Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([CH3:38])[CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:27])[F:29])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCNC2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC[C@@H](n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 104 %

Procedure:
Combine 4-[(R)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1-piperidin-3-yl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.49 mmol; 741 mg); formaldehyde (5 equiv; 7.46 mmol; 560 μL); sodium triacetoxyborohydride (2 equiv; 2.98 mmol; 632 mg) and THF (25 mL) and stir at 20° C. for 20 min. Dilute with EA, wash the organic phase 2× with saturated sodium bicarbonate, brine, dry over MgSO4, filter and evaporate to provide the title compound (790.3 mg; 1.55 mmol; 104%). MS (ES+): m/z=511 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.C(OCC)(=O)C.[Ni]>[N:11]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=12
Reactant: O=[N+]([O-])c1ccc(-c2cn3ccccc3n2)cc1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
4.50 g (18.8 mmol) 2-(4-Nitro-phenyl)-imidazo[1,2-a]pyridine and 0.45 g Raney-Nickel are stirred at RT under hydrogen (50 psi) in 50 mL ethanol and 50 mL ethyl acetate. The mixture is filtered and the solvent is evaporated.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@H:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:11][C@H:12]([P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:27]([O:26][P:21]([C@@H:12]([NH:11][C@H:10]([C:9]([OH:33])=[O:8])[CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([O:23][CH2:24][CH3:25])=[O:22])[CH3:28]
Reactant: CCOP(=O)(OCC)[C@H](CCc1ccccc1)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CCO
Product: CCOP(=O)(OCC)[C@H](CCc1ccccc1)N[C@@H](CC(C)C)C(=O)O
Yield: 101.9 %

Procedure:
To a solution of 230 mg of N-[1-(R)-diethoxyphosphoryl-3-phenylpropyl]-L-leucine benzyl ester in 5 ml of 95% ethanol was added 50 mg of 10% Pd--C, and the mixture was stirred under an atmospheric pressure of hydrogen at room temperature for 3 hours. The Pd--C was filtered off, and the solvent was distilled off under reduced pressure to yield the title compound as a colorless oil (190 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)Nc2cc(CN3C(=O)N(c4ccc(C(C)(C)C)cc4)C(=O)C3(C)C)ccn2)CC1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 31 μl of N-methylpiperazine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 94 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-4-methylpiperazine-1-carboxamide, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CCN)cc1OC

Procedure:
In a manner similar to Preparation 2 react 3,4-dimethoxybenzeneacetonitrile with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]([NH:26][C:27](=[O:53])[CH:28]([NH:32][CH2:33][CH:34]([NH:42]C(OCC1C=CC=CC=1)=O)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:29]([CH3:31])[CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH2:42][CH:34]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:33][NH:32][CH:28]([CH:29]([CH3:30])[CH3:31])[C:27]([NH:26][CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:24])([CH3:25])[CH3:23])[CH:16]=1)[CH2:12][NH2:11])=[O:53]
Reactant: [H][H]
Reactant: CC(C)C(NCC(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NC(CNC(=O)OCc1ccccc1)Cc1ccc(O)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(NCC(N)Cc1ccccc1)C(=O)NC(CN)Cc1ccc(O)c(C(C)(C)C)c1

Procedure:
To a solution of 132 mg (0.183 mmol) of N-[2-benzoxycarbonylamino-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]-2-[[2-(benzoxycarbonylamino)-3-phenylpropyl]amino]-3-methyl butanamide in methanol (2 ml), 10% palladium carbon (80 mg) was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 days. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to yield 2-[(2-amino-3-phenylpropyl)amino]-N-[2-amino-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]-3-methyl butanamide in the amount of 24.2 mg (29%).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C@H:24]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[C@@H:25]([NH2:27])[CH3:26])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C@H:24]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[C@@H:25]([NH:27][C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH3:26])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[CH:12][CH:13]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Solvent: C1CCOC1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@@H](C)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,1-carbonyldiimidazole (31 mg, 190 Amok) in THF (1 ml) was added (2R)-2-hydroxypropanoic acid (18 mg, 20 μmol) to give a colorless solution. The reaction mixture was stirred for 1 h at r.t. Then a solution of (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 μmol) in THF (0.5 ml) was added, and the stirring was continued at r.t. overnight. The solvent was removed in vacuo, the residue dissolved in acetonitrile/water mixture, and the crude product purified by preparative HPLC. Yield 16 mg (35%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:15]([N:8]1[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccccc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
In 150 ml of dimethylformamide, there were stirred 206.5 g of 2-phenyl-4-chloro-5-formylimidazole, 133 g of benzyl chloride and 103.5 g of anhydrous potassium carbonate at 110°-120° C. for an hour. The reaction mixture was poured in ice-water and the resulting precipitate was recovered by filtration and recrystallized from acetonitrile twice. By the above procedure was obtained 143 g of 1-benzyl-2-phenyl-4-chloro-5-formylimidazole as colorless needles, m.p. 117°-118° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:36]=[C:24]1[CH2:25][C:26]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=2)=[N:7][C:8]2[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]=2[NH:23]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3cc(N4CCCC4)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M36) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (65 mg).
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:26]([F:35])[CH:25]=1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:26]([F:35])[CH:25]=2)=[O:18])=[CH:19][CH:20]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 722.2 %

Procedure:
To a N,N-dimethylformamide (DMF) (10 ml) solution of (4-tert-butylphenoxy)acetic acid (50 mg, 0.2 mmol) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (40.4 mg, 0.2 mmol, J. Med. Chem. 2003, 46, 3116–3126), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (112 mg, 0.6 mmol), 1-hydroxybenzotriazole(HOBt) monohydrate (catalytic amount 5 mg) and triethylamine (0.3 ml) were added and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride. The organic layer was then washed with brine and dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with methylene dichloride/methanol=9/1 to furnish 0.59 g (75% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](C)=[C:5]([C:18]([O:20][CH3:21])=[O:19])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C:2]12[CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]([C:18]([O:20][CH3:21])=[O:19])([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]1[C:8]([O:10][CH3:11])=[O:9])[CH:4]=[N:3]2
Reactant: C=Cc1ccccc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)C1C(c2ccccc2)C2(C(=O)OC)C=NC1(C)CC2c1ccccc1
Reaction time: 3 h

Procedure:
To 0.45 g (1.5 mmol) dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1) in 25 ml CHCl3 under N2 and cooled to 0°-10° in an ice bath there was added 3.12 g (30.0 mmol) of commercially obtained styrene (4) followed by 0.64 g (4.5 mmol) boron trifluoride etherate added dropwise via syringe. The resulting solution was stirred at 0°-10° for 3 hours and then at room temperature for 16 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]2=[O:15].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([NH:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]2=[O:15])=[O:20])[CH3:17]
Reactant: Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.08 g (20 mmol) of 6-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Pharm. Sci., 11, 1051 (1963)] 2.37 ml (30 mmol) of ethyl isocyanate, 2.8 ml (20 mmol) of triethylamine and 50 ml of dimethylformamide is stirred at room temperature overnight. The solution is evaporated to dryness and the residue is treated with 1 N hydrochloric acid. The solid is filtered to give 4.56 g of 6-[[(ethylamino)carbonyl]-amino]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp>320° C.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[CH2:20][C:21]([OH:23])=O)([O-])=O.[OH-].[Na+]>C(O)C>[NH2:17][C:15]1[CH:16]=[C:11]2[C:12]([CH2:20][C:21](=[O:23])[NH:8]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)NC(=O)C2
Temperature: 90 °C
Yield: 101.3 %

Procedure:
Tin chloride dihydrate (225 g) was added to a solution of 2,4-dinitrophenylacetic acid (22.6 g) in ethanol (450 ml). The mixture was heated at 90° C. for 10 hours. The reaction mixture was cooled and adjusted to pH 11 with 12M sodium hydroxide. The solids were removed by filtration and the filtrate was concentrated. The residue was treated with ethanol (300 ml). Insoluble materials were removed by filtration and washed with ethanol (5×60 ml). The combined ethanol solutions were evaporated and the solid obtained was dried under vacuum to give 15 g of 6-amino-2-oxindole as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:4]=2[N:3]=1.[Br-].[CH2:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:16]([C:14]1[CH:13]=[CH:12][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:15]=1)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Agent: [Br-]
Product: Nc1nc2cc(CCc3ccccc3)ccc2c2cccnc12

Procedure:
8-Phenethylbenzo[f][1,7]naphthyridin-5-amine was prepared from 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) with benzyltriphenylphosphonium bromide following the procedures described for Example 91 (wittig reaction) and Example 92 (reduction). 1H NMR (acetone-d6): δ 8.99 (dd, 1H), 8.88 (dd, 1H), 8.35 (d, 1H), 7.83 (dd, 1H), 7.49 (d, 1H), 7.29-7.15 (dd, 6H), 6.70 (br s, 2H), 3.10-3.00 (m, 4H). LRMS [M+H]=300.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: c1ccccc1
Product: CCCCNc1c(C(=O)OCC)cnc2c1cnn2CC
Reaction time: 72 h

Procedure:
To a solution of 5.08 g of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.02 mol) in 20 ml of benzene is added 2.92 g of n-butylamine (0.04 mol). This mixture is kept at room temperature for 3 days. After this time, the separated butylamine hydrochloride is filtered under suction and the filtrate is evaporated in vacuo to dryness. The residue, 4-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethylester, is recrystallized from hexane, m.p. 82°-83°. The total yield amounts to 5.3 g = 91.5% of theory.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[K+].[CH:14]([B-](F)(F)F)=[CH2:15]>>[CH:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)=[CH2:15]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Product: C=Cc1ccc(C(=O)OC)c(F)c1

Procedure:
The title compound was prepared from methyl 4-bromo-2-fluorobenzoate and vinyltrifluoroborate potassium salt according to the procedure for the preparation of Example 135, part A. 1H NMR (300 MHz, CDCl3): δ 3.92 (3H, s), 5.43 (1H, d, J=11.1 Hz), 5.86 (1H, d, J=17.4 Hz), 6.69 (1H, dd, J=11.1 Hz, 17.4 Hz), 7.15 (1H, d, J=12.0 Hz), 7.21 (1H, dd, J=0.9 Hz, 7.8 Hz), 7.89 (1H, t, J=8.1 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][S:13][C:14](=[N:17]C#N)SC>>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:14](=[NH:17])[S:13][CH3:12]
Reactant: NCCSCc1ccccn1
Reactant: CSC(=NC#N)SC
Product: CSC(=N)NCCSCc1ccccn1

Procedure:
The reaction of 2-((2-aminoethyl)thiomethyl)pyridine with dimethylcyanodithioimidocarbonate by a method similar to that described in Example (3d) afforded N-cyano-N'-[(2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea, m.p. 85 - 88°. (from isopropyl alcohol-ether)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of p-toluidine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:16]=[CH:15]C(C(O)=O)=[C:10]([Cl:17])[CH:9]=1>C(Cl)Cl.CN(C=O)C>[Br:7][C:8]1[CH:16]=[CH:15][C:1]([C:2]([Cl:4])=[O:3])=[C:10]([Cl:17])[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Oxalylchloride (0.86 ml, 10.2 mmol) was added dropwise to a suspension of 4-bromo-2-chlorobenzoic acid (2.00 g, 8.5 mmol) in DCM (20 ml) at rt. After the addition of 5 drops of DMF, the reaction mixture was refluxed for 4 h, then cooled to rt and concentrated in vacuo to give 4-bromo-2-chloro-benzoyl chloride (2.15 g, 100%) which was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.98 (d, J=8.5 Hz, 1H), 7.70 (d, J=2 Hz, 1H), 7.57 (dd, J=2 and 8 Hz 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=3)=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A solution of 5.0 g (21.3 mmol) of (RS)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 2 b)] in 200 ml of 2-butanone is treated with 3.55 ml (27.6 mmol) of 4-fluorobenzyl-bromide and 5.88 g (42.5 mmol) of potassium carbonate and the mixture is stirred at 90° C. for 3 hours. For the working-up, the reaction mixture is diluted with ethyl acetate and extracted with water. The organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 98:2-mixture dichloromethane and methanol as the eluent. There are obtained 7.18 g (98% of theory) of (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=344 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([C:27](O)=[O:28])=[CH:25][N:24]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[N:22]=2)[CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:27]([C:26]2[C:21]([CH:18]3[CH2:20][CH2:19]3)=[N:22][C:23]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=3)=[N:24][CH:25]=2)=[O:28])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[4-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
Reaction SMILES: [CH3:1][N:2]([C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.O.[NH2:24][NH2:25]>CCO>[NH:24]([C:7]([C:6]1[CH:11]=[CH:12][C:3]([N:2]([CH3:1])[C:13](=[O:22])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=1)=[O:8])[NH2:25]
Reactant: NN
Reactant: COC(=O)c1ccc(N(C)C(=O)CCc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: CN(C(=O)CCc1ccccc1)c1ccc(C(=O)NN)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of methyl 4-[methyl(3-phenylpropanoyl)amino]benzoate (1600 mg, 5.38 mmol) in EtOH (14 mL) was added hydrazine hydrate (4.0 mL). The resulting mixture was stirred for 16 h at reflux and evaporated under vacuo to give the title compound (1600 mg, 100%) as a gummy colorless oil, which was used in the next step without any further purification.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:19])[C:17]=1Cl)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C(O)C>[C:1]([N:4]([C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:19])[C:17]=1[N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: CC(=O)N(C(C)=O)C1=C(N2CCN(c3ccc(F)cc3)CC2)C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1.66 g of 2-[N,N-diacetylamino]-3-chloro-1,4-naphthoquinone and 1.441 g of 1-(4-fluorophenyl)-piperazine in 50 ml of ethanol was refluxed overnight, then evaporated in vacuo. The residue was dissolved in dichloromethane, filtered through silica gel and eluted with chloroform:methanol (100:2). The eluent was evaporated and the residue crystallized from dichloromethane/-hexane, giving 800 ml of the desired product, mp 149°-150° C.