Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:38])[N:15]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ON1C2N=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[CH2:62]([O:64][C:65](=[O:70])[C@H:66]([OH:69])[CH2:67][NH2:68])[CH3:63].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:62]([O:64][C:65](=[O:70])[C@H:66]([OH:69])[CH2:67][NH:68][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:15]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[C:14]([NH:13][C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:4]=2)=[O:38])=[CH:37][CH:36]=1)[CH3:63]
Reactant: O=C(O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Reactant: CCOC(=O)[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (0.22 g, 0.39 mmol) was dissolved in DMF (3 mL) and 1-hydroxy-7-azabenzotriazole (0.06 g, 0.47 mmol) and EDAC (0.09 g, 1.2 mmol) were added. The mixture was stirred for 1.5 hour, and (R)-isoserine ethyl ester (0.10 g, 0.59 mmol) and diisopropylethylamine (0.10 mL, 0.59 mmol) in DMF (2 mL) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×10 mL) and water:saturated sodium chloride (1:1), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (35 g silica gel) using ethyl acetate and n-heptane (6:4) as eluent to afford 0.27 g of (R)-3-(4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino)-2-hydroxypropionic acid ethyl ester.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=O>O.C(O)C.C(OCC)C>[ClH:11].[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=[N:5][NH:6][C:7]([NH2:9])=[NH:8]
Reactant: O=Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: N=C(N)NN=Cc1c(Cl)cc([N+](=O)[O-])cc1Cl

Procedure:
Aminoguanidine hydrogen carbonate (0.96 g, 7.0 mmol) was added to a solution of concentrated hydrochloric acid (0.6 cm3) in water (2 cm3). After diluting the resulting solution with ethanol (20 cm3), 2,6-dichloro-4-nitrobenzaldehyde (1.53 g, 7.0 mmol) was added and the suspension heated under reflux for 2.5 h. The reaction mixture was cooled and diluted with diethyl ether to yield (2,6-dichloro-4-nitrobenzylidene amino)-guanidine hydrochloride as a yellow solid, mp 190° C. (dec).
Reaction SMILES: N[C:2]1[N:7]=[C:6](N[C@H](C2N(C3C=CC=CC=3)C(=O)C3C(C=2)=CC=CC=3C2C=CN=C(OC)C=2)C)[C:5]([C:36]([OH:38])=O)=[CH:4][N:3]=1.[CH2:39]([N:41]=[C:42]=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:39][N:41]([CH3:42])[C:36]([C:5]1[CH:6]=[N:7][CH:2]=[N:3][CH:4]=1)=[O:38]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(=O)O)n(-c4ccccc4)c(=O)c23)ccn1
Agent: CNC
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-pyrimidine-5-carboxylic acid (44 mg, 0.087 mmol) in anhydrous N,N-dimethylmethanamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25 mg, 0.13 mmol) and hydroxybenzotriazole (18 mg, 0.13 mmol) were added and the resulting mixture was stirred at RT for 30 min. To this mixture, dimethylamine (2M in THF, 0.065 mL, 0.13 mmol) and N,N-diisopropylethylamine (0.040 mL, 0.19 mmol) were added and the reaction mixture was stirred at RT for 3 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 112, (S)-2-amino-441-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-N,N-dimethylpyrimidine-5-carboxamide. ESI-MS m/z: 533.8 [M−H]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:51][CH2:52][CH2:53][C:54]1[N:55]([CH3:59])[CH:56]=[CH:57][CH:58]=1>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26]([NH:51][CH2:52][CH2:53][C:54]2[N:55]([CH3:59])[CH:56]=[CH:57][CH:58]=2)=[O:27])=[CH:18]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: Cn1cccc1CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cccc1CCNC(=O)C(C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 2 h

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.401 g, 1.01 mmol) in dry ethyl acetate (4 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.139 g, 1.03 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.199 g, 1.40 mmol). This mixture was stirred 2 hours and 0.16 g (1.3 mmole) of 2-(2-aminoethyl)-1-methylpyrrole was added. After stirring an additional 18 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, saturated aqueous sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4 and purified by flash chromatography (SiO2, 4×20 cm, 230-400 mesh, 67% ethyl acetate/hexane eluant). Concentration followed by drying under vacuum for 48 hours at 60° C. provided 0.301 g (59%) at product; 1H NMR (CDCl3) δ 1.49-1.60 (2H, m), 1.56 (3H, s), 1.70-2.00 (12H, m), 2.61 (2H, t, J 7 Hz), 3.23-3.55 (4H, m), 3.50 (3H, s), 4.82 (1H, br s), 5.20 (1H, br s), 5.76 (1H, br s), 6.00 (1H, t, J 3Hz), 6.34 (1H, br s), 6.53 (1H, br s), 6.97 (1H, br s), 7.09-7.19 (2H, m), 7.36 (1H, d, J 8 Hz), 7.59 (1H, d, J 8 Hz), 8.16 (1H, br s).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH:22]([CH3:25])[CH2:23][SH:24].Cl>CN(C)C=O>[CH2:23]([S:24][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH:22]([CH3:25])[CH3:21]
Reactant: CC(C)CS
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CSc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example B4(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.97 mmol 2-methyl-1-propanethiol and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid which was used in the next step without further purification (yield 99%). MS (m/e): 287.0 ([M−H]−, 100%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([OH:13])=[C:7]([CH2:14][C:15]([CH3:17])=[CH2:16])[C:6]=1[CH3:18])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]2[O:13][C:15]([CH2:17][OH:27])([CH3:16])[CH2:14][C:7]=2[C:6]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1c(C)c(OC(C)=O)c(C)c(C)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(CO)O2
Reaction time: 1 h
Yield: 87.3 %

Procedure:
In methylene chloride (100 ml) was dissolved 4-acetoxy-2-(2-methyl-2-propenyl)-3,5,6-trimethylphenol [30 g (40.3 mmol)]. To the solution was added at 0° C., in limited amounts, m-chloroperbenzoic acid [16.7 g (67.8 mmol)]. The reaction mixture was stirred for one hour, and there was added triethylamine (30 ml), followed by stirring for further one hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, and then dried, followed by distilling off the solvent. The residue was crystallized from isopropyl ether-hexane to obtain the desired 5-acetoxy-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran [9.3 g (yield 87.4%, m.p. 98°-99° C.)].
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:16])=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:16])=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Nc1c(-c2cccnc2)cncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cncc(-c2cccnc2)c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 5-nitro-3,3′-bipyridin-4-amine (LIX) (5 g, 23 mmol) in MeOH (20 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 15 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 3,3′-bipyridine-4,5-diamine (LX) as off white solid (3.3 g, 17.7 mmol, 76% yield). 1H NMR (DMSO-d6, 500 MHz,): δ ppm 8.63-8.53 (m, 1H), 7.90-7.83 (m, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.48-7.43 (m, 2H), 6.13 (bs, 2H), 5.31 (bs, 2H). ESIMS found C10H10N4 m/z 187.10 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(Cc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 52.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-methoxybenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.075 g; 0.240 mmol), 3-methoxyphenylboronic acid (0.038 g; 0.240 mmol), tetrakis(triphenylphosphine)palladium(0) (0.014 g; 0.012 mmol), sodium carbonate (0.051 g; 0.479 mmol), sodium iodide (0.072 g; 0.479 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.053 g (53%) of the title compound as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>Cl>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[C:20]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:32])=[O:5])=[CH:12][CH:11]=2)[CH2:19][CH2:18]1)=[O:21]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCN(C(=O)c3ccc4ccccc4c3)CC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(NC2CCN(C(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.3 %

Procedure:
A solution of (10) (0.039 g, 0.09 mmol) in HCl (5 mL, 4M in 1,4-dioxane) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was concentrated to give a white solid residue (0.02 g, 57%); 1H NMR (DMSO) δ 7.98 (m, 4H), 7.66 (d, 2H, J=8.7), 7.55 (m, 3H), 6.65 (d, 2H, J=8.8), 4.41 (m, 2H), 3.67 (m, 1H), 3.15 (m, 2H), 1.95 (m, 2H), 1.40 (m, 2H); 13C NMR (DMSO) δ 169.0, 167.4, 151.1, 133.6, 133.1, 132.3, 131.1, 128.3, 128.1, 127.7, 127.1, 126.8, 126.1, 124.3, 117.3, 111.6, 48.7, 45.9, 31.2; HRMS (FAB) m/z 375.1693 (M+H)+ (C23H22N2O3 requires 375.1709); Anal. (C23H22N2O3 ·2HCl·4H2O) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccnc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
3-Methylpyridine-2-carbonitrile (2.0 g, 16.95 mmol) in THF (50 ml) at 0° C. was added to a solution of lithium aluminium hydride (16.95 ml, 1 M in THF) and the mixture allowed to warm to RT overnight. The reaction was cooled to 0° C. and quenched with ethyl acetate (2.5 ml). Sodium hydroxide (2.5 ml, 1 M) was added and the mixture stirred at RT for 1 h, then filtered through Celite®. The filtrate was extracted with ethyl acetate (2×20 ml) and the combined organics washed with brine (50 ml) and dried (MgSO4). The crude material was purified by chromatography (0–5% MeOH in CH2Cl2+1% NH3) to yield a yellow oil (282 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH2:28][OH:29])[CH:3]=1.C(N(CC)CC)C.[C:37]1([CH3:49])[C:38]([S:43]([N:46]=[C:47]=[O:48])(=[O:45])=[O:44])=[CH:39][CH:40]=[CH:41][CH:42]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH:3]=1)[CH2:28][O:29][C:47](=[O:48])[NH:46][S:43]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH3:49])(=[O:44])=[O:45]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CO
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)NC(=O)OCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 55 °C

Procedure:
To a solution of 2-(4-chloro-2-hydroxymethyl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.050 g, 0.12 mmol) in dry toluene (2 mL) was added triethylamine (0.05 mL, 0.36 mmol) followed by o-toluenesulfonylisocyanate (0.05 mL, 0.36 mmol) and catalytic 4-dimethylaminopyridine. After 23 hours the reaction was warmed to 55° C. for 2 hours. After cooling the reaction was evaporated to dryness and the title compound purified by silica gel chromatography (0.074 g, LRMS: 618.1).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](OCC)(=[O:9])[C:6]([CH3:8])=[O:7]>>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:9])[C:6](=[O:7])[CH3:8]
Reactant: CCOC(=O)C(C)=O
Reactant: NCCO
Product: CC(=O)C(=O)NCCO
Temperature: 120 °C
Reaction time: 3 h
Yield: 11.6 %

Procedure:
Ethanolamine (16 g, 66 mmol) was added dropwise to stirred ethyl pyruvate (8 g, 69 mmol) at temperature between 22 and 48° C. Then the mixture was heated to 120° C. and stirred at this temperature for 3 hours. During the reaction, the formed ethanol and water were removed by distillation. The reaction mixture was cooled to room temperature and poured into 40 ml of water. The mixture was acidified to pH<1 and stirred for 30 minutes at room temperature. The solution was saturated with sodium chloride and extracted with ethyl acetate a few times. The ethyl acetate layer was evaporated to dryness. The remaining residual oil was purified by silica gel column chromatography using heptane/ethyl acetate to yield colorless oil (1 g, 9% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[OH:17])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>>[NH2:26]/[C:6](/[C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1)=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1
Reactant: Cc1ccc(C(=O)c2sc3ccccc3c2O)cc1
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1ccc(/C(N)=C2\Sc3ccccc3C2=O)cc1
Yield: 62 %

Procedure:
Prepared as in Example 1 from 2-(4-methylbenzoyl)-benzo[b]thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 62% theory.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[O:23][CH2:22][C:12]4([C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[NH:14][C:13]4=[O:21])[C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24].CC1C2C=[C:32]3[C:37]4(C5C(=CC=CC=5)NC4=O)[CH2:36][O:35][C:33]3=[CH:34]C=2ON=1.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][N:2]1[C:3](=[O:24])[CH2:4][O:5][C:6]2[CH:11]=[C:10]3[C:12]4([C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]([CH2:34][C@H:33]5[CH2:32][CH2:37][CH2:36][O:35]5)[C:13]4=[O:21])[CH2:22][O:23][C:9]3=[CH:8][C:7]1=2
Reactant: CN1C(=O)COc2cc3c(cc21)OCC31C(=O)Nc2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CN1C(=O)COc2cc3c(cc21)OCC31C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 4-methyl-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indole]-2′,3(1′H,4H)-dione to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 4-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dione was obtained (11%) as a colorless solid: 1H NMR (300 MHz, (CD3)2CO) δ7.35-7.30 (m, 1H), 7.23-7.13 (m, 2H), 7.08-6.99 (m, 1H), 6.75 (s, 1H), 6.35 (d, J=10.1 Hz, 1H), 4.92-4.87 (m, 1H), 4.74 (d, J=9.2 Hz, 1H), 4.45-4.44 (m, 2H), 4.31-4.20 (m, 1H), 3.97-3.62 (m, 4H), 3.33 (s, 3H), 1.95-1.66 (m, 4H); 13C NMR (75 MHz, (CD3)2CO) δ178.8, 178.7, 166.1, 158.4 (2C), 145.3, 145.1, 141.5, 133.9, 133.7, 133.2, 130.6, 130.5, 125.6, 125.3 (2C), 125.1 (2C), 124.6, 124.3, 112.9, 112.7, 111.6, 111.5, 99.2, 99.1, 82.0, 81.8 (2C), 79.6, 78.2, 77.9, 75.7, 69.4, 69.3, 69.1, 59.6, 59.5, 46.0, 45.8, 30.7, 30.4, 29.8, 29.4, 27.2, 27.1; MS (ES+) m/z 406.9 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1.CCOC(C)=O>[Cl:27][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1
Reactant: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C(=O)O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
To 6-chloro-2-diethylamino-4-(3-isopropyl-phenyl)-quinoline-3-carboxylic acid tert-butyl ester (75 mg, 0.17 mmol) was added a solution of HCl in dioxane (4N, 3 ml), and the mixture was heated to reflux for 4 h. The reaction mixture was then cooled to room temperature and then concentrated in vacuo to give a crude residue which was diluted with EtOAc (20 ml). The organic layer was washed with brine (10 ml), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 6-chloro-2-diethylamino-4-(3-isopropyl-phenyl)-quinoline-3-carboxylic acid (55 mg, 84%) as a pale yellow solid. LC-MS (ESI): 397 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([CH3:39])[N:33]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[C:32]2=[O:48]>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:33]2[C:32](=[O:48])[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([CH2:28][NH:27][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=4)[CH:30]=3)[N:35]=[C:34]2[CH3:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNC(=O)c3cccc(C(F)(F)F)c3)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a stirred solution of 3-trifluoromethyl-benzoic acid (0.30 g, 1.6 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′ carbonyldiimidazole (0.28 g, 1.7 mmol), and the mixture was stirred for one hour. Then 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamide as an off-white solid (430 mg, 59% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.20 min (98.5%); mp, 220-222° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH3), 4.62 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.25 (m, 7H, Ar), 9.42 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.90, 23.41, 30.60, 42.45, 56.53, 120.02, 123.79 (q, JC-F=11 Hz), 123.79 (d, JC-F=3 Hz), 123.95 (q, JC-F=275 Hz), 124.04, 126.67, 127.96 (d, JC-F=3 Hz), 129.19 (d, JC-F=32 Hz), 129.74, 131.38, 134.18, 134.88, 137.81, 145.88, 154.65, 160.43, 164.73, 169.45, 172.59. LCMS MH=473; Anal Calcd For C23H19N4O4F3+0.3H2O: C, 57.81; H, 4.13; N, 11.73; F, 11.93. Found: C, 57.77; H, 4.11; N, 11.69; F, 11.97.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:26]1C(C)=NC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[C:19]([CH3:26])=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ncccc1Br
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1
Product: Cc1ccc(Nc2cccnc2C)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (example 8) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=338.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[C:3]#[CH:4].Cl[CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH3:13]>>[CH2:11]([O:10][CH2:9][CH2:8][O:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4])[CH2:12][CH3:13]
Reactant: C#CC(C)(C)O
Reactant: CCCOCCCl
Product: C#CC(C)(C)OCCOCCC
Yield: 22 %

Procedure:
In accordance with the procedure of the step 1 of Example 10, 30.3 g of 3-methyl-1-butyne-3-ol was allowed to react with 48.5 g of 2-chloroethylpropyl ether to obtain 13.5 g of 3-(2-n-propoxyethoxy)-3-methyl-1-butyne.