Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCC[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:14].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[CH2:30](N(CC)CC)[CH3:31].O>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:30][CH2:31][C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:4][C:5](=[O:14])[CH:6]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: CCN(CC)CC
Reactant: O=c1ccc2ccccc2n1CCBr
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 233 %

Procedure:
To a suspension of 4-(2-bromoethyl-2(1H)-quinolinone (II-2) (30 g, 119 mmol) and 3-(4-piperidinyl)-1H-indole (23.8 g, 119 mmol) in dry dimethylformamide 300 ml was added triethylamine (33 ml, 238 mmol) at room temperature and the mixture was allowed to react under the same conditions for 48 hours. Water (600 ml) was poured into the reaction mixture and the mixture was stirred for 15 minutes at room temperature. The separated solid was filtered off by aspiration. The solid was washed with water, dried under reduced pressure and recrystallized with methanol/tetrahydrofuran/water to give the desired product (103 g) (III-2) as white solid (mp 259°-259.5 ° C. (methanol/tetrahydrofuran/water), yield 70.9 %).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:14][C:13](=[O:15])[C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:16]=1.[C:17]([O:21]C(C)(C)C)(=[O:20])[CH:18]=[CH2:19].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(Cl)[Cl:58]>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[ClH:58].[O:15]=[C:13]1[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][C:6]2[CH:16]=[C:2](/[CH:19]=[CH:18]/[C:17]([OH:21])=[O:20])[CH:3]=[N:4][C:5]=2[NH:14]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: ClCCl
Reactant: O=C1Nc2ncc(Br)cc2CN2CCC[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A suspension of (S)-6-bromo-1,2,3,4,9,10a-hexahydro-3a,8,9-triaza-benzo[f]azulen-10-one (1.46 g, 5.17 mmol) in propionitrile (40 mL) and DMF (10 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with tert-butyl acrylate (3.0 mL, 20 mmol) and (i-Pr)2EtN (1.9 mL, 11 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (0.12 g, 0.53 mmol) and P(o-tol)3 (0.34 mg, 1.12 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight then allowed to cool. The resulting precipitate was isolated by filtration, dissolved in CH2Cl2, filtered through Celite and the solvent was removed in vacuo to give the title compound (0.68 g, 40%) as an off-white solid: MS (ESI) m/e 330 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl.[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>CN(C)C=O.O>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:22][CH:24]1[CH2:25][O:26]1
Reactant: BrCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc([N+](=O)[O-])cc1OCC1CO1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
1,2-Dihydroxy-4-nitrobenzene (4.65 g, 0.030 mol), potassium carbonate (8.71 g, 0.063 mol) and methoxymethyl chloride (2.42 g, 0.030 mol) were dissolved in dimethylformamide (50 ml), which was stirred at 40° C. for 30 minutes. Epibromohydrin (7.20 g, 0.045 mol) was added to the mixture, which was stirred at 60° C. for 80 minutes. Then water was added, and extraction was conducted using ethyl acetate. The organic layer was washed with water, and concentrated. The residue was purified by alumina column chromatography (development solvent: ethyl acetate-n-hexane=1:4), to give 2-[[2-(methoxymethoxy)-5-nitrophenoxy]methyl]oxirane (2.61 g) as a white powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=2.I[CH3:32]>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([CH:23]([CH3:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=2
Reactant: CI
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cnc2ccc(C(C)C(=O)OC(C)(C)C)cc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flame-dry 100 ml 3-neck round-bottomed flask was added lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (5 ml, 5 mmol) and THF (20 mL). The mixture was cooled to −78° C. followed by adding tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.88 g, 3 mmol) in THF (10 mL)dropwise via addition funnel. After stirring at −78° C. for 30 min, iodomethane (0.4 ml, 6 mmol) was added. The reaction mixture was stirred for 30 min at −78° C. then allowed to warm to rt and stir for 1 h. The mixture was then quenched with sat. NH4Cl (3 mL). Solvent was removed. The residue was partitioned between EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and removed solvent. The crude material was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, solvent system: hexane:acetone=90%:10%, Flow=30 mL/min) to afford a final product as yellowish liquid. MS m/z: 288.4 (M+H). Calc'd. for C17H21NO3—287.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15]CC)=[O:14])=[C:8]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].[OH-].[Na+].C(O)C.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[C:8]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)O)cnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Ethyl 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate, 15.00 g (0.0445 mole), 100 ml of 3 N sodium hydroxide solution and 100 ml of ethanol was stirred at room temperature for 16 hours. The mixture was diluted with 300 ml of water and acidified to pH 6.8 with 6 N hydrochloric acid solution. The precipitate was collected by filtration, washed in succession with water and acetone and air dried for about 1.5 hr. Weight of solid was 13.41 g (98%), m.p. 272° C. (d).
Reaction SMILES: [C:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14](C)[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[C:26]1([S:32]([N:35]2[CH:39]=[C:38](Br)[C:37]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[N:36]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)C>[C:1]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:19].[C:26]1([S:32]([N:35]2[CH:39]=[C:38]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:37]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[N:36]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c(-c2cccnc2)n1
Reactant: C#CCCCCC
Solvent: CCOCC
Product: CCCCCC#Cc1c[nH]nc1-c1cccnc1
Product: CCCCCC#Cc1cn(S(=O)(=O)c2ccccc2)nc1-c1cccnc1
Yield: 90 %

Procedure:
Compound 44B was prepared following the procedure as described for the synthesis of compound 44A (see Scheme 9) using hept-1-yne and 3-(1-phenylsulfonyl-4-bromo-1H-pyrazol-3-yl)-pyridine (36A). (flash chromatography with diethyl ether) to afford 3-(1-phenylsulfonyl-4-hept-1-ynyl-1H-pyrazol-3-yl)-pyridine (43B) as an oil (90%). 1H-NMR (400 MHz, CDCl3): δ 9.25 (bs, 1H), 8.6 (bs, 1H), 8.34 (bd, J=8 Hz, 1H), 8.21 (s, 1H), 8.06 (bd, J=8 Hz, 2H), 7.67 (bt, J=7 Hz, 1H), 7.57 (bt, J=7 Hz, 2H), 7.36-7.30 (m, 1H), 2.42 (t, J=7 Hz, 2H), 1.63-1.55 (m, 2H), 1.44-1.28 (m, 4H), 0.89 (t, J=7 Hz, 3H). Compound 43B was converted to the title compound 44B, using the methodology described for the conversion of 43A to 44A (see Scheme 9). Yield: 98% (oil). 1H-NMR (400 MHz, CDCl3): δ 9.25 (d, J=2 Hz, 1H), 8.59 (dd, J=5 Hz, 2 Hz, 1H), 8.37 (dt, J=8 Hz, 2 Hz, 1H), 7.72 (s, 1H), 7.38-7.33 (m, 1H), 2.42 ((t, J=7 Hz, 2H), 1.65-1.57 (m, 2H), 1.46-1.30 (m, 4H), 0.90 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1C=O.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].[Cl-].[Ca+2].[Cl-].[CH2:20](Cl)Cl>>[C:12]([N:16]=[CH:20][C:8]1[CH:9]=[N:10][C:3]([O:2][CH3:1])=[CH:4][C:7]=1[CH3:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: ClCCl
Reactant: COc1nccc(C)c1C=O
Reactant: CC(C)(C)N
Agent: [Ca+2]
Agent: [Cl-]
Product: COc1cc(C)c(C=NC(C)(C)C)cn1
Yield: 89 %

Procedure:
2-Methoxy-4-methylnicotinaldehyde (1.8 g, 12 mmol), tert-butylamine (15 mL), 3 Å molecular sieves (8 g) and dry DCM (10 mL) were mixed and allowed to stand at RT under protection from moisture (calcium chloride tube). After two days the mixture was filtered and the molecular sieves were washed several times with dry DCM. The combined washings were concentrated to give 2.2 g (89%) of the title compound as a crude oil that was used immediately in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7].[CH3:31][O:32][CH2:33]Cl>C1COCC1>[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([N:14]([CH2:31][O:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:16])=[O:17])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7]
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a suspension of sodium hydride (314 mg, 7.86 mmol) in 8 mL of THF was added a mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (3.0 g, 6.55 mmol) and chloromethyl methyl ether (0.741 mL, 9.825 mmol) in 8 mL of THF. The mixture was stirred at room temperature overnight. After the removal of the solvents the residue was purified by flash column (20% ethyl acetate in hexane) to afford 2.70 grams of the title compound as a white solid. (M+H)+ expect 502.0. found 502.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH2:15])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:40][CH2:41][CH2:42][CH2:43]Br>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N)n2)CC(C)(C)O1
Reactant: BrCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N3CCCC3)n2)CC(C)(C)O1
Temperature: 130 °C
Reaction time: 48 h
Yield: 39.1 %

Procedure:
To a solution of 2-[5-(4-chlorophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl]aniline (Example 62) (25 mg, 0.06 mmol, 1 eq) in toluene (2 mL) was added diisopropylethylamine (0.52 mL, 0.3 mmol, 5 eq), and 1,4-dibromobutane (0.5 mL, 4.1 mmol, 69 eq) and the solution stirred at 130° C. in a vial for 2 days. Added water, extracted with DCM, dried over MgSO4 and concentrated. Purification by column chromatography (8 g) eluting with 7 to 15% EtOAc/hex gave the title compound (10.9 mg, 38%).
Reaction SMILES: OC(C(F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:18]3([CH2:23][C:22](=[O:24])[N:21]([CH3:25])[C:20](=[NH:26])[NH:19]3)[CH2:17][CH:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:15][C:12]2=[CH:13][CH:14]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[NH:26]=[C:20]1[NH:19][C:18]2([C:11]3[C:12](=[CH:13][CH:14]=[C:9]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)[CH:10]=3)[O:15][CH:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:17]2)[CH2:23][C:22](=[O:24])[N:21]1[CH3:25]
Reactant: CN1C(=N)NC2(CC1=O)CC(c1ccccc1)Oc1ccc(Br)cc12
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CN1C(=N)NC2(CC1=O)CC(c1ccccc1)Oc1ccc(-c3cccnc3)cc12

Procedure:
To a solution of 6-bromo-2′-imino-1′-methyl-2-phenyl-2′,3′-dihydro-1′H-spiro[chroman-4,4′-pyrimidin]-6′(5′H)-one TFA salt (12 mg, 0.023 mmol) and pyridin-3-ylboronic acid (9 mg, 0.070 mmol) in 1,4-dioxane (3 mL) charged in a 10-mL microwave test tube is added Cs2CO3 (63 mg, 0.195 mmol) and H2O (0.5 mL), followed by
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11]([CH3:16])[CH2:12][CH:13](O)[CH3:14].[C:17]1([CH3:27])[CH:22]=C[C:20](S(O)(=O)=O)=[CH:19][CH:18]=1>O1CCOCC1>[CH3:10][CH:11]([CH3:16])[CH2:12][CH:13]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH:19]([CH2:18][CH:17]([CH3:27])[CH3:22])[CH3:20])=[O:6])[OH:3])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)CC(C)O
Reactant: O=C(O)CC(O)C(=O)O
Solvent: C1COCCO1
Product: CC(C)CC(C)OC(=O)CC(O)C(=O)OC(C)CC(C)C
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Di(4-methyl-2-pentyl)-DL-malate was prepared using a procedure similar to that in Example 8. To the reaction flask, DL-malic acid (90.76 g), 4-methyl-2-pentanol (350 mL), 1,4-dioxane (200 mL) and p-toluenesulfonic acid (15.2 g) were added. The mixture was placed under nitrogen and heated to reflux. At 105° C., one phase started to collect in the Dean-Stark trap. After 2 hr, the temperature was increased to 110° C. After 1 hr 10 min, the temperature was increased to 112° C. and held until no more liquid collected in the trap. The reaction product was neutralized with saturated sodium bicarbonate, diluted with diethyl ether, washed three times with saturated sodium bicarbonate, once with water and dried over magnesium sulfate. The diethyl ether was removed via rotary evaporation. Di(4-methyl-2-pentyl)-DL-malate was obtained as a low viscosity, light yellow, slightly hazy liquid with no detectable odor (166.8 g, 81.5% yield) after removing residual 4-methyl-2-pentanol via vacuum distillation.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH2:3]1.[CH2:10]=[C:11]=[O:12].[C:13]([O-])(=[O:15])[CH3:14].[Na+]>C(OCC)(=O)C>[C:11]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[N:5]([C:13](=[O:15])[CH3:14])[C:6]1=[O:8])(=[O:12])[CH3:10]
Reactant: CC1CC(=O)NC(=O)N1
Reactant: C=C=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)CC(C)N(C(C)=O)C1=O

Procedure:
In the manner described in IV above, 16.9 gm (0.13 mol) of 6-methyl-5,6-dihydrouracil were reacted with ketene in boiling ethyl acetate in the presence of sodium acetate. The product was recrystallized from a mixture of benzine (b.p. 70° C. to 95° C.) and isopropanol in the volume ratio of 1:1. The melting point was 84° C. to 86° C., and the elementary analysis resulted in the following values:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[S:16][CH:15]=1.[CH3:23][S:24]SC>C1COCC1>[Br:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[S:16][C:15]=1[S:24][CH3:23]
Reactant: Brc1csc2ncccc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1sc2ncccc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (3.25 mL, 1.7M in hexanes, 5.2 mmol) was added to a cooled solution of diisopropylamine (0.74 mL, 5.2 mmol) in THF (15 mL) at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction was cooled to 0° C. and 3-bromothieno[2,3-b]pyridine (prepared by the method of Klemm L. H. et al., Journal of Heterocyclic Chemistry, 1974, 11(2), 205-209) (1 g, 4.7 mmol) added. After stirring for a further 20 minutes dimethyl disulphide (443 mg, 0.42 mL, 4.7 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with water, extracted into DCM, dried (sodium sulphate), filtered and concentrated in vacuo. Chromatography (silica; DCM) yielded the title compound as a pale yellow solid (850 mg). δH (DMSO-d6) 8.57 (1H, dd, J 4.7, 1.5 Hz), 8.00 (1H, m), 7.54 (1H, dd, J 8.1, 4.5 Hz), 2.70 (3H, m). LCMS (pH 3) RT 2.64 minutes, (ES+) 259/261 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: BrCCCCCc1ccco1
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1ccco1

Procedure:
To a mechanically stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (WRAIR, 4.00 g, 0.017 mol), 1-bromo-5-(2-furyl) pentane (3.65 g, 0.017 mol) and HMPA (25 ml), at 105°-110° C., was added dropwise, during 60 min, a solution of Et3N(3.5 ml) and propylene oxide (6.5 ml). The mixture was heated at 105°-110° C. for 2 hr, allowed to cool and extracted with a solution of pet. ether (20°-40° C.) and Et2O (1:1 v/v, 200 ml), leaving behind a black residue. The organic layer was washed with 10% NaOH solution (3×50 ml). The combined basic wash solutions were re-extracted with a pet. ether (20°-40° C.)-Et2O solution (1:1 v/v, 2×75 ml) and the combined organic layers were washed with H2O (2×50 ml), dried (Na2SO4), treated with Darco, filtered and concentrated to give 5-[5-(2-furyl) pentoxy]-6-methoxy-4-methyl-8-nitroquinoline as a yellow solid, 2.5 g (40%) mp. 47°-49° C. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[C:12]([O:16][C:17](=[O:40])[NH:18][C:19]1[N:28]([CH2:29][CH2:30][CH3:31])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)[CH:25]=2)[N:20]=1)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CO>ClCCCl>[C:12]([O:16][C:17](=[O:40])[NH:18][C:19]1[N:28]([CH2:29][CH2:30][CH3:31])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][CH2:4][C:3]4[C:2]([CH3:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=4[CH3:11])[CH:34]=3)[CH:25]=2)[N:20]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CCCN1Cc2cc(Oc3cccc(N)c3)ccc2N=C1NC(=O)OC(C)(C)C
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCCN1Cc2cc(Oc3cccc(NCc4c(C)cc(C)cc4C)c3)ccc2N=C1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2,4,6-Trimethyl-benzaldehyde (0.0005 mol) was added to a mixture of [6-(3-amino-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acid tert-butyl ester (0.0005 mol) in DCE (3 mL) and the mixture was stirred for 5 min. at room temperature, and then NaBH(OAc)3 (0.0006 mol) was added and the reaction mixture was stirred overnight at room temperature. The excess NaBH(OAc)3 was decomposed with CH3OH, and the solvent was evaporated. The obtained residue was purified by Biotage column chromatography (eluent: 100% CH2Cl2). The purest product fractions were collected and then the solvent was evaporated and co-evaporated with toluene to yield the title compound as a residue.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]C.[CH3:31][O-].[Na+]>C1(C)C(C)=CC=CC=1>[C:1]([CH2:2][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([CH3:31])=[O:30])(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: C[O-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(=O)CCCCCCCCCCCCCCCCCC(=O)c1ccccc1

Procedure:
Acetophenone (30 grams; 0.25 mol), methylstearate (298 grams; 1.0 mol), xylene (300 ml) and sodium methoxide (17.3 grams; 0.3 mol) were placed into a four-necked, round bottom one liter flask equipped a in Example 1. The mixture was heated with stirring to 135°-140° C. and maintained there for 6 hours under a blanket of nitrogen. The procedure set forth in Example 1 was used to recover the desired product, benzoylstearoylmethane (43 grams; 45 weight percent yield) having a purity of 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=O)[NH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:13][N:14]=1.S(Cl)(Cl)=O.O1CCCC1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[CH2:31]([NH:38][C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:13]=[N:14][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=c1[nH]c(-c2ccccn2)nnc1-c1ccc(Cl)cc1Cl
Reactant: NCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(-c2nnc(-c3ccccn3)nc2NCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A mixture of 6-(2,4-dichlorophenyl)-3-(2-pyridyl)-1,2,4-triazin-5-one (5.00 g, 15.7 mmol) and thionyl chloride (50 ml) was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and the solvent was removed by distillation under reduced pressure. To the residue were added tetrahydrofuran (50 ml), benzylamine (4.20 g, 39.2 mmol, 2.5 eq.), and the mixture was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and water (150 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride (600 ml), and washed with a 5% aqueous potassium hydrogen carbonate solution (150 ml), and further washed with a 5% brine (150 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by flash silica gel column chromatography (methylene chloride) to give the title compound as pale yellow crystals (3.64 g, 57%).
Reaction SMILES: [C:1]1(N)[C:6](F)=[C:5](F)[C:4](F)=[C:3]([NH2:10])[C:2]=1F.Cl.Cl.C[C:16]1[CH:21]=[CH:20][C:19](NC)=[CH:18][C:17]=1[OH:24].OO.[NH3:27]>O>[CH:21]1[C:20](=[N:10][C:3]2[CH:4]=[CH:5][C:6]([NH2:27])=[CH:1][CH:2]=2)[CH:19]=[CH:18][C:17](=[O:24])[CH:16]=1
Reactant: N
Reactant: CNc1ccc(C)c(O)c1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Agent: OO
Solvent: O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Reaction time: 4 h

Procedure:
0.05 mole (10.55 g) methoxyparaphenylenediamine dihydrochloride is dissolved in 250 cc water and the pH is adjusted to 8 by addition thereto of ammonia. This solution is immediately added to 0.025 mole (3.5 g) 2-methyl 5-methylamino phenol previously dissolved in 250 cc water and to which 75 cc ammonia 22° Be have been added. 300 cc hydrogen peroxide are added to the mixture to 20 volumes and then the mixture is allowed to stand at room temperature for 4 hours. By filtering the mixture, there are then obtained 4.17 g of the above indoaniline in crystalline form, which, after washing with water and recrystallization from a mixture of acetone and water, exhibits a melting point of 125°.