Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH3:24][S-:25].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([S:25][CH3:24])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(SC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 70 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (200 mg, 0.60 mmol) and sodium thiomethoxide (126 mg, 1.80 mmol) in DMF (5 mL) is heated at 70° C. overnight. After cooling, water (20 mL) is added and the resulting mixture is extracted with EtOAc. The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel to give 6-(2,6-diethyl-phenyl)-2-methyl-4-methylsulfanyl-nicotinic acid ethyl ester.
Reaction SMILES: C(C1CCCN([CH2:14][C:15]([C:17]2[CH:27]=[CH:26][C:20]3[NH:21][C:22](=[O:25])[CH2:23][O:24][C:19]=3[CH:18]=2)=[O:16])C1)C1C=CC=CC=1.O1C2C=CC=CC=2NC(=O)C1.[Cl:39]CC(Cl)=O>>[Cl:39][CH2:14][C:15]([C:17]1[CH:27]=[CH:26][C:20]2[NH:21][C:22](=[O:25])[CH2:23][O:24][C:19]=2[CH:18]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: O=C1COc2cc(C(=O)CN3CCCC(Cc4ccccc4)C3)ccc2N1
Agent: O=C1COc2ccccc2N1
Product: O=C1COc2cc(C(=O)CCl)ccc2N1

Procedure:
from 7-(2-(3-benzylpiperidino)-1-oxoethyl)-2,3-dihydro-1,4-benzoxazin-3-one ("F"; obtainable by reaction of 2,3-dihydro-1,4-benzoxazin-3-one with chloroacetyl chloride to give 7-chloroacetyl-2,3-dihydro-4H-1,4-benzoxazin-3-one ("G"), then reaction with 3-benzylpiperidine):
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].Cl[Si](C)(C)C.[CH3:21][CH2:22]O>>[CH2:10]([C:9]1[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:2]([O:1][CH2:21][CH3:22])=[O:3])=[CH:15][CH:14]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: CCO
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: C[Si](C)(C)Cl
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of ibuprofen 1A (9.89g, 48 mmol) in anhydrous EtOH (35 mL) was added chlorotrimethylsilane (18.27 mL, 144 mmol) at room temperature, and the mixture was stirred at the same temperature for 2 h. After the removal of the excess EtOH and chlorotrimethylsilane under reduced pressure, the oily residue was treated with ice-cold saturated NaHCO3 (150 mL), and the resulting mixture was extracted with hexanes (450 mL). The hexanes solution was washed with brine (3×50 mL), and dried over anhydrous Na2SO2. Evaporation of the solvent afforded ethyl 2-(4′-isobutylphenyl)propionate 2A (11.24 g, in 100% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[I:12]Cl.O>C(O)(=O)C>[NH2:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]([CH3:8])=[CH:6][C:7]=1[I:12]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: ClI
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Yield: 25.6 %

Procedure:
A solution of 4-amino-3-nitrotoluene (30.4 g) in acetic acid (250 ml) was refluxed with iodine monochloride (65.0 g) for 7 h with stirring, then was cooled and added to excess water. The precipitate was filtered off, washed with aqueous sodium sulfite and after column chromatography yielded 4-amino-3-iodo-5-nitrotoluene (14.2 g). δ (360 MHz, DMSO-d6) 2.19 (3H, s, CH3), 6.88 (2H, bs, NH2), 7.88 (1H, d, 2-H) and 7.94 (1H, d, 6-H).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[P:20](Cl)([O:40][C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][C:23]=1[C:36]([CH3:39])([CH3:38])[CH3:37].Cl>O1CCCC1.C(#N)C>[P:20]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:20]([O:40][C:41]3[C:42]([C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:43][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:45][C:46]=3[C:47]([CH3:50])([CH3:49])[CH3:48])[O:21][C:22]3[C:23]([C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:24][C:25]([C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:26][C:27]=3[C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([O:40][C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][C:23]=1[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP(Oc2ccc(C(C)(C)c3ccc(OP(Oc4c(C(C)(C)C)cc(C(C)(C)C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C(C)(C)C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 1.16 grams of 4,4'-isopropylidenebisphenol (0.005 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-isopropylidenebisphenol solution under nitrogen, 0.24 gram (0.01 mol) of sodium hydride, as a 50 weight percent dispersion in mineral oil was added to the 4,4-iso-propylidenebisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,4,6-tri-t-butylphenyl) phosphorochloridite (6.0 grams, 0.01 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,4,6-tri-t-butylphenyl)-4,4'-isopropylidenebisphenyl diphosphite was 4.87 grams. The molecular weight, FD/MS was 1332.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]1=[O:11].Cl.NC1(CCC(O)=O)CCCCC1.[P:25]([OH:28])([OH:27])[OH:26].P(Cl)(Cl)Cl>O>[NH2:1][C:5]1([CH2:4][CH2:3][C:2]([OH:11])([P:25]([OH:28])(=[O:26])[OH:27])[P:25]([OH:28])(=[O:27])[OH:26])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C1CCC2(CCCCC2)N1
Reactant: OP(O)O
Agent: Cl
Agent: NC1(CCC(=O)O)CCCCC1
Solvent: O
Solvent: ClP(Cl)Cl
Product: NC1(CCC(O)(P(=O)(O)O)P(=O)(O)O)CCCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
19.1 g. 1-Aza-spiro(4,5)decan-2-one (prepared as described in J. Org. Chem., 22, 832) are boiled for 90 hours in 190 ml. concentrated hydrochloric acid. After cooling, the reaction mixture is filtered and evaporated and the residue is reprecipitated with methanol/diethyl ether. There are obtained 17.5 g. (68% of theory) of the hydrochloride of 3-(1-aminocyclohexyl)-propionic acid; m.p. 183° C. sinters; 188°-192° C. melts with decomposition. 7 g. thereof are mixed with 5.5 g. phosphorous acid and, after melting at 80° C., mixed dropwise with 5.9 ml. phosphorus trichloride. After stirring for 8 hours at 80° C., 43 ml. 6N hydrochloric acid are added thereto, the temperature is increased to 100° C. and stirring continued for a further 8 hours. The yellowish suspension is then filtered hot, the filtrate is evaporated and the residue, a colourless oil, is stirred into 2 liters of acetone. The precipitate obtained is filtered off with suction and washed with acetone and diethyl ether. There are obtained 4.6 g. (43% of theory) of product which are dissolved in a little water. Purification takes place by fractionation on an Amberlite IR-120 column (H+ form). The individual fractions are tested electrophoretically for purity. After combining the pure fractions, the aqueous solution is again evaporated and again precipitated with acetone. There are obtained 2.9 g. (27% of theory) of white crystals; m.p. 143° C. sinters, 155°-158° C. foaming up; Mrel =0.29.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:44]=[CH:43][C:12]([CH2:13][N:14]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:35][CH2:34][CH2:33][N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:44][CH:43]=1)[C:15](=[O:32])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]3[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=3[N:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)cc3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N(CCN)Cc4ccc(Cl)cc4)cc3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
TFA (182 μL, 2.36 mmol) was added to a solution of (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamido)ethylcarbamate (49 mg, 0.094 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo. The crude product was purified by reverse phase HPLC to give (R)—N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide as an oil (9 mg, 22%). MS (APCI+) [M+H]+421.2. 1H NMR (D2O, 500 MHz) δ 9.09 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.15 (D, J=8.0 Hz, 2H), 4.63 (s, 2H), 3.87 (t, J=6.5 Hz, 2H), 3.82-3.79 (m, 1H), 3.26-3.11 (m, 4H), 2.63 (s, 2H), 2.50-2.42 (m, 1H), 1.86-1.81 (m, 1H), 0.86 (s, J=7.00 Hz, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].O.[NH:11]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][C:18]3[C:23]([CH:12]12)=[CH:22][CH:21]=[CH:20][CH:19]=3>[N+](C)([O-])=O>[N+:6]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH:13]3[CH2:14][C:15](=[O:16])[NH:11][CH:12]32)=[CH:19][CH:20]=1)([O-:9])=[O:7]
Reactant: O=C1CC2Cc3ccccc3C2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=C1CC2Cc3ccc([N+](=O)[O-])cc3C2N1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
Sulphuric acid (72 mL) was added to a cooled mixture of nitric acid (63.5 mmol, 4.4 mL) and water (11.3 mL), and the mixture was added dropwise to a cold (2-8° C.) suspension of 3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (10 g, 57.7 mmol) in nitromethane (100 mL). The mixture was stirred 1.5 h at 2-8° C. after end of addition, and poured onto a mixture of ice and water (1 L). The white suspension was stirred for one hour, filtered and washed with water. The white solid was suspended in 1 L of ethyl acetate, dried and concentrated under vacuum. 7-nitro-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (9.2 g, 73%) was obtained. 1H NMR (400 MHz, CD3OD) δ 8.16-8.08 (2H, m), 7.39 (1H, d), 6.89 (1H, brs), 5.09 (1H, d), 3.49-3.37 (2H, m), 2.93 (1H, d), 2.78 (1H, dd), 2.26 (1H, dd) ppm.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH2:16])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27].O>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH:16][C:26](=[O:27])[CH2:25][CH2:24][Cl:23])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCCl
Reactant: C=CCn1c(NN)nc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCn1c(NNC(=O)CCCl)nc2ccccc2c1=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a stirred mixture of 4.50 g of 3-allyl-2-hydrazino-quinazolin-4(3H)-one (0.0208 mol) and 5.75 g of anhydrous potassium carbonate (0.0416 mol; 2 eq) in 100 ml of chloroform at room temperature as added 2.2 ml of 3-chloropropionyl chloride (2.91 g; 0.023 mol; 1.1 eq). Almost immediately, a precipitate appeared and after 1 hr, 50 ml of water were added to the stirred mixture to dissolve any potassium carbonate. The mixture was filtered and the product was washed twice with water then twice with ether, crystallized from ethanol and dried under vacuum over P2O5 at 80° C. to obtain 5.79 g (91% yield) of 3-allyl-2-(2-(3-chloropropionyl)hydrazino)quinazolin-4(3H)-one melting at 151°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:10]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:15][CH2:14][CH2:13][O:12]1)[CH3:11]
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(c2ccc(OC)cc2)OCCO1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of 4′-methoxypropiophenone (250.0 mg, 1.52 mmol) in toluene (20.0 mL) was added ethylene glycol (255.0 μL, 4.57 mmol) and p-toluenesulfonic acid monohydrate (13.0 mg, 0.04 mmol) and the reaction mixture refluxed overnight using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, then washed with saturated aqueous sodium bicarbonate solution followed by water. The toluene solution was then dried (MgSO4) and evaporated under reduced pressure to afford 2-ethyl-2-(4-methoxyphenyl)-1,3-dioxolane (16) as a yellow oil (184 mg, 58%). 1H nmr (CDCl3, 300 MHz) 0.76, t (6.6 Hz), CH3; 1.78, q (6.9 Hz), CH2; 3.65, m, CH2O, 3.73, s, 4′-OMe; 3.95, m, CH2O; 6.88, d (7.2 Hz), H3′,5′; 7.02, d, (7.5 Hz), H2′,6′. ESI (+ve) MS m/z 209 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:18][C@@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.BrC1C=C(C=CC=1C)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[C:20]1([C@H:19]([NH:26][C:5]([C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([Br:1])[CH:3]=2)=[O:7])[CH3:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(C(=O)Cl)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a solution of 3-bromo-4-methylbenzoic acid (5.0 g, 0.023 mol) in CH2CH2 (100 mL) was added oxalyl chloride (8.67 g, 0.069 mol). After 10 minutes, 1.0 mL of DMF was added slowly and the mixture was continued to stir at RT for 2 hours. The volatile was removed in vacuo. The residue was re-dissolved in CH2CH2 (100 mL) and transferred to a 125 mL additional funnel. To a 500 mL Erlenmeyer flask equipped with a stir bar was added 100 m]L of sat. aq. NaHCO3 solution followed by 2.79 g of (R)-α-methylbenzylamine (0.023 mol) in 100 mL of CH2CH2. 3-Bromo-4-methylbenzoyl chloride in CH2Cl2 (from above) was added dropwise to the Erlenmeyer flask and the reaction mixture was continued to stir at RT for 16 hours. The organic phase was diluted with 50 mL of CH2CH2, separated from aqueous phase, dried over Na2SO4 and concentrated in vacuo. The residue was washed with 50 mL of Et2O and dried in an oven at 40 C overnight to afford light yellow solid (7.0 g, 0.022 mol, 96%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=3[C:7]=2[CH:18]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([F:31])[CH:21]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:16][C:11]1[NH:10][C:9](=[O:17])[C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][NH:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([F:31])[CH:21]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1F
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a 500 mL 3-neck flask equipped with a magnetic stirrer, a nitrogen inlet, and a reflux condenser were added 5.00 g of 9-bromomethyl-3-methylbenzo(f)quinazolin-1(2H)-one, 3.02 g of ethyl 4-amino-2-fluorobenzoate, 4.17 g of NaHCO3, and 42 mL of anhydrous DMF. The reaction mixture was heated to 100° C. with stirring under nitrogen for 1.5 h.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].N1C=CC=CC=1.[CH3:17][C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](Cl)=[O:20]>CC(C)=O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:10])=[C:2]([NH:1][C:19](=[O:20])[C:18]([CH3:17])=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COc1ccc(C)c(NC(=O)C(C)=Cc2ccccc2)c1
Yield: 84.3 %

Procedure:
2-Amino-4-methoxytoluene (13.2 g, 89.7 mmol) and pyridine (10 ml) were dissolved in acetone (112 ml), to which α-methylcinnamoylchloride (19.4 g, 107.6 mmol) was added while cooling and stirring. The mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in chloroform, washed with water, dried, and condensed. The residue was purified by alumina chromatography (chloroform), and subjected to recrystallization with chloroform--n-hexane to obtain 21.27 g of the title compound as colorless crystals (84.4%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH3:29])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH2:28][CH3:29])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:12][N:13]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (300 mg) and ethyl 4-bromobutyrate (85%1) are dissolved in N,N-dimethylformamide (1 ml) and thereto is added potassium carbonate (82 mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=97:3% 17:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (296 mg). MS (m/z): 721 [M+H]+
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[N+:9]([O-:10])=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=[C:6](Cl)[N:5]=1.[H][H]>C(O)C.[Pd]>[NH2:3][C:4]1[N+:9]([O-:10])=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=[CH:6][N:5]=1
Reactant: CCCCCCNc1cc(Cl)nc(N)[n+]1[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCNc1ccnc(N)[n+]1[O-]
Reaction time: 2 h
Yield: 52.9 %

Procedure:
0.7 g of potassium hydroxide was dissolved in 100 ml of absolute ethanol, in a three-necked flask. 2.2 g of 2-amino-4-hexylamino-6-chloropyrimidine 3-oxide were then added. After complete dissolution, 0.5 g of palladium-on-charcoal was added and the mixture was reacted in a hydrogenator at a hydrogen pressure of 3 bar. After 2 hours, the medium was filtered through filter paper and concentrated under vacuum. The pale yellow solid obtained was recrystallized from 20 ml of acetonitrile. It was filtered off and the filter cake was washed with 10 ml of water. The solid was dried in a desiccator under vacuum. 1 g of the expected compound was thus obtained, for a yield of 53%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.C([Cu])#N.[CH3:29][CH2:30][Mg+].[Br-]>C1COCC1>[CH2:29]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1)[CH3:30]
Reactant: CC[Mg+]
Reactant: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Agent: N#C[Cu]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1cc(Oc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)ncn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-p-tolyl-urea (Example 97; 106 mg, 0.3 mmol) is dissolved in THF (10 mL) under an argon atmosphere and CuCN (215 mg, 2.4 mmol) is added. The mixture is then cooled to −78° C. and EtMgBr (1.8 ml of a 3 M solution in THF) is added via a canula. The reaction mixture is allowed to stir for 30 min at −78° C. and then warmed to rt resulting in a brown suspension. It Is stirred for additional 30 min at rt and then the solvent is removed in vacuo. The residual crude product is re-dissloved in CH2Cl2/MeOH 1:1 and purified by flash chromatography (SiO2, gradient hexanes/ethyl acetate 1:1 to 3:7) to give the title compound which is further purified by preparative TLC (SiO2, hexanes/AcOEt 3:7): m.p.=160-162° C.; C20H20N4O2: M+=349.1; 1H-NMR (DMSO-d6): 9.55 (s, 1H, HN), 9.45 (s, 1H, HN), 8.64 (s, 1H), 7.55 (d, 2H); 7.40 (d, 2H), 7.10-7.06 (m, 4H), 6.92 (s, 1H), 2.70 (q, 2H), 2.24 (s, 3H), 1.22 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:36]1([S:42][CH2:43]Cl)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:43][S:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: ClCSc1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 75 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.21 gm) from Preparation No. 40 in DMF (4 mL) is treated with cesium carbonate (0.30 gm) and chloromethyl phenyl sulfide (0.08 mL). The mixture is tightly capped and heated to 75° C. for 8 hrs. The reaction mixture is allowed to cool to room temperature, diluted with dichloromethane (50 mL) and washed with water (2×10 mL), brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 2% to 4% methanol in dichloromethane and then by recrystallization from ethyl acetate-hexanes to afford 0.19 gm of the title compound as a white solid.