Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:33])=[C:13]([C:28]([O:30]CC)=O)[C:14](=[O:27])[N:15]2[CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:33])=[C:13]([C:28]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[O:30])[C:14](=[O:27])[N:15]2[CH2:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccncc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC(=O)N2CCOCC2)c1=O
Product: O=C(NCc1ccncc1)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-(2-morpholin-4-yl-2-oxoethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(aminomethyl)pyridine employing methods similar to those employed in Example 11. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.48 (1H, br t, J=6 Hz), 8.62 (1H, d, J=1.1 Hz), 8.58 (2H, d, J=6 Hz), 7.38-7.29 (3H, m), 7.27 (2H, d, J=6 Hz), 7.19 (2H, d, J=7 Hz), 7.02 (1H, s), 4.93 (2H, s), 4.65 (2H, d, J=6 Hz), 4.16 (2H, s), 3.69 (4H, m), 3.57 (2H, m), 3.51 (2H, m); ES+ MS: 514 (M+H+, 100).
Reaction SMILES: O[N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[C:4]1=[O:15].[H][H]>CCO.N.[Ni]>[NH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[C:4]1=[O:15]
Reactant: CN1CCc2ccccc2C(=NO)C1=O
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CN1CCc2ccccc2C(N)C1=O

Procedure:
1-Hydroxyimino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one was dissolved in EtOH/NH3 (20:1) and hydrogenated in a bomb using Raney nickel and hydrogen (500 psi/3447 kPa) at 100° C. for 10 hours. The resulting mixture was filtered and concentrated to provide an oil which was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].[N+:32]([C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O)([O-:34])=[O:33].C1CC23[N+](=[N-])C(CCC2)=C3C1>C(#N)C>[N+:32]([C:35]1[CH:36]=[C:37]([CH:38]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)[CH:40]=[CH:41][CH:42]=1)([O-:34])=[O:33]
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Br-]
Agent: [N-]=[N+]1C2=C3CCCC31CCC2
Solvent: CC#N
Product: COC(=O)c1ccc(C=Cc2cccc([N+](=O)[O-])c2)cc1
Reaction time: 1 h
Yield: 95 %

Procedure:
71.2 g of 4-methoxycarbonylbenzyltriphenylphosphonium bromide and 23 g (0.15 M) of 3-nitrobenzaldehyde are added to 360 ml of acetonitrile in a 1000 ml reactor. 19 ml (0.15 M) of 1,5-diazobicyclo[4.3.0]non-5-ene (DBN) are then added and the reaction medium is then refluxed with stirring for 1 hour. The solvent is then evaporated off and the residue obtained is then purified by chromatography on silica, using dichloromethane as eluent. After evaporation, 41.6 g of a white solid are obtained (yield: 95%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][C@H:40]([C:48](O)=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:48](=[O:49])[C@H:40]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
300 mg (0.702 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 223 mg (0.842 mmol) of (S)-N-tert.-butyloxycarbonyl-phenylalanine, 214 mg (0.842 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 215 μl (1.54 mmol) of triethylamine. The title compound is obtained as mixture of diastereomers in the form of a yellow oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.37, FD-MS: M+ =674.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:1]2[O:13][CH2:12][CH2:11][O:10]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: OCCO
Reactant: O=Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(C2OCCO2)cc1
Yield: 68.5 %

Procedure:
To 134 g of terephthalaldehyde and 62 g of ethylene glycol, was added 400 mL of toluene, and then was added thereto 2 g of p-toluenesulfonic acid, to conduct dehydration reaction under azeotropic conditions. After the time when the reaction of water stopped in the reaction, the reaction liquid was heated under reflux for another 2 hours, followed by cooling. The resultant reaction liquid was poured into an aqueous sodium bicarbonate solution. The organic phase was concentrated, and then purified by silica gel column chromatography (yield amount 122 g, and yield 68.5%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)=[N:30][CH:31]=1
Reactant: Nc1ccc(Oc2ccc(C[C@H](N)C(=O)O)cc2)nc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(C[C@H](Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)cc2)nc1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-amino-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][C:20](=O)[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:23])=[CH:5][CH:4]=1.[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][CH:20]([N:32]5[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]5)[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:23])=[CH:5][CH:4]=1
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccc(Cn2c(=O)ccc3ncc(N4CC(=O)C4)cc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cn2c(=O)ccc3ncc(N4CC(N5CCN(C(C)C)CC5)C4)cc32)cc1
Yield: 72.3 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-7-(3-oxoazetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-7) (5.796 g, 17.3 mmol, 1.0 eq) and 1-isopropylpiperazine (4.432 g, 34.6 mmol, 2.0 eq) in DCM (150 mL) and acetic acid (0.5 mL) was heated at reflux temperature for 3 h, then NaBH(OAc)3 (7.33 g, 34.6 mmol, 2.0 eq) was added in portions and the resulting mixture was kept reflux overnight. The reactant mixture was cooled and diluted with H2O (300 mL) and extracted with DCM (4×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-5% MeOH-DCM) to afford the desired product 1-(4-methoxybenzyl)-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-8) (5.6 g, 72.3% yield) as a pale solid. 1H NMR (300 MHz, CDCl3-d6) δ: 7.83 (d, J=7.5 Hz, 1H), 7.78 (s, 1H), 7.15 (d, J=6.9 Hz, 2H), 6.85 (d, J=6.6 Hz, 2H), 6.72 (d, J=7.2 Hz, 1H), 6.37 (s, 1H), 5.40 (s, 2H), 4.02 (m, 2H), 3.78 (m, 5H), 3.67 (m, 1H), 3.51 (m, 1H), 3.42 (m, 1H), 2.97 (m, 1H), 2.80 (m, 4H), 2.55 (m, 2H), 1.17 (d, J=4.8 Hz, 6H); ESI-MS m/z: 448.3 [M+H]+.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:8]#[N:9])[C:5]([NH2:7])=[O:6].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH2:14]([O:13][C:11]([O:2][N:3]=[C:4]([C:8]#[N:9])[C:5]([NH2:7])=[O:6])=[O:12])[CH3:15]
Reactant: CCOC(=O)Cl
Reactant: N#CC(=NO)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)ON=C(C#N)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a mixture of water (100 ml) and acetone (15 ml), sodium salt of 2-hydroxyimino-2-cyanoacetic acid amide (19.6 g) is added, and the obtained solution in which a part of the sodium salt is present in a suspended state is cooled at 0°C. Ethyl chloroformate (15 g) is dropwise added thereto, and the resulting mixture is, after adjusted to pH 7 to 8 with the addition of an aqueous solution of sodium hydrogencarbonate, stirred at room temperature for 1 hour and then filtered to collect the precipitated crystals. To the filtrate, a small amount of acetonitrile is added, and the mixture is extracted with ether. The ether layer is washed with water, dried and concentrated to give crystals, which are put together with the above obtained crystals to obtain 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (22.5 g). A part of the product is recrystallized from ethyl acetate to give crystals melting at 194° to 196°C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[NH:8][C:9]([CH2:11][CH3:12])=[CH:10][C:5]=2[C:4](=O)[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH3:1][C:2]1[NH:7][C:6]2=[N:8][C:9]([CH2:11][CH3:12])=[CH:10][C:5]2=[C:4]([Cl:16])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc2c(=O)nc(C)[nH]c2[nH]1
Product: CCc1cc2c(Cl)nc(C)[nH]c-2n1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 3.50 g (19.8 mmol) of 1,7-dihydro-2-methyl-6-ethyl-4H-pyrrolo[2,3-d]pyrimidin-4-one in 180 mL of phosphorous oxychloride was heated to reflux for 4 hours. The reaction was cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in 100 mL of methylene chloride and poured onto 100 g of ice. The mixture was neutralized to pH 7 by the addition of powdered potassium carbonate. After an additional 200 mL of methylene chloride and 200 mL of water were added, some solids remained and were removed by filtration. The solids were shown to be desired product by thin layer chromatography (silica, 19:1 methylene chloride-methanol). The solids were combined with the organic phase and concentrated to 4.0 g of brown residue. The residue was purified by flash chromatography (200 g of silica, 19:1 methylene chloride-methanol) to provide 3.32 g (86%) of 2-methyl-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine as an off-white solid. nmr (500 MHz, dmso-d6) δ1.25 (t, J=7.5 Hz, 3H), 2.56 (s, 3H), 2.73 (q, J=-7.5 Hz, 2H), 6.21 (s, 1H), 12.15 (s, 1H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:18])[CH2:13][CH2:14][C:15]=2OC)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:20]>ClCCCl>[Br:20][C:15]1[CH2:14][CH2:13][C:12](=[O:18])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: BrP(Br)Br
Reactant: COC1=C(c2ccc(C(C)(C)C)cc2)C(=O)CC1
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C2=C(Br)CCC2=O)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of Example 7C (245 mg, 1.003 mmol) in 1,2-dichloroethane (5 mL) was added PBr3 (0.142 mL, 1.504 mmol). The resulting mixture was heated to reflux for 1 hour, then cooled to ambient temperature, and poured over cracked ice. The organic layer was separated, washed with saturated aqueous NaHCO3 (5 mL), and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (on silica gel, eluted with dichloromethane/methanol=200:1, v/v) to afford the title compound (200 mg, 0.682 mmol, 68.0% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.38 (s, 4H), 3.00-3.03 (m, 2H), 2.62-2.65 (m, 2H), 1.26 (s, 9H); LC/MS (ESI) m/z 293 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([N:6]=[C:22]=[O:24])=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12]
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCOc1cc(N=C=O)c(F)cc1Cl

Procedure:
To a stirred solution of 4-chloro-2 fluoro-5-[(2-propynyl)oxy]-aniline (5.0 gm) and triethylamine (5.1 gm) in CH2Cl2 (100 mL) under N2, at 10° C. (ice-bath) was added triphosgene portionwise. The solution was heated to reflux for 5 hours. The solution was evaporated under vacuum and suspended in Et2O (200 mL). The suspension was filtered and the filtrate evaporated to dryness to give the title compound as a white solid (4.68 gm), 83%; IR (nujol, cm-1): 3295 (C≡C) and 2257 (N=C=O). This crude product was used as such in the next reaction.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:18][C:19]1[CH:20]=[C:21]([CH:31]=[C:32]([O:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[CH:33]=1)[C:22]([NH:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1)=[O:23]>C(#N)C>[OH:39][CH2:38][C@@H:35]([O:34][C:32]1[CH:33]=[C:19]([O:18][C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH:20]=[C:21]([C:22]([NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)=[O:23])[CH:31]=1)[CH2:36][CH3:37]
Reactant: CC[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 16.3 %

Procedure:
Methyl 5-chloropyrazine-2-carboxylate (104 mg, 0.60 mmol) and cesium carbonate (467 mg, 1.43 mmol) were added to a solution of 3-hydroxy-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (175 mg, 0.570 mmol), in acetonitrile (5 mL) and the mixture heated in a microwave reactor at 160° C. for 330 minutes. The acetonitrile was removed in vacuo and the residue dissolved in ethyl acetate (25 mL), washed with water (20 mL), brine (20 mL), dried (MgSO4) and evaporated to a residue which was chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product (41 mg). 1H NMR δ (CDCl3): 0.97 (t, 3H), 1.78 (quin, 2H), 3.82 (s, 3H), 3.91 (s, 3H), 4.52 (m, 3H), 4.66 (quin, 1H), 6.59 (t, 1H), 6.89 (d, 1H), 7.05 (t, 1H), 7.15 (t, 1H), 8.19 (d, 1H), 8.79 (d, 1H), 9.86 (s, 1H); m/z 442 (M+H)+
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]([CH3:45])[N:34]=[CH:35][C:36]=2[CH2:37][O:38]C2CCCCO2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]([CH3:45])[N:34]=[CH:35][C:36]=4[CH2:37][OH:38])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3c(COC4CCCCO4)cnn3C)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3c(CO)cnn3C)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-{3-[2-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-2H-pyrazol-3-yl]-phenyl}-3-oxo-propionyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M63) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (272 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.C(OCC)C.S(=O)(=O)(O)O>C(O)C>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:7])=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
First, 4-hydroxybenzaldehyde (0.488 g, 4 mmole) and 4′-hyroxyacetophenone (0.66 g, 4.84 mmole) are introduced to a 25 mL flask and dissolved completely by adding 10 mL of diethyl ether and 4 mL of ethanol thereto. Next, 4 mL of sulfuric acid is introduced thereto and the reaction mixture is agitated for 3 hours. The reaction mixture is precipitated in water (300 mL) and filtered to obtain a solid, which in turn is washed with distilled water three times, dried under vacuum, and purified by column chromatography using diethyl ether/hexane (1/1, v/v) as eluent to obtain 4,4′-dihydroxychalcone (DHC) having the following structure. The resultant product has a yield and melting point of 30% and 203° C., respectively.
Reaction SMILES: O=O.[CH:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]1[CH:15]=[C:14]([CH2:16][OH:17])[CH2:13][CH2:12][N:7]12>O1CCCC1>[CH:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]1[CH2:15][C@@H:14]([CH2:16][OH:17])[CH2:13][CH2:12][N:7]12
Reactant: OCC1=Cc2cc3ccccc3n2CC1
Agent: O=O
Solvent: C1CCOC1
Product: OC[C@H]1CCn2c(cc3ccccc32)C1
Yield: 99.4 %

Procedure:
The glass attachment of a 30 ml autoclave is charged in a glove box (oxygen content <1 ppm) with 0.20 g (1.0 mmol) of 6,7-dihydropyrido[1,2-a]indole-8-methanol, 9 ml of tetrahydrofuran and 1 ml of the above-mentioned catalyst solution. The hydrogenation is carried out at 80° C., an initial pressure of 60 bar of H2 and while stirring vigorously. After a hydrogenation time of 18 hours, the conversion is 99.9% according to GC. The pale yellow hydrogenation solution is evaporated. The residue is dissolved in diethyl ether and, in order to separate the catalyst, the solution is allowed to flow through a 5 g silica gel column. Rinsing of the column with diethyl ether, evaporation of the eluate and drying of the pale brown crystalline residue yields 0.20 g (100%) (S)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol; GC 100 area %; 91.0% e.e.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:12][C:3]=1[CH2:4][C:5]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Si:17]([O:16][C:13]1[CH:14]=[CH:15][C:2]([C:26]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=2[F:24])=[C:3]([CH2:4][C:5]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:12]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CC2(C#N)CCCC2)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2CC2(C#N)CCCC2)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of 1-(2-bromo-5-((tert-butyl(dimethyl)silyl)oxy)benzyl)cyclopentanecarbonitrile (471 mg), 2-fluoro-5-methoxyphenylboronic acid (361 mg), tris(dibenzylideneacetone)dipalladium(0) (23 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (39 mg) in toluene (5.0 mL) was added 2.0M aqueous sodium carbonate solution (1.8 mL), and the mixture was stirred at 90° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound. The obtained crude product was directly used for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[CH2:11][CH2:12][CH:13]2[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O.CC#[N:30].CCOCC>>[NH2:30][N:2]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:20])[CH2:11][CH2:12][CH:13]2[O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(NC(=O)CCC2CCCC(=O)O2)cc1
Reactant: CC#N
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NN=Cc1ccc(NC(=O)CCC2CCCC(=O)O2)cc1

Procedure:
The title compound was prepared from the product of step B (770 mg, 2.83 mmol) in a manner similar to example 1, step G to give 430 mg (38%) of product as TFA salt after reverse phase chromatography and trituration with CH3CN/Et2O (m.p. 151°-153° C. dec.).
Reaction SMILES: Cl.[C:2]([NH2:8])(=[NH:7])[CH2:3][CH2:4][CH2:5][CH3:6].[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O.C[O-].[Na+]>CO.[Cl-].[Na+].O.O>[CH2:3]([C:2]1[NH:8][C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[N:7]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)CC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(C)cc(=O)[nH]1

Procedure:
A solution of 2.0 g valeramidine hydrochloride, 1.9 g ethyl acetoacetate, and 791 mg sodium methoxide in 20 mL methanol was refluxed for 24 hours. The mixture was diluted with brine and water and was extracted three times with ether. The combined organic material was washed with brine, was dried over MgSO4, was stripped of solvent in vacuo, and then was Still flash chromatographed in 4% MeOH in CH2Cl2 to give the title compound as a white solid 1H NMR (250 MHz, CDCl3) δ13.01 (br s, 1H), 6.18 (s, 1H), 2.67 (3 line m, 2H), 2.31 (s, 3H), 1.76 (m, 2H), 1.42 (m, 2H), 0.95 (3 line m, 3H).
Reaction SMILES: [CH:1]([OH:3])=O.C(N(CC)CC)C.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])CBr)#[N:12].Cl>C(#N)C.CO.O>[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:1][OH:3])#[N:12]
Reactant: N#Cc1cc(CBr)ccc1F
Reactant: O=CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: N#Cc1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 85% formic acid (0.63 mL) and triethylamine (2.32 mL, 16.7 mmol) in acetonitrile at 0 ° C. was treated with the product from Example 82A (1.3 g, 5.6 mmol), stirred at room temperature for 3 hours, the reaction evaporated to dryness partitioned between ethyl acetate/water, the organic layer dried with sodium sulfate, filtered and solvent evaporated to provide a crude formate ester. This residue was dissolved in methanol:water (5:1), treated with a catalytic amount of concentrated hydrochloric acid, stirred at room temperature overnight, evaporated to dryness, and flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1) to provide 0.40 g 3-cyano-4-fluorobenzyl alcohol. 1HNMR (CDCl3) δ 1.81 (t, 1H), 4.72 (d, 2H), 7.21 (t, 1H), 7.62 (m, 2H).