Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[CH:16].Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:13][CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[C:16][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: C#Cc1ccc2c(nnn2CC2CC2)c1Cl
Reactant: Cc1ccncc1Br
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccncc1C#Cc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 4-chloro-1-(cyclopropylmethyl)-5-ethynyl-1H-benzotriazole (20 mg, 0.086 mmol), 3-bromo-4-methylpyridine (30 mg, 0.17 mmol), copper (I) iodide (5 mg, 0.026 mmol), and triethylamine (156 μL, 1.12 mmol) in DMF (0.54 mL) was sparged under nitrogen and heated at 90° C. for 18 hours. The mixture was treated with Quadrapure TU, stirred for 18 hours and filtered. The filtrated was concentrated in vacuo and the residue was purified by preparative reverse-phase HPLC, providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 8.78 (s, 1H), 8.53 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.44 (s, 1H), 4.67 (d, J=7.3 Hz, 2H), 2.56 (s, 3H), 1.40 (m, 1H), 0.58 (d, J=7.7 Hz, 2H), 0.50 (d, J=5.0 Hz, 2H) ppm; high resolution mass spectrometry (ES+) m/z 323.1058 [(M+H)+; calculated for C18H16ClN4: 323.1058].
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=O)[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:29][NH2:30]>C(O)C>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=[N:29][NH2:30])[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1

Procedure:
A solution of 100 g (0.275 mol) of the levorotatory enantiomer of methyl (3aRS,4RS,7aSR)-2-benzyl-4-phenyl-7-oxoperhydroisoindole-3a-carboxylate and of 50 g (1 mol) of hydrazine hydrate in 750 cm3 of ethanol is brought to reflux for one and a half hours. After concentrating the ethanol under reduced pressure, the residue is taken up in 400 cm3 of dichloromethane and the organic phase is washed with distilled water and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. 100 g (960%) of the levorotatory enantiomer of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-phenylperhydroisoindole-3a-carboxylate are thus obtained in the form of a yellow oil used as is in the following stage.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH2:23]O)[CH:22]=1)[CH2:10][CH2:9]2>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH2:23][Cl:3])[CH:22]=1)[CH2:10][CH2:9]2
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(CCl)c1
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 121.7 %

Procedure:
Thionyl chloride (1.4 mL, 19.0 mmol) was added slowly at 0° C. to a solution of 6-chloro-2-(5-hydroxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 3 [B]) (1.1 g, 3.8 mmol) in DCM (50 mL). After the addition, the reaction mixture was stirred at 2-5° C. for 2 hours before it was poured into satd. aq. NaHCO3 solution (50 mL) and extracted with EtOAc (2×150 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (1.42 g, 92%) as light yellowish solid. MS: 307.0 & 309.0 (M+H+).
Reaction SMILES: N[CH2:2][C:3]1[C:4]([CH3:24])=[N:5][C:6]2[N:7]([N:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.CCN(CC)CC>C1COCC1>[C:29]([O:28][C:26]([CH2:2][C:3]1[C:4]([CH3:24])=[N:5][C:6]2[N:7]([N:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:25])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1nc2nc(C)c(CN)c(-c3ccc(Cl)cc3Cl)n2n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1nc2nc(C)c(CC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3Cl)n2n1
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a stirred solution of methyl 6-(aminomethyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (Example 27, 50 mg, 0.14 mmol) in THF (3 mL) was added (BOC)2O (75 μL, 0.34 mmol) and Et3N (100 μl, 0.70 mmol). After 2 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography (50% EtOAc in hexanes) afforded methyl 6-((tert-butoxycarbonyl)methyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (13 mg, 20%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[CH3:25][N:26]([CH3:31])[CH2:27][C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH3:25][N:26]([CH2:27][C:28]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1)=[O:29])[CH3:31]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)CN(C)C)C1
Reaction time: 4.5 h

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benziniidazol-1-yl]pyrimidine (EXAMPLE 18) (21 mg, 0.065 mmol) in CH2Cl2 (0.6 mL) was added N,N-dimethylglycine (10 mg, 0.098 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg, 0.098 mmol) at room temperature. After stirring for 4.5 h, the reaction mixture was diluted with EtOAc (5 mL) and was washed with H2O (2×2 mL) and brine. The organic layer was dried over Na2SO4. After removal of the solvent, the crude product was purified by preparative thin layer chromatography (1:9 2M NH3 in MeOH:CH2Cl2) to obtain the title compound. Presence of rotamers in Partial 1H NMR (500 MHz, CDCl3): δ 8.6 (s, 1H); 8.35 (br s, 1H); 8.12 (d, J=7.5 Hz, 1H); 7.82 (br s, 1H); 7.35 (br s, 2H); 6.75 (two d, J=5.3 Hz, 1H); 4.54 (m, 1H); 2.24 (s, 3H); 2.19 (s, 3H); 1.28 (br s, 3H). Mass spectrum 408.4 (ESI, M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[Cl:23])[NH2:19].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:16]([Cl:15])[CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1Cl
Reaction time: 48 h

Procedure:
190 mmol of 1-benzyl-4-piperidone, 240 mmol of 3,4-dichloroaniline, 0.02 g of PTSA and 200 ml of toluene are placed in a round-bottomed flask equipped with a reflux condenser and a Dean and Stark apparatus. The whole mixture is brought to reflux for 24 hours. After evaporation of the solvent, the residue is taken up in 500 ml of methanol and 450 mmol of sodium borohydride are progressively added. The whole mixture is kept stirring for two days. The expected product is obtained after concentration by filtration of the precipitate formed.
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:19][C:18]([F:30])=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([F:16])=[C:9]([NH:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:30][C:18]1[CH:17]=[C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([F:16])=[C:9]([NH:11][S:12](=[O:14])(=[O:15])[NH2:13])[CH:10]=2)[C:2]([NH:1][S:34]([CH:31]2[CH2:33][CH2:32]2)(=[O:36])=[O:35])=[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[CH:19]=1
Reactant: Nc1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1ccc(F)c(NS(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Nc1cc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)ccc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
547 mg crude N-(5-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-2-fluorophenyl)sulfuric diamide (Intermediate 14.A) (0.993 mmol, 1. eq.) was dissolved in 8.5 mL pyridine, cooled to 0° C. and treated with 140 mg cyclopropanesulfonyl chloride (0.993 mmol, 1 eq.). The reaction mixture was stirred at rt for 18 h. Another 70 mg of cyclopropanesulfonyl chloride (0.497 mmol, 0.5 eq.) were added and stirring was continued for 24 h. The reaction mixture diluted with toluene and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the aqueouse layer reextracted twice with ethyl acetate. The combined organic layers were washed once with half saturated brine and once with brine, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 40 mg of the desired product (6% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1c(F)ccc(F)c1F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)ccc(F)c3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,3,6-trifluorobenzoyl chloride (30 μL, 0.229 mmol) and mixing for 24 h, 47.7 mg (>100%) of the title compound were recovered.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH2:12]1>>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:14]1[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[O:11][CH2:12][C:13]2=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Product: Fc1ccc2[nH]c3c(c2c1)COc1ccccc1-3

Procedure:
Following the procedure described in Example 4, using (4-fluoro-phenyl)-hydrazine hydrochloride salt and chroman-4-one (2.5 g, 17 mmol) as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]([F:23])([F:22])[C:11]([F:21])([F:20])[C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[F:18][C:12]([F:19])([C:11]([F:20])([F:21])[C:10]([F:9])([F:22])[F:23])[C:13](=[O:14])[CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1cccs1
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1cccs1

Procedure:
The compound was synthesized according to example 1 using 2-acetylthiophene and ethyl heptafluorobutyrate as starting materials. 1H NMR (CDCl3): 6.49 (s, 1 H); 7.21 (dd, 1H, J=3.8 & 5.1); 7.77 (dd, 1H, J=1.2 & 5.1 Hz); 7.85 (dd, 1H, J=1.2 & 3.8 Hz). IR (film): 1589 (C═O); 1230 (C—F).
Reaction SMILES: [NH2:1][C:2]1[C:7](C2C=CC=CC=2)=[C:6]([NH:14][CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[N:5]=[C:4](N=NC2N=CC=CN=2)[N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:40]([NH2:42])=O>>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:7]=1[N:42]=[CH:40][N:14]2[CH2:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23]
Reactant: Nc1nc(N=Nc2ncccn2)nc(NCc2c(F)cccc2Cl)c1-c1ccccc1
Reactant: NC=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 42 %

Procedure:
In formamide (60 ml) was suspended 4-amino-6-(2-chloro-6-fluorobenzyl)amino-5-phenylazopyrimidine (1.07 g, 3 mmols). To the suspension was added portionwise sodium dithionite (3.28 g, 15 mmols; purity 80%) with stirring at 120°-130° C. After stirring at the same temperature for 30 minutes, the mixture was stirred at 140°-150° C. for another 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, the residue washed with ether (2×30 ml), and water (50 ml) added. After ice-cooling, the insoluble matter was collected by filtration and washed. This product was put in 2 N NaOH (10 ml) and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was collected by filtration, dissolved in chloroform, and purified by silica gel column chromatography [100 g, eluent: chloroform and, then, chloroformmethanol (19:1)]. Recrystallization from ethanol gave 6-amino-9-(2-chloro-6-fluorobenzyl)purine as colorless crystals (350 mg, yield 42%), m.p. 249°-250° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1nc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.718 g, 1.0 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.295 g, 1.1 mmol), tetrakis(triphenylphosphine)palladium (0.058 g, 0.044 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (384 mg, 59%). MS (ISP) 590.4 [(M+H)+]; mp>250° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21](N1C2C(=CC=CC=2)CCC1)=[O:22]>>[Cl:11][C:12]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1)=[O:22]
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: c1ccc2c(c1)NCCN2
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 1, from 1,2,3,4-tetrahydro-quinoxaline (commercially available; CAS RN 3476-89-9) and 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate). Light yellow foam (99%). MS (ESI): m/z=400.06 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH2:16])[CH3:15])=[N:9]2.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH:16][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH3:15])=[N:9]2
Reactant: CC(N)c1nc2ccc(F)c3c2n1CCO3
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1CCO3
Temperature: 100 °C
Yield: 82 %

Procedure:
A mixture of 1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (85 mg, 0.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (92 mg, 0.38 mmol) and DIPEA (132 μL, 0.76 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% MeOH in DCM) to afford the title compound as a pale yellow oil (132 mg, 82%). LCMS (Method J): RT=2.22 min, [M+H]+=424
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH:21]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
30 g of p-nitrobenzaldehyde was reacted with 30 g of p-methoxyacetophenone in 200 ml of acetic acid in the presence of 34 ml of sulfuric acid at room temperature for 1 day, and the reaction mixture was poured into 1 liter of ice-water. After neutralizing the mixture with 48 g of NaOH, cyrstals formed were collected by filtration, and recrystallized from acetoneacetonitrile (0.2 liter/1.3 liter) to obtain 37.6 g of the desired compound. m.p. 171°-173° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:6]1[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]2=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=2)[CH:7]=1
Reactant: Clc1cc(-c2ncco2)nc2c1CCC2
Reactant: Nc1ccc(CCO)cc1
Product: OCCc1ccc(Nc2cc(-c3ncco3)nc3c2CCC3)cc1
Yield: 56.5 %

Procedure:
Following general procedure B1, 2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxazole (0.059 g, 0.27 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.044 g, 0.32 mmol) to afford the title compound (0.049 g, 57%) as a light yellow solid. MW=321.37. 1H NMR (DMSO-d6, 500 MHz) δ 8.19-8.14 (m, 2H), 7.45 (s, 1H), 7.30-7.28 (m, 1H), 7.24 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 4.64 (s, 1H), 3.66-3.59 (m, 2H), 2.90 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.0 Hz, 2H), 2.72 (t, J=7.0 Hz, 2H), 2.09 (quin, J=7.5 Hz, 2H); APCI MS m/z 322 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C[O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][CH2:35][O:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([OH:38])=[O:26])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Product: COc1ccc2c(c1)c(C1CCN(CCOc3ccccc3C(=O)O)CC1)cn2CCc1ccsc1

Procedure:
This compound was prepared following the procedure described in example 87 (part E) starting with 1.7 g (5 mmol) of 5-methoxy-3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole and 1.2 g (5.5 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up and purification by flash chromatography, 0.6 g (24% of yield) of the expected acid were obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[I:19]Cl>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCOCc1ccccc1
Reactant: ClI
Solvent: C1CCOC1
Product: ICCCCCOCc1ccccc1
Reaction time: 0.75 h

Procedure:
5-Benzoxy-1-pentene (30 mmol, 5.7 g) was hydroborated with BH3 -THF (10 mmol) at 0° C. for 1 hr. Iodinemonochloride (20 mmol, 1.0 ml) was added at room temperature; after 45 min,the product was isolated via chromatography (alumina): yield 5.63 g (88% based on ICl); bp 125° C./0.25 torr; m/e 318.1 (Calcd 318.2); IR (neat) 1705(C=O), 1205(C-I)cm-1 ; NMR (neat) δ 1.7 (broad envelope, 6, alkyl), 3.0 (t, 2, --CH2I), 4.2 (t, 2, --CH2O--),7.6 (m, 5, ArH).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[C:18](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][CH:20]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[N:29]1([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[N:17]=[C:18](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:19][CH:20]=3)=[CH:10][CH:9]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CS(=O)(=O)OCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1c[nH]cn1
Product: C(=C/c1nc(COc2ccc(CCn3ccnc3)cc2)co1)\c1ccccc1
Yield: 38 %

Procedure:
In substantially the same manner as in Working Example 25, 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethyl methanesulfonate was allowed to react with imidazole to give 4-[4-[2-(1-imidazolyl)ethyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 38%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 165-166° C.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[C:11]([C:23]#[N:24])[CH:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:20])[F:21])[CH:17]=2)[N:12]=[C:11]([C:23]#[N:24])[CH:10]=1
Reactant: COc1ccc(COc2cc(C#N)nc3ccc(C(F)(F)F)cc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(O)c2cc(C(F)(F)F)ccc2n1

Procedure:
A solution of 4-((4-methoxybenzyl)oxy)-6-(trifluoromethyl)quinoline-2-carbonitrile (5 g, 14 mmol) from above step C, in 15 mL DCM and 45 mL TFA was stirred for 2 h. Solvent was removed under vacuum and the residue was evaporated form toluene twice. The residue was dried under high vacuum. The resulting yellow solid was triturated with hot toluene, filtered and washed with ether to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[C:6]2[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[C:6]2[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][C:22]([F:21])([F:32])[F:33])[CH:25]=2)[CH2:17][CH2:16]1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: COc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Product: COc1ccc2oc(=O)cc(NC3CCN(Cc4cccc(OC(F)(F)F)c4)CC3)c2c1

Procedure:
According to Procedure A above, 6-methoxy-4-(piperidin-4-ylamino)-chromen-2-one and 3trifluoromethoxybenzaldehyde were allowed to react to give the title compound. MS (DCI/NH3) m/z 449 [M+H]+; 1H NMR (500 MHz, DMSO) δ ppm 7.66 (m, 2H), 7.59 (m, 2H), 7.51 (m, 1H), 7.27 (m, 2H), 7.22 (m, 1H), 5.39 (m, 1H), 4.40 (m, 2H), 3.83 (m, 4H), 3.51 (m, 2H), 3.12 (m, 2H), 2.20 (m, 2H), 1.84 (m, 2H).