Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C([O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O)=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:14]=[C:15]1[CH:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[N:2][N:1]1[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C(O)c1ccc(N2N=C3CCCC3C2=O)cc1

Procedure:
A solution of 4-hydrazinobenzoic acid (0.3 g), ethyl-2-oxocyclopentanecarboxylate (0.31 g) and p-toluenesulfonic acid (340 mg) in ethanol (12 ml) was boiled under reflux for 12 hours. The concentrated reaction solution was purified by preparative HPLC. The isolated reaction product (as ethyl ester) was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 244.25 (C13H12N2O3); MS (ESI): 245 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:19]=[CH:20][C:21]=2[F:22])[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])=[CH:4][C:3]=1Br.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:19]=[CH:20][C:21]=2[F:22])[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])=[CH:4][C:3]=1[C:25]#[C:24][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: C#Cc1ccccn1
Reactant: Nc1ncc(CNc2cc(C(=O)NC3CC3)ccc2F)cc1Br
Product: Nc1ncc(CNc2cc(C(=O)NC3CC3)ccc2F)cc1C#Cc1ccccn1

Procedure:
3-((6-amino-5-bromopyridin-3-yl)methylamino)-N-cyclopropyl-4-fluorobenzamide (38 mg, 0.1 mmol) was reacted with 2-ethynylpyridine (0.1 mL) as described in procedure D of Example 5 to afford 3-((6-Amino-5-(2-(pyridin-2-yl)ethynyl)pyridin-3-yl)methylamino)-N-cyclopropyl-4-fluorobenzamide as a solid. It was used without further purification. LC/MS; (M+H)+=402.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([SH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:24][CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=1[CH2:38][CH2:39][CH3:40].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([S:22][CH2:24][CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=2[CH2:38][CH2:39][CH3:40])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCBr)ccc(C(C)=O)c1O
Reactant: CCCc1c(S)ccc(C(C)=O)c1OCCCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCCSc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 9 h
Yield: 51.9 %

Procedure:
A mixture of ethyl 4-(6-acetyl-3-mercapto-2-propylphenoxy)-butyrate (2.0 g), (4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl)ethanone (2.0 g), potassium iodide (0.5 g) and potassium carbonate (1.7 g) in acetone (40 ml) was heated with refluxing and stirring for 9 hours. After cooled, inorganic materials were separated by filtration and the filtrate was concentrated. The resultant residue was separated, and was purified through silicagel column chromatography (eluting with benzene:ethyl acetate=9:1) to give the title compound (1.8 g, 50.8%) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[C:21](=[O:24])[NH:22][N:23]=[C:4]2[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.Cl[CH2:36][C:37]([NH:39][CH3:40])=[O:38]>>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:12]2[C:8]([C:7]3[C:2]([CH3:1])=[C:3]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)[C:4]4[N:5]([C:21](=[O:24])[N:22]([CH2:36][C:37]([NH:39][CH3:40])=[O:38])[N:23]=4)[CH:6]=3)=[CH:9][CH:10]=[N:11]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CNC(=O)CCl
Product: CNC(=O)Cn1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2c1=O

Procedure:
The title compound was prepared from 4-{5-[7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 9, 55 mg. 0.12 mmol) and 2-chloro-N-methylacetamide (19 μL, 0.18 mmol), using a similar method to that used in Example 11 (25 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+]>C1COCC1.O>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: NCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCNC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Benzyl chloroformate (0.630 mL, 753 mg, 4.4 mmol, 1 equiv) and 4-aminobutyric acid (440 mg, 4.3 mmol, 1 equiv) were added to a solution of NaOH (188 mg, 4.7 mmol, 1.1 equiv) in THF-water (25 mL each). More NaOH (175 mg, 4.4 mmol, 1 equiv) was added to make pH>7. The solution was stirred for 3 h. The solution was concentrated in vacuo. Water was added and the solution was washed three times each with dichloromethane and ethyl acetate. The aqueous layer was concentrated in vacuo to yield N-Cbz-4-aminobutyric acid. To a solution of mono-Boc p-xylylene diamine (271 mg, 1.1 mmol, 1 equiv) in dichloromethane (25 mL) was added N-Cbz-4-aminobutyric acid (258 mg, 1.1 mmol, 1 equiv). The mixture was cooled to 0° C. HOBT (165 mg, 1.2 mmol, 1.1 equiv) and EDC (233 mg, 1.2 mmol, 1.1 equiv) were added. NMM (30 drops) was added to adjust pH. The solution was stirred at 0° C. for 1 h and at r.t. over the weekend. Dichloromethane was added, and the solution was washed with 0.05N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Ethanol (30 mL) and palladium (270 mg, 5%/C) were added to the residue (432 mg) and the mixture was stirred under hydrogen (1 atm) for 20 h. The mixture was filtered, and the ethanol was removed in vacuo. To the residue (206 mg, 0.64 mmol, 2.1 equiv) was added dichloromethane (25 mL) and DMF (2 mL). Triethylamine (0.091 mL, 66 mg, 0.65 mmol, 2.2 equiv) and terephthaloyl dichloride (60 mg, 0.3 mmol, i equiv) were added and the solution was stirred overnight. The solution was washed with 0.05N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was concentrated in vacuo. TFA and dichloromethane (10 mL each) were added and the solution was stirred for 1 h. The solution was concentrated under vacuum and rinsed twice with ether. The crude product was purified on the Waters LC (2-30% gradient) to yield 50 mg of >95% pure bis TFA salt of the title compound.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.C[N:23](C)C=C(C1C=CN=CC=1)C(C1C=CC(F)=CC=1)=O>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=3)=[CH:3][NH:2][N:23]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(F)c1
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(F)c2)cc1
Yield: 88 %

Procedure:
The reaction was carried out in the same manner as in Example 1-2) except for using 4.17 g (14.5 mmol) of 3-dimethylamino-1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)-2-propen-1-one obtained in Example 17-1) in place of 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one to obtain 3.28 g of the title compound as a white powder. (Yield: 88%)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[S:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:26]2[CH2:27][CH2:28][S:24][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CSCN1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCSC2)cn1
Yield: 28 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using thiazolidine instead of 2-aminoethyl isopropylether, to the title compound (68 mg, 28%) which was obtained as a white solid. MS: m/e=382.2 [M+H]|.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:36][C:37]1[N:42]=[CH:41][C:40]([C:43]2[CH:65]=[CH:64][C:46]3[N:47]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:48]([C:50]4[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=4[C:52]([NH:54]O)=[NH:53])=[N:49][C:45]=3[CH:44]=2)=[CH:39][N:38]=1>CN(C=O)C>[C:60]([N:47]1[C:46]2[CH:64]=[CH:65][C:43]([C:40]3[CH:41]=[N:42][C:37]([NH2:36])=[N:38][CH:39]=3)=[CH:44][C:45]=2[N:49]=[C:48]1[C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[C:52]1[N:54]=[C:1]([CH3:2])[O:4][N:53]=1)([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(=O)O
Reactant: CC(C)(C)n1c(-c2ccccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of acetic acid (30 mg, 0.5 mmol) and HATU (189 mg, 0.5 mmol) in DMF (2 mL) is added triethylamine (0.07 mL, 0.5 mmol). The reaction mixture is stirred at room temperature for 10 minutes and 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (200 mg, 0.5 mmol) is added. The reaction mixture is stirred at room temperature for 0.5 hours then warmed to 80° C. and stirred for 15 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. EtOAc (20 mL) is added and the organics washed with H2O (30 mL) then dried (Na2SO4), filtered and concentrated. Purification via prep HPLC (0.1% TFA/MeCN) affords the title compound (27 mg, 8%) as 2TFA salt. LCMS (ESMS): m/z 426.20 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH:16]([CH3:18])[CH3:17])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[CH:16]([CH3:18])[CH3:17])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)C(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid (3.2 g) and 4-nitrophenol (2.2 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.7 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up. crystallization of the crude product from 2-propanol-hexane yielded 3.55 g of (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid 4-nitrophenyl ester, mp 111.5°-113° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[CH2:1]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: N#Cc1ccc2c(c1)CNCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN1CCc2ccc(C#N)cc2C1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To an ice-cold, stirred solution of 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (J. Med. Chem. 1997, 40, 3997) (485 mg, 3.1 mmol) and triethylamine (0.47 mL, 3.4 mmol) in methylene chloride (5 mL) is added DMAP (37 mg, 0.3 mmol) and bromobutane (0.5 mL, 4.6 mmol). The reaction mixture is stirred for 20 h, diluted with methylene chloride, washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) affords the title compound. ESI MS m/z 215 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][N:13]([CH2:20][CH2:21][OH:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:22][CH2:21][CH2:20][N:13]([CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CN(CCO)c1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: CN(CCOc1ccc([N+](=O)[O-])cc1F)c1ccccn1

Procedure:
In substantially the same manner as in Reference Example 54, 3,4-difluoronitrobenzene was reacted with 2-[N-methyl-N-(2-pyridyl)amino]ethanol to yield 3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]nitrobenzene. The product was recrystallized from ethyl acetate-hexane to give yellow prisms, m.p.95-96° C.
Reaction SMILES: [NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1>C(O)C.[Pd]>[NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:10]=1
Reactant: C[C@H](CCc1ccc(C#CCCCC2CCCCC2)s1)C(N)O
Agent: [Pd]
Solvent: CCO
Product: C[C@H](CCc1ccc(CCCCCC2CCCCC2)s1)C(N)O
Reaction time: 2 h
Yield: 83.8 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol (175 mg, 0.53 mmol) obtained in Example 1 was dissolved in ethanol (9 ml), and 10% palladium-charcoal (90 mg) was added thereto, and then the mixture was stirred under a hydrogen atmosphere for 2 hours. After the palladium-charcoal was filtered out through Celite, the filtrate was evaporated to dryness under reduced pressure to give the title compound (150 mg, 85% yield).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7].[O:14]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:14]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][O:7][C@@H:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5]2)=[CH:27][CH:28]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCNC[C@@H](O)c1ccccc1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: c1ccc(Oc2ccc(CN3CCO[C@@H](c4ccccc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8 %

Procedure:
200 mg of (S)-2-Phenyl-morpholine (see synthesis in Example 1) was dissolved in 2 mL of dichloroethane and 253 μL of 4-Phenoxy-benzaldehyde was added. The reaction was stirred at room temperature 30 minutes and then 467 mg of sodium triacetoxyborohydride was added. The reaction was stirred overnight at room temperature. The reaction solution was then washed with aqueous saturated sodium bicarbonate solution several times followed by a brine wash. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparatory chromatography gave the title compound. 8% yield. EI m/z 346=MH+
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20]([CH3:22])=O.C[O-].[Na+]>CO>[CH3:16][O:17][C:18]([C:19]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=2)=[N:2][O:1][C:20]=1[CH3:22])=[O:23]
Reactant: COC(=O)CC(C)=O
Reactant: ON=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccc(OC(F)(F)F)cc2)noc1C
Yield: 67 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-4-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylacetoacetate (7.76 g, 66.78 mmol) and sodium methoxide (5.41 g, 100.17 mmol), a white solid required compound (6.74 g, 22.36 mmol, 67%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1)([O-:3])=[O:2].[NH3:16]>[Cl-].C([N+](CC)(CC)CC)C.O>[NH2:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([Cl:10])=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: N
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 10 h

Procedure:
260 g of 3-nitro-2,5-dichlorobenzotrifluoride, 130 ml of water and 10 g of tetraethylammonium chloride were introduced into an autoclave, and 120 ml of liquid ammonia were injected. The mixture was then heated to 130° C. and stirred for 10 hours at this temperature. After cooling, the batch was filtered and the precipitate which had been separated off was washed with water and dried. 194 g of 2-amino-3-nitro-5-chloro-benzotrifluoride with a melting point of 67° C. were obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:23][N:22]([CH2:30][C:31](O)=[O:32])[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)CCCN=C=NCC.O>ClCCl>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:31](=[O:32])[CH2:30][N:22]1[CH2:23][C:24]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21]1)([CH3:13])[CH3:12]
Reactant: O=C(O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Temperature: -10 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
130 μl (0.69 mmol) of 2,6-diisopropylaniline are added to a solution of 180 mg (0.65 mmol) of (1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetic acid in 20 ml of dichloromethane. The solution is cooled to −10° C. and 132 mg (0.69 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide are added. The medium is allowed to return to room temperature and stirred for 4 h and then at reflux for one day and again at room temperature for 5 days. The medium is then poured into water and extracted with dichloromethane. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 90/10, v/v). 25 mg of N-(2,6-diisopropylphenyl)-2-(1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetamide are obtained in the form of a white solid. M.p. 151-3° C., yield=8.8%.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])=O>C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[CH:9][CH:10]=1
Reactant: CN(C)C=CC(=O)c1ccccc1C(F)(F)F
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: FC(F)(F)c1ccccc1-c1ccnc2ncnn12

Procedure:
A mixture of 1.68 g. of 3-amino-1,2,4-triazole and 4.86 g. of 3-dimethylamino-2'-trifluoromethylacrylophenone in 25 ml. of glacial acetic acid refluxed for 16 hours. The resulting mixture is worked up as described in Example 54 to yield the product of the Example, m.p. 149°-151° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>ClCCCl.CC(O)(C)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Fc1ccc(-c2cc3c(Cl)ncnc3s2)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Fc1ccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3s2)cc1
Temperature: 90 °C
Yield: 49.9 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (40 mg, 0.15 mmol) in 1,2-dichloroethane/t-BuOH (1:1, 1 ml) was added 3-chloro-4-fluoroaniline (22 mg, 0.15 mmol). The mixture was heated at 90° C. for 2 days. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (28 mg, 50%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)[N:9]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:11]=[C:10]([N:19]2[CH2:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH2:24]2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(N)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
tert-Butyl N-[1-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]-4-piperidyl]carbamate (1.30 g, 2.77 mmol) was dissolved in methanol (10 mL). 4M Hydrochloric acid in dioxane (10 mL) was added. The reaction was stirred at RT for 3 hours. Saturated aqueous sodium bicarbonate was added until pH7 was reached and the organic solvents were removed in vacuo. Water (20 mL) was added and the product was extracted into ethyl acetate (50 mL). The aqueous layer was extracted with a second portion of ethyl acetate (25 mL). The combined organics were evaporated to give the desired material as a yellow foam (1.05 g).
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].CO.[N+](=[CH2:22])=[N-]>CCOCC>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([O:10][CH3:22])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of BOC-L-Gln (20 g, 81 mmol) in 50 mL of EtOAC and MeOH at 0° C. was added diazomethane in 250 mL of Et2O with stirring. The resulting yellow solution was stirred at 0° C. for 5 minutes and then warmed up to room temperature and stirred for 20 minutes. Argon gas was then bubbled through the yellow reaction mixture to remove excess diazomethane. The crude product was concentrated and purified by crystallization from methyl-tert-butyl ether. Yield 100%. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.96 (m, 1H), 2.21 (m, 1H), 2.36 (m, 2H), 3.76 (s, 3H,), 4.34 (m, 1H), 5.32 (m, 1H), 5.44 (bs, 1H), 6.16 (bs, 1H). Anal. (C11H20N2O5) C, H, N.