Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[CH:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[C:14]2[N:13]=[CH:12]1.I[C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1)=[CH:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[N:20]=[C:14]2[N:13]=[CH:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(C=CCOC3CCCCO3)cnc-2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)COC2CCCCO2)cc1)C(=O)OCC
Reaction time: 12 h

Procedure:
A mixture containing 3.48 g of 3-(3-tetrahydropyr-2-yloxyprop-1-en-1-yl)-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine, 3.12g (1.2 equiv.) of diethyl N-(4-iodobenzoyl)glutamate, 546 mg (20%) of tris-(2-methylphenyl)phosphine, 201 mg (10%) of palladium acetate and 85.5 mg (5%) of cuprous iodide in 15 ml of triethylamine and 240 ml of acetonitrile is heated at reflux under nitrogen. After 12 hours., 1.17 g of diethyl N-(4-iodobenzoyl)glutamate are added and the reaction mixture is heated at reflux under nitrogen for an additional 12 hours. The reaction mixture then is concentrated under reduced pressure and the residue chromatographed on silica gel, eluting with 20:1 ethyl acetate:hexane. (Any recovered starting material can be recycled through the foregoing procedure.) The concentrated material is dissolved in 1:5 ethyl acetate:ether and this solution is refrigerated for 15 hours. The solid which forms is collected by filtration, washed with cold ethyl acetate and dried to yield diethyl N-[ 4-(1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6 -pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)prop-2-en-2yl)benzoyl]glutamate.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:6]1[C:3]2[CH:4]=[C:15]([C:14]([O:18][CH3:19])=[O:17])[S:16][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C(F)(F)F)cccc2s1
Temperature: 130 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of 1.00 g of 2-fluoro-6-(trifluoromethyl)benzaldehyde, 633 mg of methyl thioglycolate, 1.21 g of potassium carbonate and 15 ml of DMF was stirred at 130° C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure, to obtain 480 mg of methyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 3).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.O.[NH3:15]>>[N:7]1[C:2]([NH2:15])=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: N
Reactant: Brc1cccc(-c2ccccn2)n1
Solvent: O
Product: Nc1cccc(-c2ccccn2)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a mixture of 6-bromo-2,2′-bipyridine (3.0 mmol, 705 mg) and Cu2O (0.01 mmol, 1.0 mg) in glycol in autoclave NH3 was feed. The reaction was maintained under 10 atm of NH3 at 110° C. for 24 h. After cooling to room temperature, water was added and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine and dried over MgSO4. After solvent evaporation, the crude product was purified by column chromatography on silica gel (Hexanes:ethyl acetate=1:1 as eluent) to afford a white solid (437 mg, 85% yield). 1H NMR (500 MHz, CDCl3, ppm): 8.65 (s, 1H), 8.25 (d, 1H, J=7.9 Hz), 7.79-7.76 (m, 1H), 7.71-7.70 (m, 1H), 7.57 (t, 1H, J=7.1 Hz), 7.26 (t, 1H, J=7.1 Hz), 6.65 (d, 1H, J=7.9 Hz), 4.53 (br, 2H). 13C NMR (125 MHz, CDCl3, ppm): 157.97, 156.38, 154.57, 149.11, 138.58, 136.73, 123.31, 120.94, 111.59, 108.87.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:21][C:17]1[NH:29][N:28]([CH2:27][C:26]2[CH:25]=[C:24]([Cl:23])[CH:32]=[C:31]([Cl:33])[CH:30]=2)[C:15](=[O:14])[CH:16]=1
Reactant: NNCc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)cc(Cl)c2)[nH]1
Reaction time: 8 h

Procedure:
After adding 1 g of p-toluenesulphonic acid to a solution of 49.6 g of β-amino-β-ethoxyacrylic acid ethyl ester in 220 ml of ethanol, 59 g of 3,5-dichlorobenzylhydrazine were added dropwise under nitrogen. The solution was left to stand overnight and the solids which precipitated melted at 175°-176° after recrystallisation from ethanol. Yield: 40 g (48%) of the compound identified above.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: N#Cc1cc(CCl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(C#N)c1
Temperature: 80 °C
Yield: 4 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (600 mg, 2 mmol), (prepared as described for the starting material in Example 24), 4-chloromethyl-2-cyanopyridine hydrochloride (620 mg, 3 mmol) and potassium carbonate (1.0 g 7 mmol) in DMF (8 ml) was heated at 80° C. for 30 minutes. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation and azeotroped with toluene. The residue was triturated with ethyl acetate/hexane, the solid product collected by filtration and purified by column chromatography eluting with ethyl acetate and further chromatography eluting with methylene chloride/methanol (99/1). The purified product was recrystallised from ethyl acetate/hexane to give 4-(4-chloro-2-fluoroanilino)-7-((2-cyano-4-pyridyl)methoxy)-6-methoxyquinazoline (35 mg, 4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CC(C)CCI
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(CCC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (57 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) was added Cs2CO3(85 mg, 0.26 mmol) and 1-iodo-3-methyl-butane (0.025 mL, 0.19 mmol). The mixture was stirred for 2 h at room temperature. The reaction was diluted with EtOAC (10 mL) and washed with saturated aqueous NaHCO3 solution, brine and water. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-{5-[1-(3-methyl-butyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester. Calcd for C30H40F3NO2 (M+H) 504.64, Found 504.4 (methyl ester) and Calcd for C31H42F3NO2 (M+H) 518.67, Found 518.7 (ethyl ester).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]nnn1-c1ccc(Br)cc1
Product: C[Si](C)(C)CCOCn1nnn(-c2ccc(Br)cc2)c1=O

Procedure:
Compound 53a was treated with SEMCl as described in Example 51, Step C to obtain compound 53b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C13H19BrN4O2Si: 371.0 (M+H). Found 371.1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1S(C1C=CC(C)=CC=1)(=O)=O)([CH3:3])[CH3:2].[OH-:26].[Na+].Cl>CO.O>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[OH:26])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C(C)C)c(O)cc1C(F)(F)F
Yield: 80.4 %

Procedure:
A solution of 1-Isopropyl-5-methoxy-2-(toluene-4-sulfonyl)-4-trifluoromethyl-benzene (0.40 g, 1.03 mmol) and NaOH (0.5 g, 12.5 mmol) in MeOH (5 ml) and H2O (5 ml) was heated at 90° C. for 2 hrs. The cooled reaction mixture was acidified with 3N HCl and extracted into methylene chloride. The combined extracts was dried with Na2SO4, filtered and concentrated to give desired 2-Isopropyl-4-methoxy-5-trifluoromethyl-phenol (0.194 g, 81%) as an oil.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][CH:12]([CH2:14][CH:15]=[O:16])[CH3:13])[CH3:8]>ClCCl>[CH3:13][CH:12]([CH2:11][CH2:10][CH:9]=[C:7]([CH3:8])[CH3:6])[CH2:14][CH:15]([OH:16])[CH:4]([N+:1]([O-:3])=[O:2])[CH3:5]
Reactant: CC[N+](=O)[O-]
Reactant: CC(C)=CCCC(C)CC=O
Solvent: ClCCl
Product: CC(C)=CCCC(C)CC(O)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Nitroethane (7.5 g) was added to a stirred solution of 13.82 g of citronellal in dichloromethane. Approximately 12-14 g of Amberlyst A-21 ion exchange resin was added, and the mixture was stirred at room temperature overnight. After filtration, the resin was rinsed 4 times with 75 mL of dichloromethane. The filtrate was dried over anhydrous MgSO4 and the solvent was removed by rotary evaporation, affording 20.1 g (95%) of a mixture of stereoisomers of the desired nitro alcohol 6. 1H NMR δ (ppm) 5.2 (t, C═CH), 4.4 (m, CH3CHNO2), 2.5 (broad s, CHOH), 2.0 (br m, ═CHCH2), 1.60 and 1.65 (both s, CH3C(CH3)═), 1.5 (d, CH3CHNO2), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.95 (d, CH2CH(CH3)CH2).
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:14]1[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]2=[C:16]([Cl:24])[CH:15]=1>O1CCOCC1.C(Cl)Cl>[Cl:24][C:16]1[CH:15]=[C:14]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N+:19]([O-:20])=[C:18]2[CH2:21][CH2:22][CH2:23][C:17]=12
Reactant: [O-][n+]1c(Cl)cc(Cl)c2c1CCC2
Reactant: SC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: [O-][n+]1c(SC2CCCC2)cc(Cl)c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of cyclopentyl mercaptan (0.112 g, 1.10 mmol) in dioxane (4 mL) at rt was added potassium tert-butoxide (0.100 g, 0.88 mmol). The mixture was stirred at rt for 1 h. After this time, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.150 g, 0.74 mmol) in dioxane (1 mL) was added and the mixture was heated to 100° C. for 1 h. Then, the mixture was diluted with methylene chloride and washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.170 g, 86%) as a brown oil. MW=269.79. 1H NMR (CDCl3, 500 MHz) δ 6.99 (s, 1H) 3.60-3.52 (m, 1H), 3.22 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.5 Hz, 2H), 2.26-2.15 (m, 4H), 1.88-1.79 (m, 2H), 1.77-1.64 (m, 4H); APCI MS m/z 270 [M+H]+.
Reaction SMILES: Br[CH:2]([CH3:24])[CH2:3][CH2:4][C:5](=[O:23])[C:6]([N:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[O:11][CH2:10]1)([CH3:8])[CH3:7].C([O-])(=[O:27])C.[Na+].O>CN(C)C=O>[CH3:22][C:12]1[O:11][CH2:10][N:9]([C:6]([CH3:8])([C:5](=[O:23])[CH2:4][CH2:3][CH:2]([OH:27])[CH3:24])[CH3:7])[C:14](=[O:15])[C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCC(C)Br)CO1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCC(C)O)CO1
Temperature: 70 °C
Yield: 25.2 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylheptan-3-one (1.04 g), sodium acetate (0.43 g) and water (0.10 g) in N,N-dimethylformamide was heated at 70° C. for 2 hours. Water was added and the mixture extracted (dichloromethane) and the organic phase dried (magnesium sulphate) and evaporated. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (3:1), to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-3-oxo-heptan-6-ol (Compound 212, 0.22 g) as a brown gum, NMR 1.2(d,3H), 1.4(2s,6H), 1.6(m,1H), 1.9(m,2H), 1.9(s,3H), 2.5(m,1H), 2.8(m,1H), 3.8(m,1H), 5.3(m,2H), 7.3(m,5H).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4C(=O)C5=CC=CC=C5C4=O)=[CH:28][CH:27]=3)[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[C:15]2=[O:25])=[CH:27][CH:28]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)cc1
Yield: 43.4 %

Procedure:
A solution of 160 mg (0.253 mmol) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[4-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.5 ml of hydrazine hydrate in 5 ml of ethanol was stirred at room temperature under an atmosphere of nitrogen for 4 hours. The reaction mixture was evaporated and the residue purified by flash chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) as the eluent. Product containing fractions were combined and evaporated and the residue re-evaporated with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated to give 55 mg (43%) of 1-[4-(aminomethyl)phenyl]-7-anilino-3-(2-bromophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 133-136° C. [Mass spectrum (ESI) MH+ =501].
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].C[O:18][C:19]([CH3:21])=[CH2:20].OS([O-])(=O)=O.[K+]>O>[CH3:1][C:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:3][CH:4]=[CH:20][C:19](=[O:18])[CH3:21]
Reactant: C=C(C)OC
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CC(=O)C=CC=C(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Yield: 7.3 %

Procedure:
190 g of 3,7,11-trimethyldodec-1-yn-3-ol (purity 95%, 0.848 mol) and 200 g of 2-methoxypropene (2.78 mol) and 0.58 g of KHSO4, dissolved in 1.74 g of water, were introduced into a pressure-resistant vessel. The reactor was flushed with nitrogen and closed. After a reaction time of 1 hour at 120° C., the mixture was cooled to about 50° C. and a further 0.58 g of KHSO4, dissolved in 1.74 g of water, was added. The mixture was once again heated to 120° C. After a reaction time of one hour, the reaction was complete. Distillation was carried out as in Example 1.147 g of a mixture comprising mainly 2-methoxypropene and 2,2-dimethoxypropane and 213 g of a fraction comprising 1.6% of 3,7,11-trimethyldodec-1-yn-3-ol, 67% of 6,10,14-trimethylpentadeca-4,5-dien-2-one, and 7.3% of 6,10,14-trimethylpentadeca-3,5-dien-2-one were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([CH3:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.[OH-].[Na+].O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N+:12]([O-:30])=[C:11]([CH3:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(C)c(C)c(OCc3ccccc3)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc2c(c1)c(OCc1ccccc1)c(C)c(C)[n+]2[O-]
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 83.4 %

Procedure:
To an ice-cold solution of 4-(benzyloxy)-2,3,6-trimethylquinoline (1.36 g) in chloroform (25 mL) was added m-chloroperbenzoic acid (75%, 1.35 g), and the mixture was stirred for 4.5 hours. A 1M aqueous sodium hydroxide solution (10 mL) and water (10 mL) were added to the reaction mixture, followed by extraction with chloroform (20 mL). The organic layer was washed sequentially with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to obtain 4-(benzyloxy)-2,3,6-trimethylquinoline-1-oxide (1.20 g).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>ClCCl.O>[CH3:25][N:26]([CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4])[CH2:27][CH2:28][O:29][CH3:30]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COCCN(C)CC(=O)N1CCc2cc(OC)c(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and N-methyl-2-(methyloxy)ethanamine (1.4 g, 15.2 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT overnight. The reaction mixture was diluted with 100 mL of water, the organic solvents were washed with water (2×100 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting residue was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, and the reaction was stirred at RT overnight under a balloon of H2 pressure. The catalyst was removed via filtration and the solvent was evaporated under reduced pressure to yield the 1-({methyl[2-(methyloxy)ethyl]amino}acetyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine as a white solid (3.1 g, 89%). 1HNMR (400 MHz, DMSO-d6) δ ppm: 2.28(s, 3H), 2.62 (t, J=5.77 Hz, 2H), 2.94 (t, J=8.24 Hz 2 H), 3.19 (s, 3H), 3.25(s, 2H), 3.41 (t, J=5.77 Hz, 2 H), 3.68(s, 3H), 4.04 (t, J=8.33 Hz,2H), 4.61 (s, 2H), 6.67 (s, 1 H), 7.52 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][S:13][C:14]2[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CS(C)=O>[CH3:21][C:16]1[N:15]=[C:14]([S:13][CH2:12][C:11]2[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:19]=[C:18]([OH:20])[CH:17]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(O)nc(SCc2cc3ccccc3nc2Cl)n1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(O)nc(SCc2cc3ccccc3nc2N2CCCCC2)n1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of 2-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (0.5 g, 1.57 mmol) and piperidine (1.33 g, 15.7 mmol) in DMSO was heated overnight at 90° C. Water was then added, and the product was extracted in dichloromethane and back washed with water. The organic layer was separated, dried, and evaporated to provide the titled product as a beige solid (0.35 g, 61% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 2.31 (s, 3H), 4.95 (s, 2H), 6.04 (bs, 1H), 7.87 (t, J=7.8, 15.0 Hz, 1H), 8.08 9 m, 2H), 8.26 (d, J=8.1 Hz, 1H), 8.48 (d, J=8.2 Hz, 1H), 9.00 (d, J=8.2 Hz, 1H); M+ 366.5.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.O[CH2:11][C:12]1(CO)[CH2:17][C:16]2[CH:18]=[CH:19][S:20][C:15]=2[S:14](=[O:22])(=[O:21])[N:13]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.C(N(CC)CC)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:13]2[C:12]([CH2:11][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:17][C:16]3[CH:18]=[CH:19][S:20][C:15]=3[S:14]2(=[O:21])=[O:22])=[CH:25][CH:26]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN2C(CO)(CO)Cc3ccsc3S2(=O)=O)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(CN3CCOCC3)=Cc3ccsc3S2(=O)=O)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
Methanesulfonic anhydride (1.24 g, 7.13 mmol) was added to a solution of the product of Example 11, Step C (1.3 g, 3.86 mmol) and triethylamine (1.17 g, 11.6 mmol) in anhydrous THF (50 mL) at ambient temperature. After stirring for 1 h, morpholine (3 mL) was added and the reaction mixture was heated at reflux temperature for 1 h followed by removal of solvent. A saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 30% to 60% ethyl acetate/hexane) to give a solid (1.39 g, 88%): mp 112°-114° C.