Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[NH:32])=[CH:24][CH:23]=2)[C:7]1=[O:34].O.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH:8]([CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:27]=3)[C:7](=[O:34])[N:6]([CH2:5][C:4]3[CH:35]=[CH:36][CH:37]=[C:2]([Cl:1])[CH:3]=3)[C:11]=2[CH:12]=1
Reactant: N=C(N)NCCc1ccc(OCCC2Oc3ccc([N+](=O)[O-])cc3N(Cc3cccc(Cl)c3)C2=O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N=C(N)NCCc1ccc(OCCC2Oc3ccc(N)cc3N(Cc3cccc(Cl)c3)C2=O)cc1
Yield: 85 %

Procedure:
4-(3-Chlorobenzyl)-3,4-dihydro-2-{2-[4-(2-guanidinoethyl)phenoxy]ethyl}-6-nitro-3-oxo-2H-1,4-benzoxazine (0.3 g) was warmed in ethanol (5 ml) and H2O (4 ml) until completely in solution. Iron powder (0.19 g, 6.8 eq) was stirred in followed by NH4Cl (0.02 g, 0.7 eq) and the reaction continued at reflux for 5 hours. While still hot, the mixture was filtered through celite and the yellow filtrate concentrated down to a yellow oil. After drying in vacuo at 80° C., the product was collected as a yellow solid in 85% yield, mp (dec) >94° C.; MS (CI) MH+ 494; IR (KBr) 3332, 1667, 1614, 1512, 1467, 1396, 1243, 830, 774, 680 cm-1 ; 1H NMR (DMSO-d6 /CDCl3) δ 7.66 (br s, 1H), 7.58-6.50 (v br s, 3H), 7.36 (m, 4H), 7.20 (m, 3H), 6.91 (d, 2H, J=8.6 Hz), 6.74 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=2.2 Hz), 6.21 (dd, 1H, J=2.2, 8.4 Hz), 5.08 (d, 1H, J=16.7 Hz), 4.99 (d, 1H, J=16.5 Hz), 5.12-4.78(v br s., 1H), 4.79 (dd, 1H, J=4.0, 8.9Hz), 4.15 (m, 2H), 3.33 (m, 2H), 2.71 (t, 2H, J=7.5 Hz), 2.30 (m, 1H), 2.18 (m,1H). Anal. Calc'd for C26H28ClN5O3. HCl.0.5H2O: C 57.89, H 5.61, N 12.98. Found: C 57.64, H 5.48, N 12.63.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Br:13])=[C:7]([O:14][CH3:15])[CH:6]=1)=O.CCOC(C)=O.C([O-])(O)=O.[Na+].[CH:27]([NH2:29])=[O:28]>>[Br:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([C:3]2[N:29]=[CH:27][O:28][CH:2]=2)=[CH:6][C:7]=1[O:14][CH3:15]
Reactant: COc1cc(C(=O)CBr)cc(OC)c1Br
Reactant: NC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(-c2cocn2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
A solution of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.8 g, 0.96 mmol) in formamide (7 mL) in an oven-dried flask under argon was heated at 100° C. for 10 hours then 110° C. for 5 hours. After cooling to room temp, EtOAc and saturated aqueous NaHCO3 were carefully added and the mixture was stirred for 15 minutes. It was then extracted with EtOAc twice and the combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated. Purification by chromatography (20-40% EtOAc-hexanes) provided 4-(4-bromo-3,5-dimethoxyphenyl)oxazole as a yellow solid (0.387 g, 58% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][NH2:42])[CH:37]=[CH:38][CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][NH:42][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:31]=[CH:30][N:29]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: NCCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1)C1CCNCC1

Procedure:
Intermediate 30 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 484. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (s, 1H), 8.3 (d, 1H) 8.1 (d, 1H) 7.7 (d, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.1 (m, 2H), 6.9 (t, 1H), 4.6 (s, 2H), δ 3.4 (t, 2H), 3.09 (s, 3H), δ 3.05 (m, 5H), 3.04 (t, 2H), 2.08 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:48][CH:49]1[NH:53][CH2:52][C:51]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([OH:54])[CH2:50]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:53]3[CH:49]([CH3:48])[CH2:50][C:51]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([OH:54])[CH2:52]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CC1CC(O)(c2ccccc2)CN1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CC(O)(c3ccccc3)CC2C)cc1
Yield: 52.9 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 5-methyl-3-phenylpyrrolidin-3-ol (5 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (6 mg). MS (ESI, pos. ion) m/z: calcd for C22H22N2O4: 378.1580, found 378.1580.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[C:21]([C:11]1[CH:10]=[CH:9][C:8]([S:7][C:1]2[CH:2]=[CH:3][C:4]([C:21](=[O:22])[CH2:20][CH2:19][CH3:18])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)(=[O:22])[CH2:20][CH2:19][CH3:18]
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)c1ccc(Sc2ccc(C(=O)CCC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Diphenylsulfide (33.3 ml, 0.20 mol) is added to a suspension of AlCl3 (54.7 g, 0.41 mol) in 350 ml of CH2Cl2. n-Butyryl chloride (41.4 ml, 0.40 mol) is added dropwise slowly in an ice bath and the reaction solution is stirred at room temperature for 15 h. Then, the reaction solution is poured into ice-water. The crude product is extracted with CH2Cl2, washed with 1N NaOH and brine, dried over MgSO4, and concentrated. The product is obtained as a white solid. 1H NMR (CDCl3), δ[ppm]: 1.00 (t, 6H), 1.77 (tq, 4H), 2.92 (t, 4H), 7.40 (d, 4H), 7.90 (d, 4H).
Reaction SMILES: [CH3:1]I.[CH2:3]([O:5][C:6](=[O:22])[C:7](=[C:13]([SH:21])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[Na]>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:7](=[C:13]([S:21][CH3:1])[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:22])[CH3:12]
Reactant: CI
Reactant: CCOC(=O)C(C(=O)OCC)=C(S)Nc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccccc1)SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
Over a 30 min period, methyl iodide (17.7 g, 125 mmol) was added dropwise to a solution of sodium 2-(mercapto-phenylamino-methylene)-malonic acid diethyl ester (33 g, 104 mmol) in DMF (100 mL) cooled in an ice bath. The mixture was stirred at room temperature for 1 h, and then poured into ice water (300 mL). The resulting solid was collected via filtration, washed with water and dried to give 2-(methylsulfanyl-phenylamino-methylene)-malonic acid diethyl ester as a pale yellow solid (27 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([CH:8]([OH:14])[C:9]([F:13])([F:12])[CH2:10][OH:11])[CH:7]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([CH:8]([OH:14])[C:9]([F:13])([F:12])[CH2:10][O:11][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(F)(F)C(O)c1cc(Br)ccc1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)C(O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of 1-(5-bromo-2-fluorophenyl)-2,2-difluoropropane-1,3-diol (17.0 g, 59.8 mmol) in dry DCM (200 mL) was added imidazole (12.2 g, 179.2 mmol) at 0° C. and stirred for 15 min. tert-butyldimethylsilylchloride (13.5 g, 89.5 mmol) was added to the resultant reaction mixture portion wise for a period of 30 min. and stirring continued for 2 h. Reaction was monitored by TLC analysis. The solids formed in the reaction mixture were separated by filtration and filtrate was concentrated under reduced pressure to obtain crude product which was purified by column chromatography on silica gel with 2% Ethylacetate in Hexane as eluent to furnish title compound as a colorless liquid. Yield=19 g (80%). TLC (20% ethyl acetate in Hexane): Rf=0.75),
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[C:37]1([CH2:43]O)([CH2:41][OH:42])[CH2:40][CH2:39][CH2:38]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:38]1[C:37]2([CH2:41][O:42][C:24]3([CH2:23][CH2:22][CH:21]([N:11]4[C:10](=[O:28])[C:9]([CH2:8][C:7]5[CH:6]=[CH:5][C:4]([C:29]6[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=6)=[CH:3][C:2]=5[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]5[N:18]=[CH:19][N:20]=[C:12]45)[CH2:26][CH2:25]3)[O:27][CH2:43]2)[CH2:40][CH2:39]1
Reactant: OCC1(CO)CCC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCC2(CCC2)CO3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
A mixture of 3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.5 g), cyclobutane-1,1-diyldimethanol (1 g), p-toluenesulfonic acid monohydrate (0.014 g) and toluene (60 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.6 g, 86%).
Reaction SMILES: [H-].[Na+].[C:3]([NH:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl[CH2:23][C:24]([CH2:26]Cl)=[CH2:25]>CN(C=O)C>[C:18]([O:17][C:15]([N:14]1[CH2:26][C:24](=[CH2:23])[CH2:25][N:13]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NNC(=O)OCc1ccccc1
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C1CN(C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (3.81 g, 95.4 mmol) in DMF (80 mL) is add dropwise a solution of N-Cbz-N′-Boc-hydrazine (12.1 g, 45.4 mmol) in DMF (20 mL). The reaction mixture is stirred about 20 minutes and 3-chloro-2-chloromethyl-propene (5.8 mL, 50 mmol) is added dropwise and the reaction is allowed to stir at room temperature until the reaction is complete by TLC, approximately 12 hours. The reaction solution is partitioned between ethyl acetate and water, the water layer being extracted several times more with solvent. The combined organic layers are dried, filtered, and concentrated to afford the desired product as a clear oil which is used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[NH:14][CH:13]=[C:12]([C:15]2[CH:38]=[CH:37][C:18]3[N:19]([C:22]4[CH:23]=[C:24](N)[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=5[F:35])[CH:27]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH:42][S:43]([N:46]2CCOC2=O)(=[O:45])=[O:44])[CH2:41][CH2:40]1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:38]=[CH:37][C:18]3[N:19]([C:22]4[CH:23]=[C:24]([CH:40]5[CH:39]([NH:42][S:43](=[O:44])(=[O:45])[NH2:46])[CH2:41]5)[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=5[F:35])[CH:27]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(C4=CNC(OCc5ccccc5)C=C4)ccc32)c1
Reactant: O=C1OCCN1S(=O)(=O)NC1CC1
Solvent: c1ccncc1
Product: NS(=O)(=O)NC1CC1c1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(OCc5ccccc5)nc4)ccc32)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (120 mg, 0.2380 mmol) in pyridine was added N-cyclopropyl-2-oxooxazolidine-3-sulfonamide (78 mg, 0.380 mmol, 1.6 eq.). The mixture was stirred at 50° C. for 16 h, quenched with water and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with 1 N HCl and 1N NaOH, water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 10% yield (15 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccccc1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (7.927 mmol) of 2-amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile are initially charged in 15 ml of DMF, 2.13 g (8.720 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.99 g (23.781 mmol) of sodium bicarbonate are added and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the precipitated solid is filtered off, washed with MTBE and dried under high vacuum. This gives 3.87 g (100% of theory) of the target compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2.[CH2:26]([NH:29][C:30]1[C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:27][CH3:28]>C1COCC1.ClCCl>[CH3:28][CH2:27][CH2:26][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([C:23]([C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([F:13])=[CH:15][C:16]=3[CH:17]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CCCNc1cccnc1N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCNc1cccnc1N1CCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (0.48) is added to a 20°-25° solution of 5-fluoroindole-2-carboxylic acid (I, 0.53 g) in THF (6 ml). After 1 hour of stirring the above reaction is added dropwise via cannula to a solution of [3-(propylamino)-2-pyridinyl]piperazine (II, PREPARATION 7, 0.72 g) in THF (6 ml) at -10° (ice/acetone bath). The reaction is stirred for 30 minutes at -10°, slowly warming to 20°-25°, and stirred 4 hours. The reaction is diluted with dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (40 ml), saline (40 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (40 g silica gel) eluting with ethyl acetate/hexane (1/1). The appropriate fractions are pooled and concentrated to give the title compound, mp 196°-198°; IR (mineral oil) 3200, 2920-3000, 1630 and 1424 cm-1 ; NMR (300 MHz, CDCl3) 9.82, 7.72, 7.35, 7.27, 7.03, 6.95, 6.86, 6.78, 4.32, 4.09, 3.21, 3.08, 1.71 and 1.05 δ; CMR (300 MHz, CDCl3) 162.3, 159.5, 149.7, 137.4, 135.1, 132.3, 130.7, 127.5, 127.4, 120.4, 116.3, 113.4, 112.9, 112.7, 112.5, 106.1, 105.8, 105.1, 105.0, 49.0, 45.2, 22.5 and 11.6 δ; MS (m/e) 382, 381, 190, 176, 164, 162, 134 and 120.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:29][CH:28]([CH2:30][C:31](OC)=[O:32])[CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[CH2:30][CH:28]5[CH2:29][O:26][CH2:27]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)CC1COC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (22.9 mg, 76.3%), MS (ISP) m/z=429.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and methyl 2-(oxetan-3-yl)acetate.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([CH3:12])=[CH:4][C:3]=1[CH3:13].[CH3:14][O-:15].[Na+]>CO.N1C=CC=CC=1>[N+:9]([C:6]1[C:7]([CH3:8])=[C:2]([O:15][CH3:14])[C:3]([CH3:13])=[CH:4][C:5]=1[CH3:12])([O-:11])=[O:10]
Reactant: C[O-]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1Br
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1c(C)cc(C)c([N+](=O)[O-])c1C
Temperature: 85 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
To a solution of 2-bromo-4-nitro-1,3,5-trimethylbenzene (2.0 g, 8.19 mmol) in methanol (20 mL) and pyridine (1.0 mL) under nitrogen was added sodium methoxide (6.2 mL, 32.8 mmol, 30% in methanol), and cuprous chloride (1.62 g, 16.4 mmol). The reaction mixture was heated to 85° C. After 16 hours, it was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (2×80 mL). The organic phases were combined and washed with saturated aqueous NaCl (2×) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 3-nitro-2,4,6-trimethyl-1-methoxybenzene (0.86 g, 54%) was obtained as a light-yellow liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:8][C:5]1[CH:4]=[C:3]([C:2]([Br:1])=[CH:7][N:6]=1)[C:9]([O:11][CH3:12])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(=O)[nH]cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cc(OCc2ccccc2)ncc1Br
Temperature: 65 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a suspension of methyl 5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (2.5 g, 10.77 mmol) in MeCN (35 mL) was added silver carbonate (4.46 g, 16.16 mmol) and benzyl bromide (1.54 mL, 12.93 mmol). The reaction mixture was heated to 65° C. and stirred for 18 hours. The reaction mixture was filtered through a plug of Celite® and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50-100% DCM in cyclohexane to give the title compound (3.31 g, 95%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:24]([O:26][CH:27]([O:38][CH2:39][CH3:40])[N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=[O:37])[CH3:25].[H-].[Na+]>C1COCC1>[CH2:39]([O:38][CH:27]([O:26][CH2:24][CH3:25])[N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:29]1=[O:37])[CH3:40]
Reactant: CCOC(OCC)N1C(=O)Cc2ccccc21
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2ccccc21
Reaction time: 0.75 h
Yield: 79.2 %

Procedure:
4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (338 mg, 1 mmol) was dissolved in THF (20 ml) at 40° C., and 1-diethoxymethyloxindole (705 mg, 3 mmol), (prepared according to Synthesis 1975, 168), and sodium hydride (138 mg, 5.8 mmol, pre-washed with petroleum ether) were added successively to the solution at ambient temperature. After stirring for 45 minutes, the volatiles were removed by evaporation and the residue dissolved in methylene chloride. The solution was washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column flash chromatography using methylene chloride/ethyl acetate (1/1) followed by an increasingly polar mixture of methylene chloride and methanol (2 to 4%) as eluent. The purified product was triturated with ether. collected by filtration, washed with a 1/1 mixture of ether/petroleum ether and dried under vacuum to give 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (425 mg, 84%) as a yellow-orange solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>CC(O)=O>[N+:15]([C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[OH:14])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-phenoxyphenol (10.0 g, 54 mmol) in 100 mL AcOH was added slowly dropwise nitric acid (69-70%, 3.2 mL, 54 mmol) over about 3 min from an addition funnel. The reaction became warm and was cooled with a water bath. After 1 h, the reaction was poured onto ice and allowed to warm to rt. A gummy solid resulted, which was partitioned between MTBE and water. The organic layer was washed 1× water, 1× brine, dried over sodium sulfate, filtered, and concentrated to a dark oil. This was adsorbed onto 36 g silica gel and dried, and purified in two parts by silica gel chromatography, ISCO, 0-10% EtOAC/hexanes. Product-containing fractions were combined and concentrated to give 2-nitro-4-phenoxyphenol as an orange oil. MS (ESI) m/z: Calculated: 231.1; Observed: 230.0 (M−−1).
Reaction SMILES: ClN[NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8].[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C(O)C>[CH3:15][O:14][C:13]1[C:4]2[NH:3][C:26]3[CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][C:25]=3[C:5]=2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(OC)c(NNCl)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(OC)c2[nH]c3c(c12)CN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Methyl 3-(2-chlorohydrazino)-4-methoxybenzoate (from step 1) (0.0042 mol) and N-Boc-4-piperidone (0.0063 mol) in ethanol (20 ml) was stirred for 18 h at room temperature. Reaction was concentrated under vacuum and product was isolated with silica gel column chromatography using 20% ethyl acetate in petroleum ether.