Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][CH2:30][NH:29][C:28]2=[O:33])[CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]3=[O:33])[CH2:23][CH2:22]1)=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C1NCCCN1C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCNC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(2S)-3-[(6-Chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid, 1-(piperidin-4-yl)tetrahydropyrimidin-2(1H)-one, and HOBt (23.0 g) were dissolved in DMF, WSC was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, diluted with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was washed with an aqueous 5% citric acid solution and saturated saline solution, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound as a colorless powder.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[P:6]([O:15]C(C)C)([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9]>C(OCC)(=O)C>[CH:8]([O:7][P:6]([CH2:2][CH:3]1[CH2:5][CH2:4]1)(=[O:15])[O:11][CH:12]([CH3:14])[CH3:13])([CH3:10])[CH3:9]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: BrCC1CC1
Solvent: CCOC(C)=O
Product: CC(C)OP(=O)(CC1CC1)OC(C)C
Temperature: 144 °C
Yield: 94.3 %

Procedure:
Bromomethyl-cyclopropane (26.00 g, 0.193 mol) was added to triisopropyl phosphite (35.9 mL, 0.30 mol) at ambient temperature, under a nitrogen atmosphere. The resulting solution was stirred and heated at reflux (144° C. bath temperature) overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation and then under high vacuum to yield 39.96 g of cyclopropylmethyl-phosphonic acid diisopropyl ester (0.182 mol, 94% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ 4.63-4.54 (m, 2H); 1.67-1.60 (d of d, 2H) 1.27-1.24 (d of d, 12H); 0.85-0.75 (m, 1H); 0.52-0.46 (m, 2H); 0.21-0.16 (m, 2H); ESMS (m/z): M+1)+ found, 221; (M+23)+ found, 243.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.[BH4-].[Na+]>CN(C=O)C>[CH2:22]([N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:1][C:5]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2ccncc2n1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c([nH]1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butyl 2-ethyl 1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate (1.0 eq) in DMF was added benzyl bromide (1.0 eq.) and heated to 80° C. for 4 hrs. Reaction mixture was evaporated to dryness. The product obtained was dissolved aqueous ethanol and NaBH4 (1.5 eq.) was added at 0° C. and stirred for 4 hrs. Reaction was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded ethyl 6-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][CH2:41][CH:40]1[CH2:49][NH2:50]>CN(C=O)C>[O:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][CH2:41][CH:40]1[CH2:49][NH:50][CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: NCC1COc2ccccc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
5-methoxyindole-3-butyric acid (1.5 g, 6.4 mmole), 1-hydroxybenzotriazole hydrate (1.0 g, 7.7 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.3 g, 6.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of TBF to remove a by-product and to give 1.8 g (74%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-1H-indole-3-yl)-butanamide, as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:16]2[CH:15]([C:17](O)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[C:16]2[CH:15]([CH2:17][OH:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COCc1cccc2c1C(C(=O)O)c1ccccc1-2
Solvent: C1CCOC1
Product: COCc1cccc2c1C(CO)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A solution of 1-methoxymethyl-9-fluorenecarboxylic acid (3.4 g, 13.4 mmol) in 100 mL of THF was charged with 1M THF solution of BH3 -THF complex (30.0 mL, 30.0 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature then quenched with water (100 mL). The organic layer was washed with 10% potassium carbonate solution, water, brine, dried over magnesium sulfate and evaporated. Short path chromatography of the residual oil (silica, 25% ethyl acetate in hexane) afforded 1-methoxymethyl-9-fluorenemethanol (2.6 g, 79.9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[C:4]([F:15])[C:5]([F:14])=[C:6]([O:8]C(OCC)=O)[CH:7]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[F:14][C:5]1[C:4]([F:15])=[C:3]([F:16])[C:2]([NH:1][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][C:6]=1[OH:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)Oc1cc(N)c(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(O)c(F)c(F)c1F
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
1.27 g (5.40 mmol) of the above 5-amino-O-ethoxycarbonyl-2,3,4-trifluorophenol was dissolved in 5 mL of pyridine, 0.80 mL (6.5 mmol) of pivaloyl chloride was added under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. 1N hydrochloric acid was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 25 mL of methanol, 1.40 g (10.1 mmol) of potassium carbonate and 15 mL of water were added and the mixture was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 2 by addition of 2N hydrochloric acid thereto and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1.20 g of 2,3,4-trifluoro-5-pivaloylaminophenol (two stage yield: 90%).
Reaction SMILES: C(=O)(O)O.[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[O:15]C(=O)OC(C)(C)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)[CH:24]=1.[OH-].[K+]>CO.O>[F:5][C:6]1[C:11]([CH:12]([OH:13])[C:37]2[C:31]3[C:32](=[N:33][CH:34]=[C:29]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[CH:30]=3)[NH:35][CH:36]=2)=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[OH:15]
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C=O)c1F
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: O=C(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To carbonic acid tort-butyl ester 2,4-difluoro-3-formyl-phenyl ester (39, 0.405 g, 15.7 mmol) in methanol (36 mL), under an atmosphere of nitrogen, was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 288.0 mg, 14.8 mmol, prepared as in Example 17, Scheme 32) and potassium hydroxide (145.0 mg, 25.9 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 4% methanol in methylene chloride to give a colorless oil (P-0009, 0.23 g, 44.1%). MS(ESI) [M+H+]+=354.1.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH-].[Na+]>CN(C)C=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][C:21]([OH:24])=[O:22])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCCCCCCCc1ccc(CC#CCCCCO)cc1
Agent: [Na+]
Agent: [OH-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(CC#CCCCC(=O)O)cc1

Procedure:
7-[p-(n-octyl)phenyl]-5-heptyn-1-ol (1.7 mmole) is dissolved in dimethyl formamide and to the resulting solution is added, with stirring, pyridinium dichromate (11.7 mmoles). After stirring for 48 hours at room temperature, the reaction mixture is poured onto a 10% sodium hydroxide solution and extracted with ethyl ether. The aqueous layer is acidified to pH of 2-3 with concentrated hydrochloric acid and extracted with chloroform. The chloroform layer is separated, the solvents removed by evaporation and the residue distilled under reduced pressure to afford the title compound, 7-[p-(n-octyl)phenyl]hept-5-ynoic acid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:33]([O:32][C:30]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Yield: 70.1 %

Procedure:
Ester reduction, Method B: A solution of 35 g (69 mmol) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 380 ml toluene/60 ml THF was treated at −47° C. to −50° C. with 44 g (152 mmol) of a 70% solution of sodium dihydrido-bis(2-methoxy-ethoxo)aluminate in toluene (3.5 M Red-Al in toluene). After 3h at −50° C. and 1 h at −30° C. the solution was poured into water (1 l) with 40 g of citric acid and extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and evaporated. Column chromatography on silica gel with hexane/EtOAc (7:3) gave 23.0 g (69%) (2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 476 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH3:20]>C(O)C>[NH2:20][C:14]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]=2[N:15]=1
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Reactant: N
Solvent: CCO
Product: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Yield: 72 %

Procedure:
Reaction of 4-(3-bromoanilino)-6-fluoropyrido [3,2-d) pyrimidine (0.12 g, 0.38 mmol) (described in a previous experimental) with a saturated solution of ammonia in ethanol in a pressure vessel at 100° C. for 18 h gives 6-amino-4-(3-bromoanilino)pyrido[3,2-d]pyrimidine, (87 mg, 72%). 1H NMR (CDCl3) δ 8.76 (1H, brs), 8.64 (1H, s), 8.23 (1H, brs), 7.93 (1H, d, J=9.0 Hz), 7.81 (1H, dt, Jd =7.7 Hz, Jt =1.8 Hz), 7.28-7.22 (2H, m), 7.00 (1H, d, J=9.0 Hz), 4.90 (2H, brs).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1F
Yield: 85.9 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (4.8 g), triethylamine (3.3 mL), 2-fluorocinnamic acid (3.9 g), WSC.HCl (4.5 g), and methylene chloride (150 mL), to give the captioned compound (6.0 g, 86%) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](C(=O)C)=[C:11]([O:18][CH2:19][C@H:20]2[CH2:22][O:21]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=[C:26]([C:30]([O:32]O)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:32][C:30](=[O:31])[CH3:26])=[C:11]([O:18][CH2:19][C@H:20]2[CH2:22][O:21]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OC[C@H]1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(OCc2ccccc2)cc1OC[C@H]1CO1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-[4-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl]ethanone (1.62 g, 5.43 mmol) in DCM (60 ml) was added m-chloroperbenzoic acid (2.15 g) and solid NaHCO3 (3.24 g). Stirring was continued at 40° C. for 1 h. The mixture was filtered and the filtrate was washed once with 10% NaHSO4 solution and then twice with NaHCO3 solution. The organic layer was washed with water and brine, dried with Na2SO4. The solvent was removed under reduced pressure. The crude product obtained (1.34 g) was sufficiently pure for the next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][NH:6][NH2:7].C([O:16][C:17](=O)[CH:18]=[C:19]([NH2:23])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:23][C:19]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[C:17](=[O:16])[CH:18]=1
Reactant: NNCc1ccccc1C(F)(F)F
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccccc2C(F)(F)F)[nH]1
Reaction time: 8 h

Procedure:
46 g of 2-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 38.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue was recrystallised from ethanol. The product was the compound identified above. Melting point: 184°, 22 g (34%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]>CC(C)=O.CCCCCCC>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:18]=1[O:17][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH:22]=[O:23]
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(COc2ccc(C=O)cc2OC)cc1
Temperature: 55 °C
Reaction time: 28 h
Yield: 99 %

Procedure:
5 g (36.1 mmol) of potassium carbonate and then 4.9 ml (36.1 mmol) of 1-chloromethyl-4-methoxy-benzene are added to a solution of 5 g (33 mmol) of 4-hydroxy-3-methoxy-benzaldehyde in 100 ml of acetone. The reaction mixture is then stirred at 55° C. for 28 hours and then filtered. The filtrate is concentrated under vacuum. The residue obtained is taken up in heptane and filtered. 8.9 g (100%) of 3-methoxy-4-(4-methoxy-benzyloxy)-benzaldehyde is obtained in the form of a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=O)[CH:6]=[C:7]([O-])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[Na].Cl.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18]>>[CH2:8]([C:7]1[N:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:22]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH:6]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC([O-])=CC(=O)C(=O)OCC
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na]
Product: CCCCc1cc(C(=O)OCC)nn1C(C)(C)C

Procedure:
1-Ethoxy-1,2-dioxooct-3-en-4-olate, sodium salt (332.8 g, 1.50 mol) was treated with tert-butylhydrazine hydrochloride (186.6 g, 1.50 mol) according to the procedure described in Part B of Examples 37-39 to yield ethyl 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxylate as a brown oil.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])([CH3:14])[CH3:13].[C:25](Cl)(=[O:27])[CH3:26].O>ClCCl>[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:25](=[O:27])[CH3:26])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])([CH3:14])[CH3:13]
Reactant: COCCOCC(C)(C)c1ccc(N)cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a suspension of NaHCO3 (10 g, 0.1 mol) in dichloromethane (50 mL) was added 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5 g, 30 mmol) and acetyl chloride (3 mL, 20 mmol) at 0-5° C. The mixture was stirred overnight at 15° C. and then poured into water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×2). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness to give N-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide (5.0 g, 87%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:7]=1[N+:21]([O-])=O)[CH2:2][CH2:3][CH3:4].[H][H]>[C].[Pd].O1CCCC1>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:7]=1[NH2:21])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCNc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
To a tetrahydrofuran solution (5 mL) of 2-(4-n-butylamino-3-nitrophenyl)benzoxazole (see Working Example 74-1) (353 mg, 1.13 mmol) was added 10% palladium-carbon (50 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 15 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (305 mg, 96% yield).
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[CH3:28][C:29](=[CH:33][CH3:34])[C:30](Cl)=[O:31]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:30](=[O:31])[C:29]([CH3:28])=[CH:33][CH3:34])[CH2:24][CH2:23]2)[N:9]=1
Reactant: CC=C(C)C(=O)Cl
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC=C(C)C(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.7 g of 2,3-dimethylacryloyl chloride, after which the mixture was stirred at room temperature for 12 hours. The crystals which were produced were collected by filtration, washed with water and recrystallized from ethanol, to give 1.04 g of the desired Compound No. 3 in the form of pale yellow prisms melting at 219.5°-221.5° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.Cl>CC(N(C)C)=O>[C:17]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=3)[N:3]=[C:2]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:11]=2[C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc2nc(N3CCCCC3)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 18.6 %

Procedure:
A mixture of 2-chloro-4-phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-quinoline (105 mg, 279 μmol), piperidine (47.6 mg, 55.3 μl, 559 μmol) and triethylamine (84.8 mg, 117 μl, 838 μmol) in DMA (2 ml) was heated to 100° C. in a sealed tube. After 4 h 0.1N HCl was added at room temperature and the mixture was extracted with EtOAc. The combined organic layers were washed with 0.1N HCl and brine and dried with Na2SO4. The remaining brown oil was purified by chromatography (silica gel, DCM/MeOH 98:2 to 95:5). The product fractions were concentrated and the remaining solid was dissolved in EtOAc, filtered through silica gel and evaporated. The remaining residue was finally purified by preparative thin-layer chromatography (DCM/MeOH 95:5) to obtain the title compound (22 mg, 18%) as light yellow solid. MS (ESI): 425.4 (M+H)+.