Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[C:36]([O:40][C:41](=[O:65])[CH2:42][N:43]([S:55]([C:58]1[CH:63]=[CH:62][C:61](Br)=[CH:60][CH:59]=1)(=[O:57])=[O:56])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:39])([CH3:38])[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C>[C:36]([O:40][C:41](=[O:65])[CH2:42][N:43]([S:55]([C:58]1[CH:63]=[CH:62][C:61]([C:16]2[CH:15]=[CH:14][C:13]([C:12]3[C:11]4[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=4[O:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:17]=2)=[CH:60][CH:59]=1)(=[O:57])=[O:56])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 80 °C
Yield: 23 %

Procedure:
A solution of 2-benzyl-3-[4′-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran (268 mg 0.653 mmol) in anhyd DMSO (5 mL) was added to a stirred suspension of tert-Butyl-[(4-bromobenzenesulfonyl)-(3-trifluoromethylbenzyl)amino]-acetate (296 mg, 0.58 mmol) and tripotassium phosphate (0.37 g, 1.76 mmol) in anhyd DMSO (5 mL). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (60 mg, 0.07 mmol) was added as a solid, and the resulting suspension was heated to 80° C. for 25 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered though celite, and washed with sat'd aq LiCl (3×10 mL), sat'd aq NaCl (1×10 mL), dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (heptane) afforded the title compound as a white solid (95 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=2)[CH:10]=[C:9]1[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[C:35]([CH3:37])[C:34]([OH:38])=[C:33]([CH3:39])[CH:32]=2)[N:28]=[N:27][C:26]=1[O:40]C)=O)(C)(C)C.C[Si](Cl)(C)C.[I-].[K+].Cl>C(#N)C>[OH:38][C:34]1[C:33]([CH3:39])=[CH:32][C:31]([C:29]2[CH:30]=[C:25]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=4)[C:26](=[O:40])[NH:27][N:28]=2)=[CH:36][C:35]=1[CH3:37]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CN3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [I-]
Solvent: CC#N
Product: Cc1cc(-c2cc(-c3cc4ccc(CN5CCN(C)CC5)cc4[nH]3)c(=O)[nH]n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
475 mg 2-[6-(4-Hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-6-(4-methyl-piperazin-1-ylmethyl)-indole-1-carboxylic acid tert-butyl ester are dissolved in 10 mL acetonitrile. 432 □L TMSCl and 565 mg potassium iodide are added. The reaction mixture is heated to reflux for 3 hours. After cooling to rt, 1 mL conc. HCl is added and the reaction mixture stirred for 1 hour. Then the mixture was concentrated in vacuo. Purification by HPLC and addition of 1 N aq. HCl before lyophilisation affords 53 mg (13%) 6-(4-hydroxy-3,5-dimethyl-phenyl)-4-[6-(4-methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-2H-pyridazin-3-one as its chloride salt.
Reaction SMILES: [CH3:1][S:2][CH:3]1[N:6]([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5](=[O:18])[CH2:4]1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH3:1][S:2]([CH:3]1[N:6]([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:18])[CH2:4]1)=[O:27]
Reactant: CSC1CC(=O)N1CC(=O)CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of 4-methylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one (0.4 g, 1.5 mmol) in dichloromethane (40 ml) was cooled to -60° C. To this a solution of meta-chloroperbenzoic acid (m-CPBA, 0.52 g, 1.5 mmol) in dry dichloromethane (50 ml) was added dropwise over 10 minutes, maintaining the temperature between -50 and -60° C. The mixture was stirred at room temperature for 60 minutes, washed with dil. Na2SO3, dil. NaHCO3, H2O (×2) and dried (MgSO4). Evaporation under reduced pressure gave a residue which was purified by flash chromatography on silica gel using ethyl acetate then petroleum ether/ethyl acetate to give 4-methylsulphinyl-1-(4-phenyl-2-oxobutyl)azetidin-2-one as a waxy yellow solid (0.18 g, 43%). 1H NMR demonstrated that this was a 1:1 mixture of diastereoisomers.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>C1COCC1>[CH3:35][N:34]1[C:27]2[N:28]([C:29](=[O:31])[N:30]=[C:25]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([O:13][C:14]4[CH:15]=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=4)=[C:9]([CH:12]=3)[C:10]#[N:11])[CH:26]=2)[CH2:32][CH2:33]1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (6.52 mg, 0.272 mmol), 5-(hydroxymethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile (80 mg, 0.272 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50.5 mg, 0.272 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH3:11][Li].O>C1COCC1>[C:5]([C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1)(=[O:7])[CH3:11]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccnc(Cl)c1
Temperature: -70 °C

Procedure:
In 440 ml of THF was suspended 22 g of 2-chloroisonicotinic acid, and under nitrogen flow, the mixture was cooled to −70° C. or lower, 245 ml of methyl lithium (1.14 M solution in diethyl ether) was added dropwise to the mixture. After stirring at the same temperature for an hour, a temperature of the mixture was raised to 0° C. over an hour, and stirred at the same temperature for further an hour. To the reaction mixture was added 500 ml of water, and the reaction mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. Activated charcoal was added to the mixture, and after filtration, the filtrate was concentrated under reduced pressure to give 19.5 g of 4-acetyl-2-chloropyridine as colorless crystals. Melting point: 36° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N=C=N.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([NH:38][CH:39]3[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1.C(O)C(N)(CO)CO>CN(C=O)C>[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([NH:38][C@@H:39]3[CH2:40][CH2:41][C@H:42]([NH:45][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:43][CH2:44]3)=[CH:33][CH:34]=[N:35]2)=[CH:30][CH:29]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCc1ccccc1)N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Reaction time: 8 h

Procedure:
31 mg (0.16 mmol) of 5-phenylvaleric acid, 112 mg (0.22 mmol) of PS-carbodiimide and 28 mg (0.18 mmol) HOBT in DMF (1 mL) were mixed for 15 min. 30 mg (0.11 mmol) of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine was added and the reaction was allowed to proceed overnight. 116 mg (0.54 mmol) of PS-trisamine was added and the reaction mixture was filtered after two hours. The solvent was evaporated and the product was purified by reverse phase HPLC to provide the titled compound. MS (ESI(+)) m/e 436 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 13.86 (brs, 1 H), 8.82 (d, 1 H), 8.72 (d, 1 H), 8.54 (d, 1 H), 7.94 (d, 1 H), 7.78 (dd, 1 H), 7.69 (d, 1 H), 7.21 (m, 5 H), 6.96 (d, 1 H), 3.89 (m, 1 H), 3.80 (m, 1 H), 2.58 (m, 2 H), 2.50 (m, 2 H), 2.16 (m, 2 H), 1.82 (m, 6 H), 1.47-1.70 (m, 6 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:12]([O-])=O)[CH:3]=1>CO.[C].[Pd]>[NH2:12][C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: Cc1cc(C)c(C(N)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C(N)=O)c(N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.4 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (3 g, 18.07 mmol) in acetic acid (20 mL) and 6 N HCl (60 mL) at 0° C. was added a solution of sodium nitrite (2.18 g, 31.62 mmol) in water (5 mL). The reaction mixture was stirred at 0° C. for 30 min after completion of addition and copper (I) cyanide (3.24 g, 3 mmol) was added pinch by pinch. The resulting mixture was stirred at 0° C. for h and at room temperature for an additional 2 h. The mixture was passed through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=7:1) to yield 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 81%) as a light yellow solid. A solution of 2-chloro-1,5-dimethyl-3-nitro-benzene (2.6 g, 15.7 mmol) and copper (I) cyanide (7.05 g, 78.3 mmol) in DMAC (20 mL) was stirred at reflux for 14 h. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), filtered through a Celite pad, extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford a solid residue. The solid was further purified by column (SiO2, hexanes/EtOAc=6:1) to yield 0.64 g of 2,4-dimethyl-6-nitro-benzonitrile (23%). A solution of 2,4-dimethyl-6-nitro-benzonitrile (1.1 g, 6.24 mmol) in MeOH (20 mL) and water (10 mL) was mixed with hydrogen peroxide (10 mL), DMSO (10 mL) and potassium hydroxide (0.636 g, 11.36 mmol). The reaction mixture was stirred at 60° C. for 3 h, diluted with water (100 mL), extracted with EtOAc (3×100 mL), and concentrated using a rotary evaporator to afford 4,6-dimethyl-2-nitrobenzamide (0.52 g, 43%). A solution of 4,6-dimethyl-2-nitrobenzamide (0.52 g, 2.68 mmol) in MeOH (30 mL) was mixed with palladium carbon (0.25 g). The resulting suspension was stirred at room temperature under hydrogen for 14 h. The mixture was passed through a Celite pad, concentrated using a rotary evaporator to afford 2-amino-4,6-dimethyl benzamide (0.42 g, 95%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:16]1[CH2:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>C(Cl)Cl.CCOC(C)=O>[O:16]1[CH2:17][CH:18]=[C:19]([C:2]2[C:3]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:20][CH2:21]1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Oc2nccnc2C2=CCOCC2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
Into a sealed tube were placed 4-(3-chloropyrazin-2-yloxy)aniline (1 g, 4.51 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.42 g, 6.77 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.25 g, 0.36 mmol), sodium carbonate (2.39 g, 22.5 mmol) and 18 mL of 4:1 DME-water. After the mixture was degassed for 5 min, the reaction was stirred at 80° C. for 18 h. The cooled reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (1×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (10% to 50% EtOAc (10% MeOH)/Hexanes) afforded 4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline (1.09 g, 90% yield) as a light yellow solid. [M+1]=270.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:34](=O)(OC)OC.C1N2CCN(CC2)C1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:34])[CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)OC
Reactant: CCOC(=O)CCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CCOC(=O)CCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12

Procedure:
To a solution of ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]butanoate (D53) (150 mg) and dimethyl carbonate (5.0 mL) in N,N-dimethylformamide (DMF) (0.5 mL) was added DABCO (18 mg). The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 150° C. for 1.5 h. After cooling the reaction, the mixture was concentrated to afford the crude product ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]butanoate (D57) (180 mg), which was used for the next hydrolysis step without further purification. MS (ES): C26H28ClN3O4 requires 481. found 482.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:25])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCO.[Pd]>[CH3:25][N:8]([C@@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCNC1
Reaction time: 1 h
Yield: 81.6 %

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)piperidine-1-carboxylate (4.00 g, 11.5 mmol) in methanol (10 mL) was slowly added to a suspension of 5% Pd on activated carbon (2.44 g, 1.15 mmol) in EtOH (20 mL). The reaction mixture was evacuated and back filled with N2 (3 cycles). The reaction vessel was then evacuated and back filled with H2 (3 cycles) using a H2 balloon. The mixture was stirred under H2 atmosphere for 1 hour and filtered through a pad of celite, washing with additional 10% MeOH/EtOAc (3×20 mL). The filtrate collected was concentrated in vacuo to provide (R)-tert-butyl methyl(piperidin-3-yl)carbamate (2.01 g, 82% yield) as an oil. LCMS (APCI+) m/z 215 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[F:23])=[CH:9][CH:8]=1)[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl.O>C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:23])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSc1ccc(Oc2ccc(N)cc2F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl[4-(2-fluoro-4-nitrophenoxy)phenylsulfanyl]acetate (4.93 g, 14.0 mmol) in ethanol (100 mL) was added tin chloride dihydrate (9.50 g, 42.1 mmol), and the resulting solution was stirred for 8 hours at 50° C. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, and evaporated, to thereby yield 3.45 g of the title compound.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>[Cu]I.O1CCCC1>[C:7]([C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Ic1cccs1
Reactant: C#CCCCCCCCCCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cccs1
Temperature: 55 °C
Reaction time: 7 h
Yield: 739 %

Procedure:
To a solution of 2-iodothiophene (31.5 g), 1-dodecyne (2.5 g), triethylamine (105 ml), and tetrahydrofuran (100 ml) was added (bis)triphenylphosphine palladium(II)chloride (1.73 g) followed by copper(I)iodide (0.24 g). The reaction mixture was warmed to 55° C. and stirred for 7 hr. The solution was allowed to cool to room temperature and stirred overnight. The mixture was filtered, and the precipitate was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled to afford 27.6 g (74%) of product, bp 145°-150° C. at 0.7 mm Hg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8]>C(N(CC)CC)C>[N:1]1([CH2:8][CH2:7][C:6]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: C=CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(O)CCn1cccn1
Yield: 97.7 %

Procedure:
In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 mmol), acrylic acid (0.50 mL, 7.3 mmol) and triethylamine (3 mL). The reaction mixture was refluxed for 6 hours. After removing triethylamine, the viscous oil was dried on high vacuo during 12 hours to yield quantitatively the desired acid (1.0 g) suitable for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:26]3[CH:25]=[CH:24][N:23]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[O:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(Cc3ccncc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.100 g (0.29 mmol) of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg (0.29 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.098 g (0.3 mmol) of TOTU. The solution was stirred for 1 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in DCM and the solution was washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate, and ethyl acetate/MeOH (10/1).
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=[O:3].[CH2:9]([O:11][C:12](=[O:30])[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[N:15][C:14]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)C>O1CCOCC1>[F:19][C:17]1[CH:16]=[N:15][C:14]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:9](=[O:3])[O:11][C:12](=[O:30])[C:13]=2[CH:18]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(F)cnc1NCc1ccc(OC)cc1
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)oc(=O)c3cc(F)cnc32)cc1
Yield: 90.2 %

Procedure:
Trichloromethyl chloroformate (11.41 mL, 94.63 mmol) was added slowly to a solution of 5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester (68) (24 g, 78.86 mmol) in dioxane and refluxed for 4 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was recrystallized by ether to yield 21.5 g (90%) of 6-fluoro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (69) as white solids. MP: 143° C.; 1H-NMR (DMSO-d6): δ 3.71 (s, 3H), 5.27 (s, 2H), 6.85 (m, 2H), 7.35 (m, 2H), 8.40 (dd, J=2.8, 6.8 Hz, 1H), 8.82 (d, J=2.8 Hz, 1H); EIMS: 303 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1>Br>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[N:10]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(Nc3ccc(Br)cc3)ncc2c1
Agent: Br
Product: Oc1ccc2nc(Nc3ccc(Br)cc3)ncc2c1

Procedure:
(4-bromophenyl)(6-methoxyquinazolin-2-yl)amine in HBr was heated at 100° C. for 16 hours. The reaction mixture was concentrated and purified on preparative chromatography. Lyophillization yielded 2-[(4-bromophenyl)amino]quinazolin-6-ol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]Cl.C([O-])([O-])=O.[K+].[K+].O>COCCOC.CCOC(C)=O>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CN(C)CCCl
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1OCCN(C)C
Temperature: 25 °C

Procedure:
A mixture of 7 (2.16 g, 9.68 mmol), 2-(dimethylamino)-ethyl chloride hydrochloride (1.53 g, 10.6 mmol) and K2CO3 (5.35 g, 3.87 mmol) in DME (28 mL)/H2O (7 mL) was heated under reflux overnight. After cooling to room temperature, the solution was diluted with EtOAc (100 mL) and the resulting solution was washed with H2O (2×100 mL) and brine (100 mL).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[O:13][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCCc1ccccc1
Reactant: Oc1cc(-c2ncco2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2ncco2)cc1OCCCc1ccccc1
Reaction time: 15 h
Yield: 51 %

Procedure:
To a solution of the title compound of Step (A) (0.42 g, 1.75 mmol) in 5 mL of DMF at 50° C., anhydrous potassium carbonate (0.29 g, 2.09 mmol) and 1-bromo-3-phenyl propane (0.52 g, 2.63 mmol) were added and stirred for 15 hr. The mixture was then added to 25 mL water and the solution was extracted with 3×25 mL EtOAc. The combined organic extracts were washed with water and dried and evaporated. The residue thus obtained was chromatographed on 25 g of silica gel using 3:1 hexane:EtOAc to afford 0.32 g (51%) of the title compound of this step as a light yellow oil.