Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>FC(C1C=CC=CC=1)(F)F>[Br:12][CH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(C(F)(F)F)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: FC(F)(F)c1cnc(CBr)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
To a solution of 2-methyl-5-(trifluoromethyl)pyrazine (1 g) in trifluoromethylbenzene (10 ml) was added N-bromosuccinimide (1.21 g) at room temperature, and the mixture to was stirred at 90° C. for 30 min. To the obtained reaction mixture was added azobisisobutyronitrile (0.051 g), and the mixture was stirred at the same temperature for 7 hr. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (404 mg).
Reaction SMILES: CC1(C)C2C=CC([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=CC=2C(C2SC=CN=2)=CC1.[CH3:29][C:30]1([CH3:59])[C:39]2[CH:38]=[CH:37][C:36](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:35][C:34]=2[C:33]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:32][CH2:31]1>>[CH3:29][C:30]1([CH3:59])[C:39]2[CH:38]=[C:37]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:36]=[CH:35][C:34]=2[C:33]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[CH:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CCC3(C)C)cc1
Reactant: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoic acid (Compound 78), 27.0 mg (0.07 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-3-yl)ethynyl]benzoate (Compound 68) was converted into the title compound (colorless solid) using 5.9 mg (0.14 mmol) of LiOH in H2O.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.O[CH2:31][C:32]1[N:33]=[CH:34][NH:35][C:36]=1[CH3:37].C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:31][C:32]4[N:33]=[CH:34][NH:35][C:36]=4[CH3:37])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]cnc1CO
Reactant: Cn1c2c(c3cccc(F)c31)C(=O)NCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Yield: 128.6 %

Procedure:
A solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (100 mg) in N-methylpyrrolidinone (10 ml) was treated with 4-toluenesulphonic acid monohydrate (17 mg) and 4-hydroxymethyl-5-methylimidazole hydrochloride (37 mg). The mixture was then heated to 125° for 18 h during which time three further portions of 4-hydroxymethyl-5-methylimidazole hydrochloride (37 mg) were added at 1,2 and 3 h respective. The solution was then poured into 8% sodium bicarbonate solution (100 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were concentrated in vacuo and the N-methylpyrrolidinone was distilled at 100°. The residue was purified by FCC eluting with System A (200:8:1) to give the title compound (100 mg), t.l.c. (System A, 100:8:1) Rf 0.3.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:9][CH:8]=1)=O.[NH2:30]N.Cl>C(O)C>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)=[N:30]1
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: CCO
Product: NCCCCOc1ccc(-c2cc[nH]n2)cc1

Procedure:
A suspension of 21.2 g of (E)-2-[4-[4-[3-(dimethylamino)-1-oxo-2-propenyl]phenoxy]butyl]-1H-isoindole-1,3(2H)-dione (Example 48) in 300 ml of boiling ethanol is treated with 6 ml of anhydrous hydrazine. A suspension quickly develops, necessitating addition of 200 ml more ethanol to permit stirring. While stirring 35 ml of concentrated HCl is then added, the mixture refluxed a further hour, and filtered hot. The insolubles are washed with 200 ml of boiling water. The combined filtrates are taken to dryness in vacuo, leaving the hydrochloride salt of the title compound as shown by mass spectrometry. The product is utilized for synthesis without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C@H:11]([CH3:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:6]([C:20]([F:23])([F:22])[F:21])[N:5]=[CH:4][CH:3]=1.[CH:24](=O)[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:24]1[NH:1][C:2]2[CH:3]=[CH:4][N:5]=[C:6]([C:20]([F:23])([F:21])[F:22])[C:7]=2[C:8](=[O:9])[N:10]1[C@H:11]([CH3:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](Cc1ccccc1)NC(=O)c1c(N)ccnc1C(F)(F)F
Reactant: COc1ccccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccccc1C1Nc2ccnc(C(F)(F)F)c2C(=O)N1[C@H](C)Cc1ccccc1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
(R)-4-amino-N-(1-phenylpropan-2-yl)-2-(trifluoromethyl)nicotinamide (16.23 g, 50.2 mmol) and ortho-anisaldehyde (8.2 g, 60.2 mmol) were combined along with a catalytic amount of 4-toluenesulfonic acid (0.174 g, 1.0 mmol) in anhydrous toluene (550 mL). This mixture was heated at reflux overnight in a round bottom flask fitted with a Dean-Stark trap. The resultant dark solution was cooled to room temperature, then concentrated in vacuo to a dark brown paste. This paste was suspended in ethyl acetate, and the resultant solids were collected by filtration to provide the product (6.94 g). The filtrate was concentrated in vacuo then purified by silica gel column chromatography using 40-60% ethyl acetate/hexanes as eluant to give 12.1 g of additional product diastereomers (84% total yield). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, 1H), 7.1-7.3 (m, 7H), 6.9 (d, 1H), 6.8 (t, 1H), 6.5 (d, 1H), 5.95 (d, 1H), 5.7 (d, 1H), 4.8 (m, 1H), 3.95 (s, 3H), 3.0 (dd, 1H), 2.4 (dd, 1H), 1.3 (d, 3H). MS m/z 442.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[O:13]1[C:17]2[CH:18]=[C:19]([CH2:22][NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14]1>>[O:13]1[C:17]2[CH:18]=[C:19]([CH2:22][N:23]([C:2]3[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=3)[S:24]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14]1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3ccoc3c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3ccoc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-(benzofuran-6-ylmethyl)sulfamoyl)benzoate (step-1 of Example 2).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]3[O:13][CH2:14][O:15][C:9](=[C:10]([F:17])[C:11]=3[F:16])[C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[F:21][C:22]([F:27])([F:26])[S:23]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]3[O:13][CH2:14][O:15][C:9](=[C:10]([F:17])[C:11]=3[F:16])[C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:23][C:22]([F:27])([F:26])[F:21]
Reactant: N#Cc1cc(N)n(-c2c(Cl)c3c(F)c(F)c2OCO3)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1nn(-c2c(Cl)c3c(F)c(F)c2OCO3)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 25.1 %

Procedure:
To a suspension wherein 5-amino-1-(2-chloro-4,5-difluoromethylenedioxyphenyl)-3-cyanopyrazole (897 mg, 3.00 mmol), sodium trifluoromethanesulfinate (936 mg, 6.00 mmol) and dimethylamine tosylate (1.629 g, 7.5 mmol) are in toluene (5 ml), thionyl chloride (714 mg, 3.00 mmol) was added dropwise under ice cooling over a period of about 10 minutes and stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 300 mg of 5-amino-1-(2-chloro-4,5-difluoro-methylenedioxyphenyl)-3-cyano-4-trifluoromethylsulfenylpyrazole. M.p. 125.6° C.
Reaction SMILES: [Li+].[BH4-].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH2:14][CH2:15][N:16]2[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]3)[CH2:17]2)=O)=[CH:7][CH:6]=1)#[N:4]>C1(C)C=CC=CC=1.C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][CH2:14][CH2:15][N:16]2[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][N:20]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:19]3)[CH2:23]2)=[CH:9][CH:10]=1)#[N:4]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCC(=O)Nc3ccc(C#N)cc3)C2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCCNc3ccc(C#N)cc3)C2)C1
Reaction time: 0.75 h
Yield: 10 %

Procedure:
LiBH4 (300 mg; 13.6 mmol) was added to a stirred solution of tert-butyl 7-{2-[(4-cyanophenyl)carbamoyl]ethyl}-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.36 g; 3.41 mmol; see Example 22 above) in toluene (10 mL) and THF (5 mL) and the reaction mixture was stirred for 45 min. The solvents were removed and the residue partitioned between DCM and NaHCO3 (aq.). The organic layer was concentrated and subjected to column chromatography (DCM:MeOH; 9:1) to give the title compound in a 10% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][CH:13]=[CH:14][N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC(C)=O>C(Cl)Cl>[N:15]1([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][CH:13]=[CH:14][N:4]3[N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Solvent: ClCCl
Solvent: CC(C)=O
Product: c1cn2nc(N3CCCCC3)c3c(c2n1)CCCC3

Procedure:
A mixture was prepared by adding 15 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine to 30.5 g of piperidine and the mixture was heated at reflux for 72 hours. The mixture was subjected to preparative liquid chromatography using 15% acetone in methylene chloride to separate the desired product from the impurities. The appropriate fractions from the chromatography were combined and the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and dried to give 6-(1-piperidinyl)-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine melting at about 95° C. This compound has the following structural formula ##STR2##
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[CH3:31].C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Yield: 48.8 %

Procedure:
A mixture of 0.03 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.015 g (0.0001 mole) of 4-amino-3-methylbenzoic acid, 0.3 mL of ethanol, 0.8 mL of water, and 1 drop of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.020 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methyl-benzoic acid (I-7) as an off-white solid.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[Na+].C(N(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)C[C:16]([O-])=[O:17].[Na+].[Na+].[Na+].C=O>O.C(O)(=O)C>[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH2:16][OH:17])[N:5]=1
Reactant: Oc1cccnc1Br
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: OCc1ccc(O)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (85% assay, 113.8 g, 1.73 mol) was dissolved in distilled water (750 ml) and to the solution was added 2-bromo-3-hydroxypyridine (300 g, 1.72 mol), ethylenediaminetetraacetic acid sodium salt (2 mmol %, 13.1 g, 0.034 mmol) and formalin (3741% w/v 470 ml, 5.95 mmol). The stirred mixture was heated at 90°-95° C. until the assay (HPLC) of remaining starting material fell below 3% (approx 5 h) . The reaction mixture was then cooled to room temperature and glacial acetic acid (103 ml) added and stirred for a further 2h. The precipitated solid was filtered from the mixture and the filtrate saturated with sodium chloride (310 g). The resulting solution was extracted with ethyl acetate (4×280ml). The combined organic extracts were dried and evaporated to dryness keeping the temperature below 85° C. The residue was assayed by HPLC to determine the quantity of contained 2-bromo-3-hydroxy-6-hydroxymethylpyridine. The yield was typically 65%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].Cl.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.CO>>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:16]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccc3c([N+](=O)[O-])cccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (2.0 g, 0.0094 mol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate hydrochloride (4.7 g, 0.019 mol) and methanol (80 mL, 2 mol). The mixture was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and was stirred overnight. LC-MS showed the starting material was completely consumed. Volatiles were removed and the resulting oil was purified by silical gel in a methanol:methylene chloride (0-10%) gradient. Fractions containing the desired product, as determined by TLC and LC-MS, were combined and concentrated to yield a yellow solid (3.22 g). MS m/z=388.1 (M+1).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([N:7]([CH:20]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:21][OH:22])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[O:6]>CN(C=O)C>[CH3:32][O:31][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:23]=1[CH:20]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[C:5](=[O:6])[CH2:4][O:22][CH2:21]1
Reactant: COc1cccc(OC)c1C(CO)N(Cc1ccc(OC(F)(F)F)cc1)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C1COCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A cooled (−25° C.) mixture of NaH (60% dispersion in mineral oil; 1 mg; 0.025 mmol) in anh. DMF (1 ml) was treated dropwise with a solution of 2-chloro-N-(1-(2,6-dimethoxyphenyl)-2-hydroxyethyl)-N-(4-(trifluoromethoxy)benzyl)acetamide (10 mg; 0.022 mmol) in anh. DMF (1 ml). The resulting mixture was further stirred at rt, under nitrogen, for 30 min. The mixture was then filtered, and the obtained filtrate was directly purified by preparative HPLC affording 5-(2,6-dimethoxyphenyl)-4-(4-(trifluoromethoxy)benzyl)-morpholin-3-one as a yellow oil. LC-MS (conditions E): tR=0.79 min.; [M+H]+: 412.06 g/mol.
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])C.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19]>CC(O)C>[CH3:13][CH2:12][O:11][C:9]([CH2:8][NH:7][C:5]([C:4]([NH:19][CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15])=[O:14])=[O:6])=[O:10]
Reactant: CCOC(=O)CNC(=O)C(=O)OCC
Reactant: COC(CN)OC
Solvent: CC(C)O
Product: CCOC(=O)CNC(=O)C(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-ethoxycarbonylmethyl-oxalamic acid ethyl ester (84.0 g, 414 mmol) 2–1 in 2-propanol (500 mL) was added aminoacetaldehyde dimethyl acetal (45.7 g, 435 mmol) in one portion. After stirring overnight at room temperature, the reaction mixture was concentrated to a thick orange oil. This thick slurry was diluted with 2-propanol (300 mL) and the solid was broken up with a spatula. Filtration afforded a solid which was further rinsed with an additional portion of 2-propanol. Removal of residual 2-propanol was accomplished via high vacuum to afford a light orange solid: 1H NMR (CDCl3) δ 7.82 (br s, 1H), 7.50 (br s, 1H), 4.41 (t, 1H, 5.3 Hz), 4.24 (q, 2H, 7.1 Hz), 4.09 (d, 2H, 5.9 Hz), 3.47 (dd, 2H, 5.3, 6.2 Hz), 3.40 (s, 6H), 1.30 (t, 3H, 7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:21])([F:22])[F:23])[CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Temperature: 80 °C

Procedure:
To a stirred solution of 6-hydroxyindan-1-one (1.48 g, 10 mmol) in 30 ml of DMF was added 3-chloro-4-fluorobenzotrifluoride (2.46 g, 12 mmol) and cesium carbonate (8.40 g, 25 mmol). The reaction mixture was heated at 80° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (2×) and brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with ethyl acetate (2-40%) in hexane. The final product was collected as brownish yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[Cl:31][C:27]1[CH:26]=[C:25]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:22][CH:21]=2)=[O:24])[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(c1ccc(O)cc1)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 40.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (89 mg) and 3-chlorophenyl 4-hydroxyphenyl ketone (279 mg) obtained in Example 27 were mixed and stirred at 180° C. for 20 minutes. The reaction mixture was then purified in the same manner as described in Example 24 to obtain 67 mg of the title compound (yield: 40%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[CH:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.C1(C=CC(O)=CC=1)O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:15]([O:14][C:12]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1)=[CH2:13])[CH2:16][CH2:17][CH3:18]
Reactant: C=COCCCC
Reactant: CC(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(OCCCC)c1ccc(NC(C)=O)nc1
Yield: 21.7 %

Procedure:
A mixture of 1.07 g (5 mmol) of N-(5-bromo-pyridin-2-yl)-acetamide, 1.00 g (10 mmol) of butyl vinyl ether, 0.245 g (0.8 mmol) of tri-o-tolylphosphine, 0.090 g (0.4 mmol) of palladium acetate, and 1.10 mL (7.9 mmol) of triethylamine in 10 mL of acetonitrile containing 15 mg of hydroquinone was heated at reflux for about 18 hours. The reaction mixture was then cooled, concentrated, and the residue was taken up in ether and water. The ether phase was separated, washed with water and brine, dried, and concentrated. The residue was chromatographed on silica gel (6:1 benzene-ethyl acetate) to afford 0.254 g of the title product as a colorless oil that rapidly crystallized, mp 55°-58° C. (recrystallization solvent=hexane). 1H nmr (deuteriochloroform): δ=8.48 (m, 1 H); 8.42 (br s, 1 H); 8.24 (m, 1 H); 7.93 (m, 1 H); 4.60 (d, 1 H); 4.23 (d, 1 H); 3.84 (t, 3 H); 2.21 (s, 3 H); 177 (m, 2 H); 1.48 (m, 2 H); 0.97 (t, 3 H). ms (El): m/z=234 (M+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH-].[Na+]>C(O)C>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:27]([Cl:28])=[C:4]([Cl:3])[CH:5]=1)[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 5 h
Yield: 10.3 %

Procedure:
Sodium borohydride (1.19 g) in ethanol was added dropwise to ethyl N-(3,4-dichlorobenzyl)-5-nitroindole-2-carboxylate (12.4 g) and stannous chloride dihydrate (35.6 g) in ethanol at 60° C. and reaction stirred for 5 hours. The mixture was then cooled, made basic with 2N sodium hydroxide and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated to give an oil which crystallised upon trituration with i-hexane. Filtration yielded the desired end product as a pale brown solid (1.18 g, 10%); NMR δ (CDCl3) 1.32 (t, 3H), 4.26 (q, 2H), 6.69 (s, 2H), 6.78-7.35 (m, 7H); M/z (−) 363 (M+), 274, 267, 265, 151, 121, 102.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl[C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:16]=1>>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:17]2[N:16]=[C:15]([NH:13][CH:10]3[CH2:9][CH2:8][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:12][CH2:11]3)[N:20]=[C:19]([C:21]([OH:24])([CH3:22])[CH3:23])[CH:18]=2)=[CH:30][CH:29]=1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Reactant: CC(C)(O)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: Cc1nsc(N2CCC(Nc3nc(-c4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)n1
Yield: 41.2 %

Procedure:
In analogy to example 29, 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine (59.5 mg, 0.3 mmol) was reacted with 2-[2-chloro-6-(4-chloro-phenyl)-pyrimidin-4-yl]-propan-2-ol (85 mg, 0.3 mmol) to give the title compound (55 mg, 41%) as off-white foam.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1C)[N:8]=[C:7]([C:13]([NH:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[O:14])[C:6](=[O:21])[NH:5]2.CC1C=C2C(=CC=1C)N=C(C(O)=O)C(=O)N2>>[O:21]=[C:6]1[NH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=[C:7]1[C:13]([NH:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[O:14]
Reactant: Cc1cc2nc(C(=O)Nc3nnn[nH]3)c(=O)[nH]c2cc1C
Agent: Cc1cc2nc(C(=O)O)c(=O)[nH]c2cc1C
Product: O=C(Nc1nnn[nH]1)c1nc2ccccc2[nH]c1=O

Procedure:
In a similar manner 3,4-Dihydro-6,7-dimethyl-3-oxo-N(1H-tetrazol-5-yl)-2-quinoxalinecarboxamide, m.p. 262° (d), was prepared from 3,4-dihydro-6,7-dimethyl-3-oxo-2-quinoxalinecarboxylic acid (40%).