Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:17]=2)=O)=[C:8]([Cl:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:22][C:8]1[C:7]([O:23][CH3:24])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[S:14][CH:15]=[C:16]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C3CCC3)cs2)c1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3nc(C4CCC4)cs3)nc2c1Cl
Yield: 84 %

Procedure:
8-Chloro-7-methoxy-2-(4-cyclobutylthiazol-2-yl)quinolin-4-ol 269b was synthesized from compound 268b (5.68 g, 1 eq.) as a beige solid in 84% yield, following the procedure as described for compound 218a (80° C. overnight). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.87-1.95 (m, 1H), 1.96-2.07 (m, 1H), 2.23-2.35 (m, 4H), 3.67-3.76 (m, 1H), 4.02 (s, 3H), 7.51 (s, 1H), 7.53 (d, J=9.30 Hz, 1H), 7.63 (s, 1H), 8.11 (d, J=9.30 Hz, 1H), 11.89 (br s, 1H); MS (ESI, EI+): m/z=347 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([NH2:14])[N:4]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([NH2:14])[N:4]=1)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1nc(SC)nc(N)c1[N+](=O)[O-]
Product: CNc1nc(S(C)=O)nc(N)c1[N+](=O)[O-]

Procedure:
Prepared from 2-methylsulphenyl-4-methylamino-5-nitro-6-amino-pyrimidine by reacting with m-chloro-perbenzoic acid, melting point: 229–234° C.
Reaction SMILES: Cl.Cl.Cl[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:6][N:5]=1.[CH2:23]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1CCCCC1>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[NH:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([N:30]4[CH2:31][CH2:32][N:27]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29]4)=[N:5][CH:6]=3)=[N:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CC(C)CN1CCNCC1
Reactant: Clc1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)c[nH]2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)CN1CCN(c2ccc(-c3ncc(-c4ccc(Cl)c(Cl)c4)[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.6 %

Procedure:
A suspension of 2-chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine dihydrochloride (1.07 g, 2.6 mmol), N-isobutylpiperazine (0.95 g, 6.72 mmol), potassium carbonate (0.5 g, 3.62 mmol), and potassium iodide (0.5 g, 0.54 mmol) in xylenes (5 mL) was heated to reflux under a nitrogen atmosphere for 24 hours. The reaction mixture was then cooled to ambient temperature and a solution of potassium carbonate (19) in water (10 mL) and cyclohexane (10 mL) were added. The mixture was stirred vigorously for 15 min, and the precipitate was collected by filtration. The filter cake was washed with water (10 mL) and triturated with methyl tert-butyl ether (4 mL) to provide 1-{5-[5(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isobutyl-piperazine (2.07 mmol).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>CO>[CH2:1]([NH:8][CH2:11][CH2:10][C:9]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNCc1ccccc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A solution of 55 mL (0.50 mole) benzylamine in 250 mL methanol was cooled in an ice bath. A solution of 54 mL (0.60 mole) methyl acrylate in 50 mL methanol was added dropwise over 30 minutes. The reaction mixture was then allowed to warm gradually to room temperature. After about 96 hours the reaction mixture was concentrated under reduced pressure and the residue vacuum distilled to provide 74.6 gm (77%) of the desired compound in two fractions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Brc1ccc(CN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2 g of 5-bromo-2-formylpyridine in 20 mL of 1,2-dichloroethane are successively added, under argon, 4.55 g of sodium triacetoxyborohydride and 0.94 mL of pyrrolidine. The reaction mixture is stirred at room temperature for 1 hour and then diluted with dichloromethane and the organic phase is washed with saturated sodium hydrogen carbonate solution, with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (98/2 by volume) to give 0.93 g of 5-bromo-2-pyrrolidin-1-ylmethylpyridine, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:17])[C:9]([O:15]C)=[C:10]([O:13]C)[CH:11]=2)[C:6](=[O:18])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:4]1)[CH3:2].B(Br)(Br)Br>ClCCl.CO>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:17])[C:9]([OH:15])=[C:10]([OH:13])[CH:11]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(OC)c(OC)c(F)c2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(O)c(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 1-ethyl-5-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (65 g, 201 mmol) in Dichloromethane (DCM) (300 mL) was added BBr3 (95 mL, 1005 mmol) at −78° C. The mixture was allowed to warm up to rt, and stirred at 25° C. overnight. LCMS indicated completion of the reaction. The mixture was diluted with MeOH and concentrated to dryness. The same process was repeated several times to afford 1-ethyl-5-fluoro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (48 g, 180 mmol, 89% yield) as yellow solid. The crude product was a mixture of acid and small amount of methyl ester, which was used in next step reaction without further purification. LCMS: (M+H)+: 268.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[C:31]([Cl:32])[N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:41]1([CH3:50])[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[C:31]([Cl:32])[N:17]2[N:16]=1)[CH2:13][CH3:14])[C:47](=[O:48])[C:44]1[CH:45]=[CH:46][C:41]([CH3:50])=[CH:42][CH:43]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of (±)-N-{3-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (0.51 g, 1.08 mmol) and Et3N (0.25 mL, 1.79 mmol) in CH2Cl2 (10 mL) at rt was added p-toluoyl chloride (0.21 mL, 1.58 mmol) under N2 and stirred at rt for 3 hr. The reaction mixture was diluted with CH2Cl2 to 100 mL, washed with aq. NaHCO3 solution (30 mL), dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1.5:8.5 to 1:3) gave the title compound as pale oil (0.43 g, 67%): 1H NMR (CDCl3) δ 7.30 (m, 2H), 7.24 (m, 1H), 7.15 (m, 2H), 7.10 (d, 1H, J=4.4 Hz), 6.53 (d, 1H, J=4.4 Hz), 5.91 (m, 1H), 4.95 (m, 1H), 3.35 (m, 2H), 2.70 (m, 1H), 2.36 (s, 3H), 2.05 (m, 1H), 1.95 (m, 1H), 1.43 (m, 3H), 1.35 (s, 9H), 0.67 (m, 3H); MS (ESI+) 592.15 (M++H).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C[CH2:16][Mg:17][Cl:18])C=CC=CC=1.C1(CC[Mg]Br)C=CC=CC=1.C1(CCC[Mg]Br)C=CC=CC=1.C[Mg]Cl>>[CH2:16]([Mg:17][Cl:18])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Cl[Mg]CCc1ccccc1
Agent: Br[Mg]CCCc1ccccc1
Agent: Br[Mg]CCc1ccccc1
Agent: C[Mg]Cl
Product: Cl[Mg]Cc1ccccc1

Procedure:
The same procedures as described in Preparation Example 1 were repeated using phenyl magnesium chloride, 2-phenylethyl magnesium chloride, 2-phenylethyl magnesium bromide, 3-phenylpropyl magnesium bromide and methyl magnesium chloride, respectively, in place of benzyl magnesium chloride to obtain functionalized amines. Each compound obtained in Preparation Examples 4 to 7 and physical properties thereof are given below in table 4.
Reaction SMILES: C([Li])CCC.[Br-].COC(C)([O:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.[C:35]1([CH2:41][O:42][C:43]2[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CCCCCC.C1COCC1>[C:35]1([CH2:41][O:42][C:43]2[CH:50]=[CH:49][C:46]([CH:47]=[CH:14][CH2:13][CH2:12][OH:11])=[CH:45][CH:44]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(C)(C)OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCC=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 20 ml) was added to a stirred suspension of finely powdered [3-(1-methoxy-1-methylethoxy)propyl] triphenylphosphonium bromide (14 g) in dry THF (100 ml) at 0°. The mixture was stirred at 0° for 30 min, treated with a solution of 4-(phenylmethoxy)benzaldehyde (5 g) in THF (25 ml), stirred at 0° for 2 h and filtered through silica. The filtercake was washed with ER, the combined filtrates evaporated in vacuo and the residual oil triturated with ER (50 ml) and filtered through silica. The filtrate was evaporated and the residue dissolved in THF-water-2 M hydrochloric acid (50:5:1, 56 ml) and kept at 23° for 20 min. The mixture was diluted with water (200 ml), extracted with ER (200 ml) and the extract was washed with water (100 ml), brine (50 ml) dried and evaporated to give a white solid which was stirred in hexane and filtered to give the title alcohol (5.2 g) m.p. 93°-95°.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1.CCO>[OH:16][B:15]([OH:17])[C:12]1[CH:13]=[CH:14][C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][OH:20])=[CH:10][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-benzoyl phenyl boronic acid (226.00 mg, 1.00 mmol) and hydroxylamine hydrochloride (84.00 mg, 1.20 mmol) in pyridine (5 mL) and EtOH (5 mL) was refluxed at 125° C. for 24 h. Reaction was then concentrated in vacuo to give a crude product which was used for next step without further purification. MS (ES+): m/z 241.89 (100)[MH+]. HPLC: tR=2.56 min (Open Lynx polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:19]=CC2N(O)N=[N:24][C:22]=2[CH:23]=1.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:16][C:10]1([CH3:17])[C@@H:11]([C:13]([N:24]2[CH2:19][CH2:18][CH2:23][CH2:22]2)=[O:15])[CH2:12][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCCC2)C1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.9 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.700 g, 2.88 mmol) in DCM (20 ml) EDCI (0.660 g, 3.456 mmol) and HOBt (0.529 g, 3.456 mmol) were added at about 0° C. and after 10 minutes, pyrrolidine (0.47 ml, 5.761 mmol) and Et3N (1.42 ml, 14.403 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous 1N HCl, then water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum. Wt: 0.400 g; Yield: 46.9%; 1H NMR (300 MHz, CDCl3): δ 5.00 (d, 1H, J=7.5 Hz), 3.89-3.77 (m, 1H), 3.57-3.29 (m, 4H), 2.78-2.68 (m, 1H), 2.31-2.22 (m, 2H), 1.98-1.78 (m, 4H), 1.43 (s, 9H), 1.35 (s, 3H), 0.89 (s, 31-1); Mass: [M+1]+ 297 (40%), [M+Na]+ 319 (100%); 1R (KBr, cm−1): 3312, 2977, 2956, 1709, 1621, 1606, 1526, 1442, 1365, 1348, 1283, 1267, 1176, 1106, 1046, 1009, 912, 877; M.R: 164.8° C.-165.5° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]>C(O)C>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([NH:2][NH2:3])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1)=[O:10]
Reactant: NN
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(NN)c([N+](=O)[O-])c1
Reaction time: 0.75 h
Yield: 85 %

Procedure:
80 ml of hydrazine hydrate were poured into the suspension of 172.5 g of methyl 4-chloro-3-nitrobenzoate in 1600 ml of abs. ethanol under stirring, then the reaction mixture was refluxed while stirring for 45 minutes. The starting material dissolved and the product started to precipitate. After cooling down, the product was filtered by suction, washed with abs. ethanol and water successively until it became free from chloride ion. Thus, 4-methoxycarbonyl-2-nitrophenylhydrazine (143.6 g, 85%) was obtained as yellow crystals m.p.: 169°-171° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][CH:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]2O)=[CH:13][CH:12]=1)([CH3:9])[CH:7]=[CH2:8])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]([CH3:9])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:13][CH:12]=1)[CH:7]=[CH2:8])[CH3:2]
Reactant: C=CC(C)(CC(=O)OCC)Cc1ccc(OCCCNC2C=CC=CN2O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: C=CC(C)(CC(=O)OCC)Cc1ccc(OCCCNc2ccccn2)cc1
Yield: 85.1 %

Procedure:
A solution of the product of STEP 6 (0.32 g), ion powder (0.07 g), triphenylphosphine (0.21 g), and acetic acid (8 ml) was heated to reflux for 15 minutes. The solution was cooled, filtrated through a celite bed, and washed with ethyl acetate. The filtrate was concentrated. The crude product was purified on a silica gel column, eluting with dichloromethane/methanol/ammonium hydroxide (97.5:2:0.5) to afford colorless oil (0.26 g). The 1H NMR was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:37][CH:27]([CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (1 g; 4.36 mmol) is dissolved in methylene chloride (50 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) [1.33 g; 4.36 mmol], triethylamine (0.61 mL; 4.36 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.84 g; 4.4 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then concentrated in vacuo at 30° C. The residue is diluted with ethyl acetate (100 mL) and washed successively with water (200 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated brine (50 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (5%→40% ethyl acetate in hexanes) affording the desired product (1.30 g) as a viscous oil. ESMS: MH+ 479.4
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[F:17][C:13]1[CH:12]=[C:11]([C:10]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:7][CH2:8][N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NCCc1ccccc1)c1cccc(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cccc(C2=NCCc3ccccc32)c1

Procedure:
289.0 g (1.19 mol) of N-phenylethyl-3-fluorobenzamide were dissolved in 1000 ml of xylene and admixed at 90° C. in portions with 202.7 g (1.43 mol, 1.2 eq.) of phosphorus pentoxide. Subsequently, 326.8 ml (3.57 mol, 3.0 eq.) of phosphorus oxychloride were added dropwise. The mixture was heated under reflux for 4 h. The reaction solution was subsequently poured while hot onto ice and adjusted cautiously to pH=12 with solid NaOH with ice cooling. The precipitate was extracted three times with 500 ml of toluene, dried over MgSO4 and concentrated under reduced pressure to a highly viscous oil which later crystallizes. 267.41 g are obtained with a purity of approx. 99%, corresponding to 99.8% of theory.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:22][C:21]3[CH:23]=[CH:24][C:25]([F:28])=[C:26]([F:27])[C:20]=3[F:19])=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(F)c1F
Yield: 53.2 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 294 mg of 2,3,4-trifluoroaniline in place of the 2,4-difluoroaniline. 195 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(2,3,4-trifluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH:10]=[CH2:11])[NH2:6].[OH:14]O>O1CCCC1>[OH:14][CH2:11][CH2:10][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:2]([F:12])([F:13])[F:1]
Reactant: OO
Reactant: C=Cc1ccc(N)cc1C(F)(F)F
Solvent: C1CCOC1
Product: Nc1ccc(CCO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
In 10 mL of anhydrous tetrahydrofuran, 2.47 g (13.2 mmol) of 3-trifluoromethyl-4-vinylaniline was dissolved, and 2.75 mL (30.0 mmol) of borane-dimethyl sulfide complex was added dropwise thereto in an argon atmosphere, and the mixture solution was stirred at room temperature four hours. To the reaction solution, 5 mL of a 1N sodium hydroxyl aqueous solution and 3 mL of a 30% hydrogen peroxide aqueous solution were added and the mixture solution was stirred at 0° C. for one hour. The reaction solution was concentrated and the residue was partitioned between water and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The product was purified by a silica gel column (n-hexane:ethyl acetate=2:1) to obtain 1.3 g (48%) of a target product as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]2[C:24]3[C:19](=[C:20]([C:26]([O:28]C)=O)[CH:21]=[C:22]([I:25])[CH:23]=3)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:31]>CC(O)C.CS(C)=O.O>[NH2:31][C:26]([C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[C:24]2[C:19]=1[N:18]=[CH:17][N:16]=[C:15]2[NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:28]
Reactant: COC(=O)c1cc(I)cc2c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)ncnc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c(C(N)=O)cc(I)cc23)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dissolved methyl 4-{[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}-6-iodoquinazoline-8-carboxylate (380.00 mg; 0.74 mmol; 1.00 eq.) in iPrOH (2.00 ml) and DMSO (2.00 ml) and then added ammonium hydroxide (5.00 ml). Stirred mixture at room temperature for 2.5 days. LCMS: M+1=498 major peak. Partially concentrated reaction. Diluted with water and filtered the resulting solids. Washed with water and dried to give an off-white solid (110 mg). LCMS: M+1=498.
Reaction SMILES: [C:1]([C:3]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[S:5][CH:4]=1)#[N:2].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:4]1[S:5][C:6]2[NH:7][C:8](=[O:13])[C:9](=[O:12])[NH:10][C:11]=2[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1csc2[nH]c(=O)c(=O)[nH]c12
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1c(Cl)sc2[nH]c(=O)c(=O)[nH]c12
Yield: 37.3 %

Procedure:
Chlorination of 7-cyanothieno(2,3-b]pyrazine-2,3(1H,4H)-dione (386 mg, 2 mmol) in acetic acid (50 ml) with sulfuryl chloride (250 pl, 3.1 mmol) was performed following the procedure outlined in example 5 (Method G) to give 170 mg (37%) of the title compound. M.P.>250° C. 1H-NMR (DMSO-D6, δ): 12.25 (br.s, 1H), 12.8 (br.s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[N:5]1C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[NH:5]1
Reactant: COCC1CCC(c2ccccc2OC)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCC1CCC(c2ccccc2OC)N1
Yield: 54.2 %

Procedure:
To a solution of 2-methoxymethyl-5-(2-methoxyphenyl)-N-(carbobenzyloxy)-tetrahydropyrrole (1.3 g, 3.66 mmol) in methanol (40 mL) was added 10% Pd-C (1.3 g) and the resulting suspension was hydrogenated (50 psi) for 3 hours. Pd-C was then filtered off and the crude reaction mixture was concentrated in vacuo to give a yellowish residue, which was purified by silica gel flash chromatography (5% MeOH-0.5% NH3♦H2O-94.5% CH2Cl2) to afford the title compound as a colorless oil (439.2 mg, 54%). MS m/z: 222 (M+H).