydrofuran was added 1.5M diisobutylaluminum hydride-toluene solution (15.5 mL) at 0° C., and the mixture was stirred for 1 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a colorless oil. To a solution of the obtained oil in tetrahydrofuran (40 mL) was added activated manganese dioxide (10.0 g), and the mixture was stirred at room temperature overnight. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19, volume ratio) to give the title compound (1.40 g, 86%) as a yellow oil.
Reaction SMILES: Cl.C(=N)OCC.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8].C1(N2[C:19]([CH:20]=[O:21])=[CH:18][N:17]=[C:16]2C)CC1>>[C:7]([N:11]1[C:19]([CH:20]=[O:21])=[CH:18][N:17]=[CH:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: Cc1ncc(C=O)n1C1CC1
Agent: CCOC=N
Agent: Cl
Product: CC(C)(C)n1cncc1C=O

Procedure:
3-tert-Butyl-3H-imidazole-4-carbaldehyde was prepared from ethyl formimidate hydrochloride (Aldrich) and tert-butylamine in the same manner as 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:27](=[O:28])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)Cc1ccccc1
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
A stirred solution of 2-methoxy-5-nitroaniline (4.86 g, 0.029 mole) and triethylamine (5.2 ml, 0.037 mole) in dichloromethane (150 ml) at 0° C. was treated with phenylacetyl chloride (5.0 ml, 0.037 mole). The mixture was stirred for 0.5 h, then treated with water (20 ml), stirred for a further 20 mins., then basified with Na2CO3 and extracted with dichloromethane. The extract was washed with dil. HCl acid/brine, then dried (Na2SO4) and concentrated in vacuo to afford the title compound as a brown solid (9.0 g, 100%).
Reaction SMILES: [Br:1][CH:2]1[CH2:5][C:4](=[O:6])[CH2:3]1.[CH2:7](O)[CH2:8][OH:9].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1C=CC=CC=1>[Br:1][CH:2]1[CH2:5][C:4]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:3]1
Reactant: OCCO
Reactant: O=C1CC(Br)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: BrC1CC2(C1)OCCO2
Reaction time: 12 h
Yield: 51 %

Procedure:
A mixture of 3-bromocyclobutanone (5.90 g, 39.6 mmol), 1,2-ethanediol (8.6 mL, 158 mmol, 4 eq.) and PPTS (1.90 g, 7.92 mmol) in benzene (40 mL) was heated to reflux using Dean-Stark assembly. After 12 h, the reaction mixture was allowed to cool and washed with water (2×30 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (ethyl acetate/hexanes 1:5) to give the title compound (51% yield starting from 3-oxocyclobutanecarboxylic acid). 1H NMR (300 MHz, CDCl3): δ=2.77-2.82 (m, 4H), 2.95-3.00 (m, 4H), 4.19-4.23 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:46])[CH2:43][CH2:44][CH3:45])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:46])[CH2:43][CH2:44][CH3:45])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 37.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-methyl-N-propylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.5 mg) was obtained.
Reaction SMILES: [C:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][C:2]=1[C:6]([OH:8])=[O:7].[H][H]>[Ni].C(O)C>[C@@H:1]1([C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)C1=C(C(=O)O)CCC1
Agent: [Ni]
Solvent: CCO
Product: O=C(O)[C@H]1CCC[C@H]1C(=O)O

Procedure:
1-Cyclopentene-1,2-dicarboxylic acid (10.0 g., 0.064 mole) in 200 ml. of absolute ethanol is hydrogenated (Paar shaker) in the presence of Raney nickel at 40-50 psi/60°. After uptake of one equivalent of hydrogen (~24 hours), the mixture is cooled, filtered through a Celite (diatomaceous earth) pad, and the filtrate concentrated in vacuo to a solid. Direct recrystallization from water (~30 ml.) followed by drying in vacuo over phosphorus pentoxide yields 6 g. (60%) of cis-1,2-cyclopentanecarboxylic acid, m.p. 132°-135°. The mother liquor from the recrystallization can be lyophilized to a solid, which is sufficiently pure for use in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][C:13]1([CH3:19])[O:18][CH2:17][CH2:16][NH:15][CH2:14]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:15]2[CH2:16][CH2:17][O:18][C:13]([CH3:19])([CH3:12])[CH2:14]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC1(C)CNCCO1
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CN(c2ncc(Br)cc2[N+](=O)[O-])CCO1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (2.00 g, 8.43 mmol) in DMSO (10 mL) was added 2,2-dimethylmorpholine (commercially available from ChemBridge Corporation) (1.9 mL, 16.9 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to afford an orange oil as 4-(5-bromo-3-nitropyridin-2-yl)-2,2-dimethylmorpholine. 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (1H, d, J=2.2 Hz), 8.25 (1H, d, J=2.2 Hz), 3.87 (2H, m), 3.36 (4H, m), 1.26 (6H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[CH2:25]([NH:29][CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CN
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CC(C)CNCc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and isobutylamine to give a yellow solid. MS m/z: 391.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C@H:8]2[OH:11])=[CH:4][CH:3]=1.C(OC(=O)CCC)=C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C@@H:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O[C@@H]1C[C@H](c2ccccc2)c2ccc(Cl)cc21
Agent: C=COC(=O)CCC
Solvent: Cc1ccccc1
Product: O[C@H]1C[C@@H](c2ccccc2)c2ccc(Cl)cc21
Reaction time: 24 h

Procedure:
Compound V (5 g, 20.4 mmol) is dissolved in 150 ml anhydrous toluene. 0.5 g Novozym 435 (Candida Antarctica lipase B) (Novozymes A/S, Fluka Cat.-No. 73940) is added followed by vinylbutyrate (13 ml, 102.2 mmol). The mixture is stirred using mechanical stirrer at 21° C. After 1 day, an additional 0.5 g Novozym 435 is added. After 4 days at a conversion of 54%, the mixture is filtered and concentrated in vacuo to obtain an oil containing a mixture of (1R,3R)-cis-6-chloro-3-phenylindan1-ol-butyrate ester and desired compound Va with an enantiomeric excess of 99.2% (99.6% compound Va and 0.4% (1R, 3R)-cis-6-chloro-3-phenylindan-1-ol).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH2:19]Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[CH3:24][N:25](C)C=O>O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH2:19][C:24]#[N:25])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cnn(Cc2ccccc2)c1-c1ccccc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1cnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 44 %

Procedure:
A mixture of 1-benzyl-4-chloromethyl-5-phenyl-1H-pyrazole (8.31 g), potassium cyanide (2.87 g), and N,N-dimethylformamide (100 ml) was stirred for 15 hours at 90° C., and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and (1-benzyl-5-phenyl-1H-pyrazol-4-yl)acetonitrile (3.50 g, yield: 44%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[N:15]1([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:25][C:24]3[CH:23]=[CH:22][C:21]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[CH:27][CH:26]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCn1c(=O)ccc2cnc(Nc3ccc(N4CCCCC4)cc3)cc21
Reaction time: 8 h
Yield: 44 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol), 4-(1-piperidinyl)aniline (0.26 g, 1.12 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (0.8 mL, 1.2 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a dark residue that was purified that purified by silica gel chromatography eluting with EtOAc. The product fractions were pooled and concentrated to a foam that was crystallized to give ethyl-7-(4-(piperidin-1-yl)phenylamino)-1H -[1,6]naphthyridin-2-one (79 mg, 44%): mp (CH2Cl2 /hexanes) 137-139° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH:11]=[CH:12][C:13]2[CH:34]=[CH:33][C:16]([O:17][CH2:18][C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([O:35][CH3:36])[CH:14]=2)=[O:10])[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH2:11][CH2:12][C:13]2[CH:34]=[CH:33][C:16]([O:17][CH2:18][C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:25][CH2:26]3)=[O:20])=[C:15]([O:35][CH3:36])[CH:14]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)N1CCC(N2CCCCC2)CC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)N1CCC(N2CCCCC2)CC1

Procedure:
Using 0.2 g of 1-{4-{2-[N-(trans-4methylcyclohexyl)carbamoyl]vinyl}-2-methoxyphenoxyacetyl}-4-piperidinopiperidine (Example 190), 0.01 g of 10% palladium-carbon, and 30 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 0.12 g of 1-{4-{2- [N-(trans-4-methylcyclohexyl) carbamoyl]ethyl}- 2-methoxyphenoxyacetyl}-4-piperidinopiperidine (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:45])[C@@H:12]([NH:20][C:21](=[O:44])[C@H:22]([NH2:43])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@H:31]([O:38][Si](C)(C)C)[CH2:32][O:33][Si](C)(C)C)=[CH:25][CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.[O:55]=[C:56](Cl)OC(Cl)(Cl)Cl.Cl.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:45])[C@@H:12]([N:20]2[C:21](=[O:44])[C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@H:31]([OH:38])[CH2:32][OH:33])=[CH:25][CH:24]=3)[NH:43][C:56]2=[O:55])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](N)c2ccc(OC[C@@H](CO[Si](C)(C)C)O[Si](C)(C)C)cc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)N2C(=O)N[C@H](c3ccc(OC[C@H](O)CO)cc3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
2-((S)-2-{(R)-2-Amino-2-[4-((S)-2,3-bis-trimethylsilanyloxy-propoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (100 mg, 0.15 mmol) and diisoproylethylamine (0.078 ml, 0.45 mmol) in dichloromethane (2 mL) were added to a solution of diphosgene (0.0143 ml, 0.12 mmol) in dichloromethane (2 mL) over 10 minute at 0° C. The mixture was stirred at 0° C. for 20 minute, diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Evaporation of solvents gave an oil which was dissolved in tetrahydrofuran (2 mL), treated with 1 N aqueous hydrochloric acid (0.45 ml, 0.45 mmol) and stirred for 3 hours. The reaction was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with brine and dried over magnesium sulfate. The crude product was purified by chromatography over silica gel gradient eluted with 100% ethyl acetate up to 3% v/v methanol in ethyl acetate to give 2-((S)-2-{(R)-4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a solid (35 mg, 42%).
Reaction SMILES: Cl.[NH2:2]O.[F:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([Cl:14])[C:6]=1[CH:7]=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([Cl:14])[C:6]=1[C:7]#[N:2]
Reactant: NO
Reactant: Cc1ccc(F)c(C=O)c1Cl
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(F)c(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (1.1 parts) is added to a solution of 2-fluoro-5-methyl-6-chlorobenzaldehyde in pyridine, and the mixture is stirred for 15 minutes at room temperature. Acetic anhydride (1.3 parts) is then added and the mixture stirred at ambient temperature overnight to effect complete dehydration of the oxime to the nitrile. Most of the pyridine is removed by concentration under vacuum, then the residue is partitioned between ether and water. The organic phase is washed with brine, dried (MgSO4), filtered through silica gel, concentrated, then triturated in hexane to afford 2-fluoro-5-methyl-6-chlorobenzonitrile as light yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2]>O.N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: [Ni]
Agent: N
Solvent: O
Product: NCc1ccc(CC(=O)O)cc1
Reaction time: 24 h
Yield: 101.5 %

Procedure:
A solution of 4-cyanophenylacetic acid (12.11 g, 0.075 mol) in water (163 mL) and concentrated aqueous ammonia (40 mL) was stirred at room temperature and Raney nickel (6.3 g) was added. The resulting suspension was stuirred under a hydrogen atmosphere for 24 hours before the reaction mixture was filtered through celite and evaporated in vacuo to give crude 4-(aminomethyl)-phenylacetic acid (12.57 g; 100%) as a pale blue solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:11])[CH:5]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:14]=[O:16])=[C:6]([CH3:11])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N=C=O)c(C)c1

Procedure:
In analogy to the procedure described in example 9.1, 4-amino-3-methyl-benzoic acid methyl ester ([18595-14-7]) was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 14 h to give the title compound as brown solid. MS: m/e=191.1 [M+].