Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:39])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:34])([F:36])[F:35])=[CH:17][N:16]=1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2F)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 2-(2-(2-(2-((2-fluoro-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (I62) (0.037 g, 0.074 mmol) in anhydrous methanol (3 mL) was added 37% aqueous formaldehyde (0.022 mL, 0.30 mmol) and sodium triacetoxyborohydride (0.081 g, 0.38 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and the residue'taken up saturated aqueous NaHCO3 solution (25 mL). The resulting mixture was extracted with EtOAc (2×25 mL) then the combined organic layers were washed with brine (25 mL), dried (phase separation cartridge) and evaporated to dryness under reduced pressure. The residue was purified using silica gel column chromatography (0-50% MeOH/EtOAc with 1% 2 M ethanolic ammonia) to give the title compound (13) (0.020 g, 52%); 1H NMR (400 MHz, d6-Acetone+d4-MeOH) δ 8.54 (s, 1H), 7.88 (dd, J=8.5 Hz, 1H), 7.16 (m, 6H), 3.80 (s, 2H), 3.63 (s, 2H), 3.10 (m, 4H), 2.95 (m, 2H), 2.54 (m, 1H), 2.27 (s, 3H), 1.79 (m, 4H). LCMS Method C: rt 4.93 min; m/z 516.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=[N+]=[N-])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[O:21]=[C:17]1[CH2:18][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][CH2:16]1
Reactant: CCOC(=O)[C@H](CCC(=O)C=[N+]=[N-])NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC(=O)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A solution of (S)-ethyl 2-((tert-butoxycarbonyl)amino)-6-diazo-5-oxohexanoate (350 g, 1.18 mol) in DCM (1500 mL) was added to a solution of Rh2(OAc)4 (3.5 g, 7.9 mmol) in DCM (750 mL) at 0° C. The reaction was then stirred at 20° C. overnight and then concentrated in vacuum. The crude sample was purified by silica gel column chromatography (5:1 petroleum ether/EtOAc) to afford (S)-1-tert-butyl 2-ethyl 5-oxopiperidine-1,2-dicarboxylate (175.9 g, 55%) as a yellow oil.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])O)#[N:2].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:19][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[C:1]#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(C(O)C#N)ccc1OC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(Cl)C#N)ccc1OC

Procedure:
To a suspension of methyl 5-(1-cyano-1-hydroxymethyl)-2-methoxybenzoate (2.15 g) in chloroform (40 ml) were added thionyl chloride (2.0 ml) and DMF (2 drops), and the mixture was refluxed for 30 minutes under heat. After cooling, the reaction mixture was washed with water, aqueous solution of sodium hydrogencarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure to obtain 2.37 g of aimed compound as an oily product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:25])[C:5]2[C:10]([CH2:11][CH2:12]O)=[CH:9][N:8]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:6]=2[N:7]=1.C[CH2:27][N:28](CC)CC.CS(Cl)(=O)=O.[CH2:38]1[CH2:42]OC[CH2:39]1>>[Cl:25][C:4]1[C:5]2[C:10]([CH2:11][CH2:12][NH:28][CH2:27][CH:38]([CH3:39])[CH3:42])=[CH:9][N:8]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: COc1c(C)cnc(Cn2cc(CCO)c3c(Cl)nc(N)nc32)c1C
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Agent: CS(=O)(=O)Cl
Product: COc1c(C)cnc(Cn2cc(CCNCC(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 2-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethanol (11.6 mg, 0.031 mmol) and Et3N (30 ul, 0.22 mmol) in THF (2 mL) was treated with MsCl (11 uL, 0.14 mmol) at rt for 15 min to give a solution of the title compound which was used without further purification. In a separate experiment, the material was purified by preparative TLC (EtOAc 100%). HPLC Rt: 4.765 min. 1H-NMR (CDCl3): δ 8.22 (s, 1H), 6.80 (s, 1H), 5.31 (s, 2H), 4.93 (s, 2H), 4.42 (t, 2H), 3.77 (s, 3H), 2.98 (t, 2H), 2.85 (s, 3H), 2.23 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([CH3:20])=[CH:22][CH:23]=3)=[C:3]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Reactant: Cc1ccc(N)cc1
Product: CCOC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)OC)cnc12
Yield: 35.7 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (0.400 g, 1.51 mmol) obtained in Example 21, step 2 and 4-methylaniline (0.242 g, 2.26 mmol), the title compound (0.191 g, 35%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.O.[C:15]([OH:19])(=O)[CH:16]=O.O.[NH2:21][NH2:22]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[C:8](=[CH:16][C:15](=[O:19])[NH:21][N:22]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: O=CC(=O)O
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: NN
Solvent: O
Product: COc1ccc2c(c1)CCc1cc(=O)[nH]nc1-2

Procedure:
In a manner similar to that described in Preparation 3, 6-methoxy-1-tetralone was treated with glyoxylic acid monohydrate and hydrazine hydrate to give 5,6-dihydro-8-methoxybenzo[h]cinnolin-3[2H]-one (m.p. 246-8°; from aqueous ethanol); ν(Nujol mull) 3320-2200, 1667, 1601, 1270 and 1048 cm-1 ; δ(DMSO-d6) 2.81 (4H,m,5,6-H2), 3.80 (3H,s,OCH3), 6.71 (1H,s,4-H), 6.90 (2H,m,7,9-H), 7.82 (1H,m,10-H), 12.73 (1H,s,NH).
Reaction SMILES: N[C:2](N)=[S:3].[OH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15]COS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].Cl>C(O)C.O>[SH:3][CH2:2][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][OH:5]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCOCCOCCOCCS
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of thiourea (0.94 g, 12.35 mmol) and toluene-4-sulfonic acid 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy)-ethyl ester (4.09 g, 11.75 mmol) in absolute alcohol (32 ml) was heated to reflux under argon atmosphere for 24 h. The mixture was cooled and a solution of NaOH (1.23 g, 30.75 mmol) in 15 ml of ethanol/water (9:1, v/v) was added. Refluxing was continued for another 2.5 h under argon. The reaction mixture was then cooled to ambient temperature and acidified to pH 2 using concentrated hydrochloric acid and then concentrated under reduced pressure. The residue was purified by flash chromatography using ethyl acetate/absolute ethanol (10:1) to afford the product as a colourless oil. Yield 1.55 g (66%).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH:15]([NH:18][C:19]4[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=4)[O:22][CH2:23][C:24]([O:26]C(C)C)=[O:25])[C:14]=3[CH:33]=2)[CH:7]=[CH:8][CH:9]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH:15]([NH:18][C:19]4[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=4)[O:22][CH2:23][C:24]([OH:26])=[O:25])[C:14]=3[CH:33]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)OC(=O)COc1cccc(NC2COc3ccc(-c4cccc(F)c4)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(NC2COc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 55.8 %

Procedure:
Aqueous lithium hydroxide (1 N, 1 mL, 1 mmol) was added to a solution of isopropyl 2-(3-((5-(3-fluorophenyl)-2,3-dihydrobenzofuran-3-yl)amino)phenoxy)acetate (22 mg, 0.052 mmol) in THF (1 mL) in a scintillation vial. The vial was sealed and heated at 40° C. After 24 h, the reaction mixture was allowed to cool and the volatiles were concentrated. The residue was acidified with hydrochloric acid (1 N, 1 mL), and extracted with ethyl acetate (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 11 mg (56%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([OH:12])[CH2:8][CH2:9][NH:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.CN1CCCC1=O.CC(C)([O-])C.[K+]>CS(C)=O>[CH3:11][NH:10][CH2:9][CH2:8][CH:7]([O:12][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CNCCC(O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Yield: 85 %

Procedure:
An improved process for the preparation in a superior yield of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine of formula (I), ##STR5## or a pharmaceutically acceptable acid addition salt thereof, the said process comprising catalytically hydrogenating 2-benzoyl-1-(N-benzyl-N-methyl)ethylamine base of formula (II), ##STR6## to obtain 1-phenyl-3-(N-methylamino)-propan-1-ol of formula (III), ##STR7## and selectively etherifying the compound of formula (III) with 1-chloro-4-trifluoromethylbenzene of formula (IV), ##STR8## in a solvent selected from the group consisting of N-methylpyrrolidone and dimethylsulfoxide in the presence of a potassium t-butoxide, whereby N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine is formed in a yield greater than 85 percent of the theoretical value.
Reaction SMILES: [C:1]1(C(=CC=CC=1)O)[OH:2].[C:9]1([CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[CH:11]=1)[OH:10].C1(C=CC(O)=CC=1)O>>[OH:10][C:9]1[CH:11]=[C:12]([OH:13])[CH:14]=[CH:15][C:16]=1[CH:1]=[O:2]
Reactant: Oc1ccccc1O
Reactant: Oc1cccc(O)c1
Agent: Oc1ccc(O)cc1
Product: O=Cc1ccc(O)cc1O

Procedure:
catechol; resorcinol; hydroquinone;
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[CH3:25])([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:1][C:2]([F:26])([F:27])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:36]([CH3:35])(=[O:38])=[O:37])[C:21]([F:23])([F:22])[F:24])[CH:12]=[CH:11][C:10]=1[CH3:25])([O:8][S:36]([CH3:35])(=[O:38])=[O:37])[C:4]([F:7])([F:6])[F:5]
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C(O)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4.25 g (10 mmol) of 2,4-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-toluene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 2.86 g (25 mmol) of methanesulfonyl chloride were added dropwise at 5° to 10° C. The mixture was stirred for 16 hours at room temperature, separated off from the precipitated salt, washed with water, dried and evaporated down. The residue was chromatographed over a silica gel column with methylene chloride/n-hexane (1:1). After the eluate had been evaporated down, 2.9 g of 2,4- bis-(2,2,2-trifluoro-1-methanesulfonyloxy-1-trifluoromethylethyl)-toluene were obtained (colorless crystals, m.p.: 107° C.).
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[N:11][N:10]=[N:9]1)C.Cl.O>C(O)(=O)C>[N:8]1([CH2:7][CH2:6][CH2:5][C:4]([OH:13])=[O:3])[CH:12]=[N:11][N:10]=[N:9]1
Reactant: CCOC(=O)CCCn1cnnn1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCn1cnnn1

Procedure:
6.65 g of 4-(tetrazol-1-yl)-butyric acid ethyl ester are stirred in 42.7 ml of acetic acid, 8.1 ml of concentrated HCl and 17.2 ml of water for 3 hours at 100°. After cooling, the reaction mixture is concentrated three times each with toluene and ether under reduced pressure in a rotary evaporator. After drying under a high vacuum, the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3ccccc3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with phenylpiperazine dihydrochloride in the presence of triethylamine to give 1-phenyl-4-(p-nitrobenzyl)piperazine
Reaction SMILES: [OH:1][CH:2]1[CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH:6]2[CH:4]([CH2:5]2)[CH2:3]1>CO.[Pd]>[CH:4]12[CH2:5][CH:6]1[CH2:7][NH:8][CH2:9][CH:2]([OH:1])[CH2:3]2
Reactant: O=C(OCc1ccccc1)N1CC(O)CC2CC2C1
Agent: [Pd]
Solvent: CO
Product: OC1CNCC2CC2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a solution of benzyl 3-hydroxy-5-azabicyclo[5.1.0]octane-5-carboxylate (110.00 mg, 420.94 umol, 1.00 Eq) in MeOH (10 mL) was added Pd—C under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 at 25° C. for 4 hr. TLC showed the starting material was consumed completely. The reaction mixture was filtered and the filter was concentrated to give 5-azabicyclo[5.1.0]octan-3-ol (37.00 mg, 290.93 umol, 69.11% yield) as colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[C:20]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[C:23]([O:22][C:20]([NH:27][C@@H:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:37])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (1.3 g, 5.17 mmole), Boc-L-Phenylalanine (1.37 g, 5.17 mmole), HBT (0.70 g, 5.17 mmole), and EDC (0.99 g, 5.17 mmole) were combined in DMF (30 ml) and stirred at room temperature. The pH of the mixture was adjusted to 9.5 with triethylamine. After 1/2 hour, the DMF was removed in vacuo and the residue treated with 10% citric acid (10 ml), neutralized with NaCO3 and extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with water, dried over Na2CO3 filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (90/3/0.3/0.3 CH2Cl2 /MeOH/H2 /HOAc) and the combined product fractions evaporated to dryness in vacuo. The residue was dissolved in CH2Cl2 (10 ml), washed with saturated Na2CO3 solution (2 ml), dried over Na2SO4, filtered and evaporated to dryness. The residue was treated with Et2O and evaporated five times to give the title compound as a mixture of diastereomers (m.p. 143°-153° C.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1.[NH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15]>CCOCC.C1C=CC=CC=1.C(O)(C)(C)C>[NH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][O:15][C:7]1[N:6]=[N:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: CC(C)(N)CCO
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC(C)(N)CCOc1ccc(Cl)nn1
Yield: 84.8 %

Procedure:
A mixture of 0.62 g of 60% sodium hydride, 1.91 g of 3,6-dichloropyridazine and 10 ml of benzene was stirred while being cooled with ice, and a solution consisting of 1.32 g of 3-amino-3-methylbutanol, 3 ml of t-butanol and 5 ml of benzene was added dropwise. After stirring at room temperature for 30 minutes, ether was added to the reaction mixture, and the solid was removed by filtration with Hyflo Super-Cel. The filtrate was concentrated under reduced pressure. n-Hexane was added to the resulting oily product, and the mixture was allowed to stand to give 2.34 g of 3-(3-amino-3-methylbutoxy)-6-chloropyridazine as colorless crystals having a melting point of 63.5° to 65.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:15](O)=O>[Pd]>[NH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[N:1]=[CH:15]1
Reactant: O=CO
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Product: COC(=O)c1cccc2[nH]cnc12
Temperature: 100 °C
Reaction time: 23 h

Procedure:
To a suspension of methyl 2-amino-3-nitrobenzoate (1.0 g) in formic acid (>87%) was added 5% palladium on carbon (100 mg) and the suspension was heated with stirring at 100° C. for 23 hours. After the reaction mixture was cooled to room temperature, the catalyst was filtered off on celite, and the mother liquor was concentrated in vacuo. The residual solid was washed with diethyl ether under stirring, the solid was collected by filtration to obtain the titled compound (872 mg) as a colorless powder.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([CH:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>O1CCCC1>[CH3:13][O:12][C:10](=[O:11])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH3:21])=[CH:4][CH:5]=1)([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[OH:30]
Reactant: COC(=O)C(c1ccc(C)cc1)c1ccc(C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(O)(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of NaH (255 mg, 10.6 mmol) in tetrahydrofuran (50 mL) was cooled to 0° C. and treated with a solution of 21 (2.29 g, 9.00 mmol) in tetrahydrofuran. The cooling bath was removed and DMF (1 mL) was added to the reaction. The resulting mixture was stirred at room temperature overnight. The mixture was treated with TMS-Cl (10 mL of 1M THF solution) and stirred at room temperature (2 h). The reaction was treated with solid MCPBA (85%, 3.49 g, 17.2 mmol) and stirred at room temperature overnight. The reaction was quenched with tetrabutylammonium fluoride and diluted with ethyl acetate and water. The aqueous layer was extracted with two additional portions of ethyl acetate and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (dichloromethane/hexane) afforded the title compound (22).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:5]2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=2)[CH2:5]3)[CH2:29][CH2:28]1
Reactant: O=C1c2ccc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)CC1
Yield: 41.1 %

Procedure:
A mixture of 5-bromo-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.039 g, 0.1 mmol), 1-methyl piperazine (0.022 mL, 0.2 mmol), Pd2.dba3 (0.009 g, 0.01 mmol), BINAP (0.012 g, 0.02 mmol), and sodium tertiary-butoxide (0.030 g, 0.3 mmol) in toluene (3 mL) was heated to reflux for 3 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(4-Methyl-piperazin-1-yl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.017 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.37 (s, 3H), 2.58 (m, 4H), 3.32 (m, 4H), 4.20 (s, 2H), 4.72 (s, 2H), 6.83-7.36 (m, 11H), 7.75 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]([F:16])=[C:4](Cl)[N:3]=1.[C:18]([NH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)(=[O:20])[CH3:19]>>[C:18]([NH:21][CH:22]1[CH2:26][CH2:25][N:24]([C:4]2[N:3]=[C:2]([Cl:1])[C:7]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]=2[F:16])[CH2:23]1)(=[O:20])[CH3:19]
Reactant: CC(=O)NC1CCNC1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)nc1Cl
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Cl

Procedure:
Ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxo-propionate (1.4 g) prepared in Reference Example 10-(3) was allowed to react with 3-acetylaminopyrrolidine to give ethyl 3-[6-(3-acetylamino-1-pyrrolidinyl)-2-chloro-5-fluoropyridin-3-yl]-3-oxopropionate (0.78 g) as a oil. This compound (0.74 g) was treated with ethyl orthoformate and acetic anhydride, and the resulting oil, ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-chloro-5-fluoronicotinoyl]-3-ethoxyacrylate, was allowed to react with cyclopropylamine to give ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-chloro-5-fluoronicotinoyl]-3-cyclopropylaminoacrylate (0.43 g) as an amorphous powder, m.p. 71°-75° C.
Reaction SMILES: [Li+].[AlH4-].C(OC(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[NH:24][C:16]2[N:17]=[CH:18][N:19]=[C:20]([N:21]([CH3:23])[CH3:22])[C:15]=2[CH:14]=1)C.[C:26](OCC)(=[O:28])C.CO>C1COCC1>[CH3:22][N:21]([CH3:23])[C:20]1[C:15]2[CH:14]=[C:13]([C:8]3[CH:7]=[CH:12][C:11]([CH2:26][OH:28])=[CH:10][CH:9]=3)[NH:24][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: CCOC(=O)c1ccccc1-c1cc2c(N(C)C)ncnc2[nH]1
Reactant: CCOC(C)=O
Agent: [AlH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ncnc2[nH]c(-c3ccc(CO)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Li[AlH4] (660 mg, 17.40 mmol) is suspended in THF (70 mL). The suspension is cooled in an ice bath and small portions of 4-(4-Dimethylamino-7H-pyrrolo[2,3-d]pyrimidin-6-yl-benzoic acid ethylester are added under an argon atmosphere. The reaction is stirred for 30 min. at room temperature and then heated to 50° C. for additional 30 min. It is then cooled to room temperature again and quenched by careful addition of dilute aqueous NaOH solution. The resulting suspension is stirred for 30 min. and then all inorganic salts are removed by filtration. The remainig solution is concentrated in vacuo to give a yellow solid which is titurated with hexanes. The product is isolated by filtration and dried in vacuo to give a white powder. C15H16N4O: M+H=269.1; 1H-NMR (400 MHz, DMSO-d6): 13.01 (s, 1H, NH), 8.23 (s, 1H), 7.89 (d, 2H), 7.39 (d, 2H), 7.19 (s, 1H), 5.21 (s, 1H, OH), 4.55 (d, 2H), 3.35 (s, 6H). m. p.=306-309° C. Rf (ethyl acetate/MeOH 9:1)=0.30.