Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.Cl.[NH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1>CN(C=O)C.O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:7]([CH:11]=1)[C:8]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:10]
Reactant: O=C1CCNCC1
Reactant: Cc1ccc(-c2ccncc2)c(C(=O)O)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2ccncc2)c(C(=O)N2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
A suspension of 5-methyl-2-(pyridin-4-yl)benzoic acid hydrochloride (2.0 g), piperidin-4-one hydrochloride (1.2 g), DMTMM (3.3 g) and N-methylmorpholine (2.6 mL) in DMF (30 mL) was stirred at room temperature for 5 hr, and then overnight at 100° C. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.73 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:29])=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:30][O:31][C:32]1[C:36](OC)=[N:35][S:34](=[O:39])[N:33]=1>CO>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:8]([CH3:29])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:36]2[C:32]([O:31][CH3:30])=[N:33][S:34](=[O:39])[N:35]=2)=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COC1=NS(=O)N=C1OC
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: CO
Product: CCOC(=O)C1=C(COCCNC2=NS(=O)N=C2OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g) and 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.2 g) were dissolved in methanol (15 ml) and heated at reflux for 14 hours. The solvent was evaporated and the residue chromatographed on silica "Kieselgel 60H" (Trade Mark), eluting with ethyl acetate. The product-containing fractions were combined and evaporated to give an oil which was triturated in ethyl acetate to give the title compound as a solid, yield 0.14 g, m.p. 183°-185°.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9].[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:11])[C:8]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([Br:12])=[CH:14][CH:15]=1)=[O:9]
Reactant: Brc1cccc2ccccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 37 %

Procedure:
To a suspension of AlCl3 (3.20 g, 24 mmol) in 100 mL DCM at 0° C., methylchloroglyoxylate (2.2 mL, 24 mmol) was added. The resulting solution was stirred for 5 min., after which 1-bromo-naphthalene (5 g, 24 mmol) was added. After stirring for 2 hrs at room temperature, water was added and the phases were separated, after which the organic layer was washed with water and dried over MgSO4. The residue obtained after evaporation of the organic solvent was purified by column chromatography (0-30% EtOAc/Hex), to afford 2.6 g of the target compound. 1H NMR (CDCl3): 8.92 (1H, d, J=9.3 Hz, H-arom); 8.31 (1H, d, J=9.3 Hz, H-arom); 7.82 (1H, d, J=8.8 Hz, H-arom); 7.72 (1H, d, J=8.8 Hz, H-arom); 7.57-7.68 (2H, m, H-arom); 3.94 (3H, s, OMe).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29].[CH2:33]([OH:35])[CH3:34]>>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:27](=[O:31])[C:28]([O:35][CH2:33][CH3:34])=[O:29])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(Cl)C(=O)Cl
Reactant: FC(F)(F)c1ccc(-c2cccc3c2ccn3Cc2ccccc2)cc1
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(C(F)(F)F)cc3)c12
Yield: 19 %

Procedure:
Ethyl {1-benzyl-4-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetate was prepared from 1-benzyl-4-[4-(trifluoromethyl)phenyl]-1H-indole (0.257 g, 0.731 mmol), oxalyl chloride (2.2 mL, 26 mmol), and ethanol (6 mL) according to the procedure described in Step 3 of Example 1. Purification by HPLC using 3% ethanol in hexane as the mobile phase afforded the title compound as a hard yellow gum (0.064 g, 19%). 1HNMR (200 MHz, DMSO-d6): δ 8.7 (s, 1H), 7.7 (d, 3H, J=7.7 Hz), 7.15-7.5 (m, 9H), 5.65 (s, 2H), 4.25 (q, 2H, J=7.0 Hz), and 1.35 ppm (t, 3H, J=7.1 Hz).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:3][C:24]1[CH2:25][CH2:26][N:21]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH2:22][C:23]=1[CH:9]=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Reactant: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC(Cl)=C(C=O)C2)cc1
Reaction time: 2 h

Procedure:
A solution of POCl3 (1.5 eq.) in DMF (2.5 eq) at 0° C. was stirred for 15 min. 1-[(4-methylphenyl) sulfonyl]piperidin-4-one (1.0 eq) obtained from step I was added to the above solution and the reaction was continued at room temperature for 2 h Reaction was quenched with water and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 4-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridine-3-carbaldehyde.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[C:23]([O:28][CH2:29][CH2:30][NH2:31])(=[O:27])[C:24]([CH3:26])=[CH2:25].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]([O:28][CH2:29][CH2:30][NH:31][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:13]([O:14][C:15](=[O:17])[CH3:16])=[C:12]([O:18][C:19](=[O:21])[CH3:20])[CH:11]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCNC(=O)c1cc(OC(C)=O)c(OC(C)=O)c(OC(C)=O)c1
Reaction time: 0.5 h

Procedure:
3,4,5-Triacetoxybenzoyl chloride (0.050 mol) was dissolved in 100 mL CH2Cl2 at 0° C. To this was added 2-aminoethyl methacrylate hydrochloride (8.28 g, 0.050 mol), followed by dropwise addition of triethylamine (14.63 mL, 0.105 mol). After 30 min, 100 mL 1N HCl was added with vigorous stirring. The organic layer was isolated, washed with saturated NaHCO3 and 50 mL 1N HCl, dried over MgSO4, and evaporated to give an oil, which crystallized rapidly after the addition of 50 mL diethyl ether. The product was isolated by filtration and vacuum dried. Yield, 17.97 g as a white solid, 88%. 1H NMR (300 MHz, CDCl3), δ1.92 (s, 3H), 2.26 (s, 6H), 2.27 (s, 3H), 3.68 (m, 2H), 4.30 (t, 2H), 5.58 (m, 1H), 6.11 (s, 1H), 6.66 (t, broad, 1H), 7.51 (s, 2H). Anal., calcd for C19H21N1O9C 56.02, H 5.20, N 3.44, found C 55.99, H 5.15, N 3.50.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH2:12][N:13](CC3C=CC(OC)=CC=3OC)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([C:31]([O:33]CC)=O)[O:9][N:8]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:31]([OH:33])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(Br)o2)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2c(-c3ccc(Br)o3)noc2c1O
Temperature: -78 °C
Reaction time: 14 h
Yield: 6.4 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)isoxazole-5-carboxylate (1.53 g, 2.78 mmol) was dissolved in 30 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (5.6 mL, 5.55 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was quenched with 5 mL of 1M HCl and 100 mL of saturated ammonium chloride solution. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 1.32 g of crude oil. The crude intermediate was dissolved in 15 mL of CH2Cl2. Thionyl chloride (0.29 mL, 3.92 mmol) was added and the reaction mixture was stirred for 4 h. The mixture was filtered through a medium porosity funnel. The solid was rinsed three times with cold CH2Cl2 and dried under vacuum to give 63 mg of the title compound. The filtrate was concentrated and the residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (0-40% EtOAc/hexanes) to give additional 443 mg of the title compound. δ=11.4 (s, 1H), 8.98 (s, 1H), 7.20-7.24 (m, 1H), 6.58-6.65 (m, 1H), 4.61 (q, 2H, J=7.0 Hz), 1.55 (t, 3H, J=7.0 Hz).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH:28]([CH2:32][OH:33])[C:29](O)=[O:30])(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:27][CH:28]([CH2:32][O:33][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:29]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:30])(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: O=C(O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: C1=COCCC1
Reactant: COC(=O)CCCCN
Agent: Cl
Product: COC(=O)CCCCNC(=O)C(COC1CCCCO1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 1 was repeated, except that dihydropyran (2.9 ml) and methyl 5-aminopentanate hydrochloride (2.158 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (3 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.059 g).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Na].[CH2:22]([SH:24])[CH3:23].CN(C=O)C>O>[CH2:22]([S:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH3:23]
Reactant: CCS
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.20 g of ethyl mercaptan sodium salt and 2 ml of DMF was stirred at room temperature for one hour. Water was added to the reaction mixture, and was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.28 g of 2-(3-ethylthio pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 41”).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])C.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:4](=[O:3])[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: CN
Product: CNC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 48 h

Procedure:
2.23 g of 3(R)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl ester and 50 ml of 33% methylamine (in ethanol) are left to stand for 48 hours at room temperature. The reaction mixture is concentrated by evaporation and the residue is crystallised from ethyl acetate. The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.24; m.p. 190-191° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([OH:14])[CH:8]=1)[CH3:6])[CH3:2].C1C=CC(O[C:23](Cl)=[S:24])=CC=1.C1CCN2C(=NCCC2)CC1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]2[NH:13][C:23](=[S:24])[O:14][C:9]=2[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Solution of 2-(4-Amino-3-hydroxy-phenyl)-propionic acid ethyl ester (570 mg) in DMF (5 mL) was added phenyl chlorothionoformate (563 mg in DMF), and DBU (829 mg, in DMF) at room temperature. The reaction mixture was stirred for 14 h at room temperature and water was added to this mixture. The resulting mixture was extracted with ethyl ether. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1 to 4:1) to afford the product as yellow oil. (90 mg, 13.2%)
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([OH:18])=[O:17])[CH2:5]1
Reactant: [H][H]
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Agent: N
Solvent: O
Solvent: CO
Product: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCCC2)O1
Temperature: 40 °C
Yield: 98.4 %

Procedure:
A solution of 0.13 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid in 20 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.2 g of water wet Raney nickel #30. The solution is heated at 40° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.13 g of (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([S:30]([N:33]1[CH2:38][CH2:37][N:36]([C:39]([C:41]3[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=3)=[O:40])[CH2:35][CH2:34]1)(=[O:32])=[O:31])=[CH:24]2>COCCOC.O.C(O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([S:30]([N:33]1[CH2:34][CH2:35][N:36]([C:39]([C:41]3[CH:42]=[CH:43][C:44]([C:2]4[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[N:7]=4)=[CH:45][CH:46]=3)=[O:40])[CH2:37][CH2:38]1)(=[O:31])=[O:32])=[CH:24]2
Reactant: CN(C)CCn1nc(Cl)ccc1=O
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CN(C)CCn1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)cc2)ccc1=O
Temperature: 150 °C
Yield: 60.7 %

Procedure:
6-Chloro-2-(2-dimethylamino-ethyl)-2H-pyridazin-3-one (76 mg, 0.38 mmol), cesium carbonate (122 mg, 0.38 mmol) and bis(triphenylphosphine)palladium II chloride (21.9 mg, 0.03 mmol) was added to a microwave vial. The vial was evacuated and filled with argon twice. 4-({4-[(5-Chloro-1H-indol-2-yl)sulphonyl]piperazin-1-yl}carbonyl)phenyl boronic acid (140 mg, 0.31 mmol) dissolved in 4 mL 1,2-di-methoxyethane/water/ethanol (7:3:2) was added and the vial was once again evacuated and filled with argon. The reaction mixture was heated at 150° C. for 100 seconds, filtrated and purified by preparative HPLC using a gradient of acetonitrile/5% acetonitrile-water phase containing 0.1M ammonium acetate, to give 107 mg of 6-{4-[4-(5-chloro-1H-indole-2-sulphonyl)-piperazine-1-carbonyl]-phenyl}-2-(2-dimethylamino-ethyl)-2H-pyridazin-3-one after evaporation and freeze drying over night (60% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14].N1C=CC=CC=1.CN1CCCC1=O>CC(OC)(C)C.[Cu]=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]2[O:9][C:13]([CH2:12][CH2:11][OH:15])=[CH:14][C:6]=2[CH:7]=1
Reactant: C#CCCO
Reactant: Oc1c(Cl)cc(Br)cc1I
Agent: O=[Cu]
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: OCCc1cc2cc(Br)cc(Cl)c2o1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 66.2 %

Procedure:
The product of step A (14.0 g, 42.76 mmol) was added to a mixture of but-3-yn-1-ol (3.24 mL, 42.79 mmol), copper(II)oxide (3.67 g, 25.67 mmol), pyridine (21.3 mL) and N-methylpyrrolidone (85.0 mL). The reaction mixture was heated to 70° C. for 12 h then 100° C. for a further 2.5 h. The mixture was diluted with MTBE (200 mL), washed successively with 5% aq NH4OH (200 mL), 0.5 M NaOH (200 mL) and saturated brine solution (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing 2-(5-bromo-7-chlorobenzofuran-2-yl)ethanol (7.8 g, 66%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.52 (d, J=1.6 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 6.52-6.51 (m, 1H), 4.02 (q, J=6.0 Hz, 2H), 3.09 (t, J=6.2 Hz, 2H), 1.65 (t, J=5.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCO)c1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CCNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.50 g, 1.7 mmol) (prepared according to Example 8, step A) and 2-(3-aminophenyl)ethanol (0.31 g, 2.3 mmol) (prepared according to Example 22, Step B) in 1,4-dioxane (14.3 mL) was added p-toluenesulfonic acid monohydrate (0.12 g, 0.61 mmol). The mixture was heated at 100° C. for 16 h and the reaction was complete. To the mixture was added NaHCO3 (saturated aqueous solution). The organic solvent was removed under vacuum and water/EtOAc was added. After layer separation, the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown powder (0.64 g, 96%). LCMS for C21H24ClN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([P:1]([Cl:4])[Cl:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClP(Cl)Cl
Reactant: c1ccccc1
Product: ClP(Cl)c1ccccc1

Procedure:
8800 g (64 mols) phosphorus(III)chloride, 780 g (10 mols) benzene and 1361 g (10 mols) anhydrous aluminum chloride of 98% strength were boiled for 5 hours under reflux in a reactor provided with a stirrer and reflux condenser. Next, 1535 g (10 mols) phosphorus oxychloride was added dropwise within 30 minutes. After a post-reaction period of 30 minutes, the whole was cooled to 25° C., the formed aluminum chloride/phosphorus oxychloride-complex was filtered off and washed with phosphorus(III)chloride. 3128 g crystalline matter moist with PCl3 was obtained (theoretically: 1535 g POCl3 +1361 g AlCl3 =2896 g). Phosphorus(III)chloride in excess and unreacted benzene were expelled from the filtrate under atmospheric pressure and the residue was distilled under vacuum. 1561 g phenyldichlorophosphane (bp: 95° C. at 25 millibars) was obtained. Yield: 0.87 mol C6H5PCl2 per mol AlCl3.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([OH:25])=O)=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[CH:10][CH:9]=1)([OH:7])=O.[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[CH:1]1([NH:4][C:23]([C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5](=[O:7])[NH:37][C:36]4[CH:38]=[CH:39][C:33]([N:30]5[CH2:29][CH2:28][CH:27]([OH:26])[CH2:32][CH2:31]5)=[CH:34][CH:35]=4)=[CH:13][CH:12]=2)[N:15]=[CH:16]3)=[O:25])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Reactant: O=C(O)c1ccc(-n2ncc3cc(C(=O)O)ccc32)cc1
Product: O=C(Nc1ccc(N2CCC(O)CC2)cc1)c1ccc(-n2ncc3cc(C(=O)NC4CC4)ccc32)cc1

Procedure:
Compound 950 was prepared according to the procedure described in Scheme IV from cyclopropylamine, 1-(4-carboxyphenyl)-1H-indazole-5-carboxylic acid, and 4-(4-hydroxypiperidin-1-yl)aniline. [M+H]+ calcd for C29H29N5O3: 496.23; found: 496.02.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[CH3:28][CH:29]([CH2:33][CH:34]1[CH2:39][O:38][CH2:37][CH2:36][NH:35]1)[C:30]([OH:32])=[O:31]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH:34]2[CH2:33][CH:29]([CH3:28])[C:30]([OH:32])=[O:31])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(CC1COCCN1)C(=O)O
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(C)C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 24.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol) was reacted with 2-methyl-3-(morpholin-3-yl)propanoic acid hydrochloride (1.26 g, 6 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.89 g, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:28][CH3:29])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Yield: 90.7 %

Procedure:
A solution of 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (451 mg, 1.1 mmol) in TFA (4.5 ml) was heated at reflux for 3 hours. The mixture was diluted with toluene and the volatiles removed by evaporation. The residue was triturated with methylene chloride, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg, 90%). 1H NMR Spectrum: (DMSOd6) 4.0(s, 3H); 7.27(s, 1H); 7.43(dd, 1H); 7.56(t, 1H); 7.57(s, 1H); 7.72(dd, 1H); 8.5(s, 1H) MS-ESI: 321 [MH]+