Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:18]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:20]=[N:19]1>>[Cl:17][C:16]1[C:11]2=[N:10][CH:9]=[C:3]([C:1]3[NH:2][N:20]=[N:19][N:18]=3)[C:4](=[O:5])[N:12]2[CH:13]=[CH:14][CH:15]=1
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: CCOC(=O)C(C#N)=CNc1ncccc1Cl
Product: O=c1c(-c2nnn[nH]2)cnc2c(Cl)cccn12
Yield: 44 %

Procedure:
The title compound (m.p. 313°-315° with decomposition, 44% yield) was prepared from ethyl 2-cyano-3-(3-chloro-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)4H-pyrido[1,2-a]pyrimidin-4-one in Example 2 of U.S. Pat. No. 4,122,274.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O>[C:11]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4.0 g. L-valine methyl ester hydrochloride dissolved in 25 ml water was added 3.35 g. benzoyl chloride while keeping the pH of the solution at approximately 8-9 with 1 N NaOH. The addition of the reactants took approximately 2 hours. Following addition of the reactants the reaction mixture was stirred at about 25° C. for 4 hours and then cooled to about 0° C. for 16 hours. The precipitated solid was collected and the filtrate was extracted twice with ether. The above collected solid was dissolved in this ether solution, which was then washed with a saturated sodium bicarbonate solution. The organic phase was dried and concentrated to give a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>C1COCC1.CN(C=O)C>[CH:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)([CH2:24][CH3:25])[CH3:23]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CCC(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(C)NC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Sec-butylamine (253 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (89 mg, 70%). NMR 1H (ppm, CDCl3): 7.95 (s, 1H), 7.68 (d, J3=7.51 Hz, 2H), 7.59 (d, J3=7.63 Hz, 2H), 7.50-7.33 (m, 4H), 5.97 (br. s., 1H), 4.30 (hept., J3=6.86 Hz, 1H), 1.58 (quint., J3=7.26 Hz, 1H), 1.23 (d, J3=6.56 Hz, 3H), 0.97 (t, J3=7.36 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][NH:24][CH3:25])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][N:24]([CH3:25])[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CNCc1cccc(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CN(C)CC(=O)c2ccc3ccccc3c2)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of α-bromo-2′-acetonaphthone (386.2 g, 1.57 mol) in dichloromethane (2.5 L) at 0° C. was added Compound 3 (249.1 g, 1.65 mol) in 30 min, followed by the addition of triethylamine (220.7 mL, 1.57 mmol) in 45 min. After stirring at 0° C. for 40 min, the reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was then washed with water (2×) and the aqueous layer was re-extracted with dichloromethane (2×). The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The ketone, Compound 4, was obtained as a reddish oil (513.3 g, quantitative), was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) δ 8.50 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.92 (d, 8.0 Hz, 1H), 7.88-7.85 (m, 2H), 7.60-7.54 (m, 2H), 7.26-7.23 (m, 1H), 6.97-6.94 (m, 2H), 6.82 (dd, J=8.0, 2.5 Hz, 1H), 3.88 (s, 2H), 3.75 (s, 3H), 3.69 (s, 2H), 2.42 (s, 3H); ESI MS m/z 320 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1.[H][H]>>[CH3:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH:9]([CH3:11])[CH2:10][C:4]=2[N:3]=1
Reactant: Cc1ccc2[nH]c(C)nc2c1
Reactant: [H][H]
Product: Cc1nc2c([nH]1)CCC(C)C2

Procedure:
20.0 g (0.137 mol) of 2,5-dimethyl-1H-benzimidazole are dissolved in 150 ml glacial acid and 2.50 g Pt-Mohr catalyst are added under argon. The solution is treated with hydrogen at 80° C. and at 3 bar pressure for 72 h. The solution is filtrated over celite and washed with glacial acid. The solvent is evaporated under vacuum and a few milliliters of water are added to the residue. Sodium hydrogen solution is added to a pH of 12-14. The mixture is extracted with ethyl acetate, the organic phase is extracted with water and dried over sodium sulfate. The ethyl acetate is evaporated under pressure and the residue is dissolved in a little bit of dichlormethane. Diethylether is added and the precipitate is filtrated and washed with diethylether to yield 1.0 g (4.87% of th.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:42])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH:39]3[CH2:41][CH2:40]3)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:39]1([C:34]2[CH:33]=[C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:42])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)[CH:37]=[C:36]([CH3:38])[N:35]=2)[CH2:41][CH2:40]1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C4CC4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C4CC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M238) (244 mg, 0.41 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (150 mg, 76%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([C@H:13]1[C:17](=[O:18])[O:16][C:15](=[O:19])[NH:14]1)([CH3:12])[CH3:11]>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:1]([N:14]1[C@@H:13]([CH:10]([CH3:12])[CH3:11])[C:17](=[O:18])[O:16][C:15]1=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H]1NC(=O)OC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Benzoyl chloride (295 mg, 2.1 mmol) was dissolved in ethyl acetate (21 mL), followed by the addition of (S)-4-isopropyl-2,5-oxazolidinedione (L-valine-NCA) (286 mg, 2.0 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (257 mg, 2.1 mmol) in ethyl acetate (11 mL) was added dropwise under ice cooling over 20 minutes. The resulting mixture was allowed to rise as was in temperature from 09. After the mixture was stirred at room temperature for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (351 mg, 80%).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21](Cl)[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH:18]=[N:17][C:16]=2[CH:27]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[C:18]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([F:2])=[CH:4][CH:5]=3)=[N:17][C:16]=2[CH:27]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Agent: [Cl-]
Product: Fc1ccc(CC2=Nc3cc(Cl)ccc3Nc3ccccc32)cc1
Yield: 77.2 %

Procedure:
4-Fluorobenzylzinc chloride (0.8 ml, 0.5 M in THF, 0.4 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (53 mg, 0.2 mmol) were reacted according GP10 to give 52 mg of the title compound (160FE59). MS (ESI) 337 (MH+). Purity for MH+ (UV/MS) 90/90.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[O:20][CH3:21])=[CH:3][C:2]=1[Cl:1]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of 3,4-dichlorophenol (38 g, 233.13 mmol, 1.00 equiv), 1-fluoro-2-methoxy-4-nitrobenzene (40 g, 233.75 mmol, 1.00 equiv) and potassium carbonate (64 g, 463.77 mmol, 1.99 equiv) in N,N-dimethylformamide (250 mL) was stirred overnight at 60° C. The resulting solution was diluted with 1000 mL of water, extracted with 3×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 60 g (82%) of 1,2-dichloro-4-(2-methoxy-4-nitrophenoxy)benzene as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:15]I>>[F:1][C:2]1[CH:8]=[C:7]([I:15])[CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4]
Reactant: II
Reactant: Nc1c(F)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1c(F)cc(I)cc1Cl
Temperature: 60 °C
Reaction time: 72 h

Procedure:
2-Fluoro-6-chloroaniline (28.8 g, 0.2 mol) is suspended in a solution of sodium bicarbonate (17.2 g, 0.2 mol in 150 mL water) and warmed to 60° C. Elemental iodine (50.8 g, 0.2 mol) is added portionwise and the resulting mixture stirred at 60° C. for 3 days. After cooling to room temperature, the reaction mixture is partitioned between CH2Cl2 (350 mL) and saturated sodium bisulfite solution (500 mL). The aqueous layer is re-extracted with additional CH2Cl2 (250 mL) and the combined organic layers dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2-fluoro-4-iodo-6-chloroaniline (m.p. 85–87° C.).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:19])[O:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]Cl)[CH2:22][CH2:21]1>>[CH2:1]([C:8]1[C:9](=[O:19])[O:10][C:11]2[C:16]([C:17]=1[O:18][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: O=c1oc2ccccc2c(O)c1Cc1ccccc1
Product: O=c1oc2ccccc2c(OCCN2CCOCC2)c1Cc1ccccc1
Yield: 88.5 %

Procedure:
Prepared as indicated in Example 8, from 13.7 g. (0.54 mol) of 3-benzyl-4-hydroxy-coumarin and 10.6 g. (0.071 mol) of 2-morpholino-1-chlorethane. After evaporation of the chloroform, there are obtained 17 g. of an oil which cannot be crystallised. Yield 88.5% (theoretical yield 19.2 g.).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: O=C(CCl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (200 mg, 0.33 mmol, 1.00 equiv, 50%) in DMF (5 mL) was added potassium carbonate (91.1 mg, 0.66 mmol, 2.00 equiv) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (73.5 mg, 0.50 mmol, 1.50 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH3HCO3 and CH3CN (5.0% CH3CN up to 50.0% in 11 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The fractions containing product were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(pyrrolidin-1-yl)ethan-1-one (40 mg) as a white solid. MS (ES, m/z): 414 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 5.97 (d, 1H), 4.02-4.04 (m, 1H), 3.49 (t, 2H), 3.35 (t, 2H), 3.21 (s, 2H), 3.09 (t, 2H), 2.95 (t, 2H), 2.39-2.51 (m, 3H), 2.25 (s, 3H), 1.95-2.03 (m, 2H), 1.69-1.88 (m, 6H), 1.33-1.51 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cc1ccccc1CCN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1CCNC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Forty (40) grams of 4-bromobenzoic acid was dissolved in 200 ml of dry dimethylformamide. While the solution was cooled with ice with stirring, 23 g of triethylamine and 22 g of ethyl chloroformate were added. After a lapse of 30 minutes, 28 g of 1-amino-2-(2-methylphenyl)ethane was added dropwise. The mixture was stirred at room temperature for 1 hour and then at 50° to 60° C. for 1 hour, and poured into ice water. The crystals precipitated were washed in water, dried, and recrystallized from cyclohexane to afford 49 g of 1-(4-bromobenzoylamino)-2-(2-methylphenyl)ethane as colorless needles having a melting point of 101.5° to 103.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:32][OH:33])[CH:22]=[C:23]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[CH:24]=1>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH2:32][OH:33])[CH:22]=[C:23]([C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: Nc1cc(CO)cc(C(F)(F)C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1nc(Nc2cc(CO)cc(C(F)(F)C(F)(F)F)c2)ncc1F

Procedure:
Intermediate 46.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and [3-amino-5-(pentafluoro-ethyl)phenyl]methanol. The residue was purified by chromatography (hexane/ethyl acetate 6:4) to give the desired product.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:6]([OH:8])=O)[CH3:2].[NH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[N:27][CH:28]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[Cl:29][C:26]1[N:27]=[CH:28][C:23]([CH2:22][NH:21][C:6](=[O:8])[C:5](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:4][O:3][CH2:1][CH3:2])=[CH:24][CH:25]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CCOCC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOCC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 3-ethoxy-2-(4-trifluoromethylphenyl hydrazono) propionic acid (0.3 g, 1 mmol), 5-aminomethyl-2-chloropyridine (0.21 g, 1.5 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (0.29 g, 1.5 mmol) and chloroform (10 ml) was left at room temperature overnight. The mixture was extracted with chloroform, washed 1N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, dried on anhydrous sodium sulfate and then filtered. The residue obtained by concentrating the resulting filtrate was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-3-ethoxy-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 170) (0.3 g, 0.72 mmol, 72%).
Reaction SMILES: C([O:8][C:9]([Cl:12])(Cl)Cl)(OC(Cl)(Cl)Cl)=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>ClCCl>[N:13]1([C:9]([Cl:12])=[O:8])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(Cl)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 65.2 %

Procedure:
Into a 500-mL round-bottom flask was placed ditrichloromethyl carbonate (10.2 g, 34.37 mmol, 1.50 equiv) and dichloromethane (100 mL). This was followed by the addition of morpholine (2 g, 22.96 mmol, 1.00 equiv) dropwise with stirring at 0° C. in 2 min. To this was added TEA (4.2 g, 41.51 mmol, 1.81 equiv) dropwise with stirring at 0° C. in 3 min. The resulting solution was stirred for 3 h at room temperature. The reaction was then washed by the addition of 100 mL of water. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Purification afforded 2.238 g (65%) of morpholine-4-carbonyl chloride as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11](Br)[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.CS(C)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(Br)C1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NCc2ccc(OC)cc2)C1
Temperature: 85 °C
Reaction time: 15 h
Yield: 61.9 %

Procedure:
To a suspension of 8.20 g (20.80 mmol) of 9-bromo-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in 208 mL of toluene was added 8.56 g (62.40 mmol) of 4-methoxybenzylamine and 14.77 mL (208.00 mmol) of dimethylsulfoxide. The reaction mixture was stirred at 85° C. for 15 hours. The cooled solution was evaporated to remove solvent. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with dichloromethane, washed with saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane methanol/ammonia 98/2/0.2 to 97/3/0.3) to afford 5.80 g (62%) of product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][NH:13][CH2:14][CH:5]3[C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]([CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:5]2[CH2:14]1)#[N:20]
Reactant: Cc1ccc2c(c1)C1CNCCC1N2
Reactant: N#CCCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C1CN(CCCC#N)CCC1N2

Procedure:
In toluene (60 ml) are dissolved 8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (5.7 g), γ-bromobutyronitrile (4.5 g) and triethylamine (4.6 g), and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The resulting residue is treated with ethanolic hydrogen chloride in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (5.5 g), m.p. 160° - 165°C (recrystallized from aqueous ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:32](Cl)(=[O:34])[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:32](=[O:34])[CH3:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2ccccc2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (6-methoxy-2′-phenylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.