Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.S(=O)(=O)(O)O>>[Cl:12][CH2:13][C:14]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[O:7][CH:16]=1
Reactant: Cc1cc(C(N)=O)ccc1F
Reactant: O=C(CCl)CCl
Agent: O=S(=O)(O)O
Product: Cc1cc(-c2nc(CCl)co2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.00 g (12.80 mmol) of 4-fluoro-3-methylbenzamide and 1.79 g (14.08 mmol) of 1,3-dichloro-acetone are stirred at 130° C. for 2 days. A melt is formed. The mixture is then cooled to RT, 3.0 ml of conc. sulfuric acid are added carefully at this temperature and the mixture is stirred for 15 min. The resulting suspension is poured into 20 ml of ice-water and stirred at RT overnight. The precipitate formed is filtered off and dried at 40° C. in a vacuum drying cabinet overnight.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]#[N:33].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(OCC#N)ccc3c2)o1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)o1
Temperature: 100 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
A mixture of ({1-bromo-6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (71 mg, 0.141 mmol), prepared in the previous step, sodium azide (27.8 mg, 0.427 mmol) and ammonium chloride (25 mg, 0.467 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 3 h. Following the reaction by MS, starting material remained. Additional sodium azide (25 mg, 0.38 mmol) and ammonium chloride (25 mg, 0.467 mmol) were added and the reaction stirred at 100° C. for two more hours. This procedure was repeated four additional times until the MS showed that the reaction went to completion. The reaction was filtered, acidified with 5 mL of 1N HCl and then diluted with 10 mL of H2O. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (52 mg, 67%) as a brown solid, mp 235-237° C. Elemental Analysis for C27H22BrN5O3+0.23 mol H2O Calc'd: C, 59.12; H, 4.07; N, 12.77. Found: C, 59.36; H, 4.27; N, 12.23.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2OCCO2)cc1
Yield: 99.4 %

Procedure:
100 g (540 mmol) of 4-bromobenzaldehyde together with 200 mg of ptoluenesulfonic acid and 30 ml (540 mmol) of anhydrous ethylene glycol are initially introduced in 600 ml of toluene, and the mixture is refluxed on a water separator with monitoring by TLC. When the reaction is complete, the reaction solution is washed twice with sat. NaHCO3 solution and once with water, dried over Na2SO4 and evaporated in a rotary evaporator, giving 123 g (99% of theory) of the dioxolane as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[C:7](OC)=[O:8])=[O:3].C(O)C.[BH4-].[Li+]>O1CCCC1>[Cl:14][C:12]1[CH:13]=[C:4]([CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1)[C:2]([NH2:1])=[O:3]
Reactant: COC(=O)c1cc(Cl)cc(C(N)=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1cc(Cl)cc(CO)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
(Step 1) To a mixed solution of methyl 3-(aminocarbonyl)-5-chlorobenzoate (2.2 g) in tetrahydrofuran:ethanol=10:1 (33 ml) was added lithium tetrahydroborate (0.34 g) at room temperature. After stirring at 60° C. for 2 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate:hexane=5:1) to give 3-chloro-5-(hydroxymethyl)benzamide (0.95 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:10]=1)=[O:5].[CH3:21][Mg]Br>C1COCC1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4](=[O:5])[CH3:21])[N:7]=[N:8]2)=[CH:17][CH:16]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(Cn2cc(C(=O)N(C)OC)nn2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(C)=O)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.3 %

Procedure:
To a solution of N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (8.0 g, 0.03 mol) in anhydrous THF (75 mL) was added dropwise methyl magnesium bromide (3.0 M in hexane, 20 mL, 0.058 mol) at 0° C. After the addition, the mixture was stirred at RT overnight. The mixture was quenched with sat. aq. NH4Cl (30 mL) then extracted with CH2Cl2 (3×50 mL). The organics were combined, washed with 1 N aq. NaOH (3×20 mL), water (3×20 mL), brine (50 mL), dried over MgSO4 and evaporated to yield the title compound (8.0 g, 75.0%) as a white solid.
Reaction SMILES: Cl[CH:2]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])=[CH:47][CH:46]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:5][CH:4]=1.CN(C=O)C.[N-:92]=[N+:93]=[N-:94].[Na+]>C(Cl)(Cl)Cl>[N:92]([CH:2]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])=[CH:47][CH:46]=1)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:5][CH:4]=1)=[N+:93]=[N-:94]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(Cl)c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOc1ccc(C(N=[N+]=[N-])c2ccc(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 9.5 %

Procedure:
To chloro-bis[4-(12-docosoxydodecyloxy)phenyl]methane (80.9 mg, 66.3 mmol) were added DMF (3 ml), chloroform (1 ml), and sodium azide (40 mg, 621 μmol) and the mixture was stirred at 80° C. for 6 hours. Sodium azide (40.4 mg, 621 μmol) was added, and the mixture was stirred at 90° C. for 1.5 hours. The mixture was cooled to room temperature. Chloroform (2 ml) was added, and the mixture was washed with purified water (3 ml)×3 for partitioning, and the organic layer was evaporated under reduced pressure. The residue was crystallized from acetonitrile to give azido-bis[4-(12-docosoxydodecyloxy)phenyl]methane (72.0 mg, 58.7 μmol, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:18][C:17]1[N:1]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc2c(c1)NC(=O)CC2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A mixture of 7-amino-3,4-dihydroquinolin-2(1H)-one (3.0 g, 18.50 mmol), hexane-2,5-dione (3.0 g, 25.9 mmol) and 4-methylbenzenesulfonic acid (3.2 g, 18.50 mmol) in toluene (40 mL) was stirred at 100° C. for 30 min. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 7-(2,5-dimethyl-pyrrol-1-yl)-3,4-dihydro-1H-quinolin-2-one (3.0 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 8.72 (brs, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.67 (s, 1H), 5.89 (s, 2H), 3.02 (t, J=8.0 Hz, 2H), 2.68 (m, 2H), 2.03 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[C:35](B2CC(C)(C)C(C)(C)C2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:34]=[C:33]([O:46][CH3:47])[C:32]([OH:48])=[C:31]([Cl:30])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: COc1cc(B2CC(C)(C)C(C)(C)C2)cc(Cl)c1O
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure D, tert-butyl trans-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexylcarbamate (56 mg, 0.200 mmol) was reacted with 2-chloro-6-methoxy-4-(3,3,4,4-tetramethylborolan-1-yl)phenol (47 mg, 0.100 mmol) to afford the desired product (35 mg, 65%) as a yellow solid: ESI MS m/z 541 [C29H34ClN3O5+H]+.
Reaction SMILES: CC1C=CC(S(Cl)(=O)=[O:9])=CC=1.[Cl:12][C:13]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:14]=1[CH2:15][N:16]([CH3:35])[C:17]([N:19]1[CH2:24][CH2:23]/[C:22](=[N:25]/O)/[CH2:21][C@@H:20]1C1C=CC(F)=CC=1C)=[O:18]>CC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:12][C:13]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:14]=1[CH2:15][N:16]([CH3:35])[C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:9])[NH:25][CH2:21][CH2:20]1)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(F)ccc1[C@H]1C/C(=N\O)CCN1C(=O)N(C)Cc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(Cc1cc(Cl)ccc1Cl)C(=O)N1CCNC(=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 117.3 %

Procedure:
A solution of p-tosyl chloride (28 mg) in acetone (0.5 mL) was added drop-wise to a mixture of intermediate 25b (43 mg) in acetone (1 mL) and 5% sodium carbonate solution (1 mL) under a Nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes, then it was heated to reflux for 45 minutes. The mixture was allowed to cool to r.t., and the aqueous residue was extracted with DCM. The organic layer was washed with a 5% sodium hydrogen carbonate solution (10 mL). The aqueous phase was re-extracted with DCM (3×20 mL). The combined organic extracts were dried and concentrated in vacuo to give the crude 7-(R)-4-fluoro-2-methyl-phenyl)-5-oxo-[1,4]-diazepane-1-carboxylic acid, (2,5-dichloro-benzyl)-methylamide (38 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]=[CH:10][CH2:11][NH2:12]>>[CH3:8][CH:9]=[CH:10][CH2:11][NH:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CC=CCN
Reactant: Clc1ccncc1
Product: CC=CCNc1ccncc1
Temperature: 130 °C
Yield: 74.9 %

Procedure:
Silane 1a was prepared by first preparing and then hydrosilating 4-(N-methylallylamino)pyridine with diethoxy(methyl)silane, (EtO)2MeSiH. The 4-(N-methylallylamino)pyridine was first obtained by reaction of 4-chloropyridine and N-methylallylamine. Thus, 4-chloropyridine (11.4 g; 0.1 mol) and N-methylallylamine (7.1 g; 0.1 mol) were combined in a glass ampoule or steel container, after which the mixture was degassed under vacuum and the vessel was sealed. The vessel was heated for three days at 130° C. The vessel was thereafter opened and the contents were dissolved in water and then neutralized with 10% aqueous NaOH. The aqueous solution was extracted with several portions of diethyl ether. The ether extract was filtered and evaporated. The residue was distilled under vacuum to give 4-(N-methylallylamino)pyridine (11.1 g; 75%; b.p. 70° C. @0.1 torr). 4-(N-Methylallylamino)pyridine (4.45 g; 0.030 mol), MeSiH(OR)2 (6.7 g; 0.050 mol) and H2PtCl6 (60 μL; 0.080 mol/L in i-PrOH; 4.6×10-6 mol) were combined and heated under vacuum in a sealed vessel for 10 hours at 130° C. Distillation of the products gave Silane 1a, N-(3-(diethoxy(methyl)silyl)propyl)-N-methyl-4-aminopyridine, as a colorless liquid (6.3 g; 74%; b.p. 122-127° C. @0.05 torr). The product was characterized by elemental analysis, infrared, 1H and 13C-NMR spectroscopy, and gas chromatography-mass spectrometry.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one (4.7 g, 0.017 mol) and POCl3 (60 ml) were sealed in 3 different bottles (20 ml). The mixture was heated at 150° C. for 15 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 15 ml MeOH, stirred for 2 hours at room temperature. The solid was collected and dried to give product (3.4 g, 68% yield). LC-MS: 289 (MH+)
Reaction SMILES: N1([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:7])C=CN=C1.Cl.ClCl>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[N:8]([CH2:9][CH2:10][O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[C:6]=[O:7]
Reactant: C=C(C)C(=O)OCCNC(=O)n1ccnc1
Agent: Cl
Agent: ClCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCN=C=O
Reaction time: 1 h
Yield: 52 %

Procedure:
In a round bottom flask 35.7 g (156 mmole, 97.8%) 2-Methyl-acrylic acid 2-[(imidazole-1-carbonyl)-amino]-ethyl ester (Example 1) were dissolved in about 100 ml chloroform at room temperature (30 min). The clear yellow solution was diluted with about 100 ml toluene. To the resulting turbid dispersion 11.5 g (313 mmole=200% of theory) dry hydrogen chloride were added at about 23° C. within about 30 min, while cooling. A second liquid phase was formed. The reaction mixture was stirred for another hour. At ambient pressure 123 g of chloroform were distilled from the reaction mixture at about 69-74° C. Thereafter, the vessel was kept at about 91-92° C. for about 1 h. Meanwhile imidazolium hydrochloride began to crystallize giving a greenish suspension. After about 1 hour of stirring at room temperature the toluene phase was decanted, precipitated washed with more toluene. The clear yellow phase was evaporated at about 40° C. and about 25 mbar under exclusion of light. This raw product (according to NMR) consisted of MOI with about 18% residual toluene. It was distilled at about 48° C. and about 1.4 mbar. The clear product was stabilized with 200 ppm phenothiazine. A yield of 52% was obtained with the distilled product. Analytics showed 96.8% purity (GC) and 400 ppm residual chlorine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24]Cl)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:33][NH2:34]>C(O)C>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24][NH:34][CH3:33])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CN
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Solvent: CCO
Product: CNCC(=O)N1CCC[C@H]1COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Yield: 47 %

Procedure:
Using a procedure similar to that described for the synthesis Example 43, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloracetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.28 g; prepared as described in Example 43, preparation of starting materials) was reacted with 33% methylamine in ethanol (5 ml) to give the title product as a foam (0.131 g, 47%); 1H NMR Spectrum: (CDCl3) 1.91-2.22 (m, 4H), 2.22 (s, 3H), 2.70-2.90 (m, 1H), 3.28-3.40 (m, 2H), 3.44-3.54 (m, 2H), 3.97-4.09 (m, 4H), 4.47-4.51 (d, 1H), 4.60-4.66 (t, 1H), 7.06-7.20 (m, 2H), 7.24 (s, 1H), 8.07-8.13 (m, 1H), 8.57-8.70 (m, 3H); Mass Spectrum: (M−H)− 472.
Reaction SMILES: C([N:8]([CH2:30][C@@H:31]([C:33]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2C=CC=CC=2)=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](=[O:51])[NH:38]2)[OH:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1.C([OH:54])C>C(O)(=O)C.[Pd]>[C:44]([OH:54])(=[O:43])[CH3:45].[OH:32][C@H:31]([C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](=[O:51])[NH:38]2)[CH2:30][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)c1

Procedure:
A solution of 3-(4-{[6-(Benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzenesulfonamide (10 mg) in ethanol (10 ml) and acetic acid (0.1 ml) was stirrer under hydrogen in the presence of palladium on charcoal (5 mg) for 2 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH3(aq) 100:10:1) and freeze-dried from water-acetic acid to give the title compound (5.8 mg).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].C(N(CC)CC)C>CO>[OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][S:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CS
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4 g (0.0017 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one in 13 ml of methanol is treated with 4.7 ml of methyl thioglycolate and 7.1 ml of triethylamine. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is worked-up with water and methylene chloride. The organic phase is dried and freed from solvent. The residue is chromatographed on silica gel with ether. There is obtained methyl [[(6E,10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]acetate which has the following bands in the IR spectrum: 1736 cm-1, 1711 cm-1, 1437 cm-1, 1408 cm-1, 1281 cm-1, 1137 cm-1, 1007 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:25](=[O:27])[CH3:26])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(C)=O
Yield: 91 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.10 gm, 0.29 mmoles), acetic anhydride (0.5 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2-(p-methoxy-benzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran, mp. 119°-120° C.
Reaction SMILES: Cl.[NH2:2]O.[Br:4][C:5]1[CH:6]=[C:7]2[C:13]([CH:14]=O)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1.C(=O)(O)[O-].[Na+]>CO>[Br:4][C:5]1[CH:6]=[C:7]2[C:13]([C:14]#[N:2])=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#Cc1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (46 mg) was added to a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde obtained by the method of described in WO 2004/101565 (150 mg) in methanol (1.0 ml) under nitrogen atmosphere, and the mixture was stirred at room temperature for one hour. After azeotropic distillation with toluene, thionyl chloride (118 μl) was added to a suspension of the residue in toluene (2 ml), and the mixture was stirred at 80° C. for 16 hours and at 100° C. for 8 hours. After leaving to cool to room temperature, saturated aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with methanol-chloroform) to give the title compound (88 mg).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:16][S:17](O)(=[O:19])=[O:18]>C(OCC)C>[CH2:1]([C:9]1[C:10]([CH3:15])=[C:11]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccccc1C
Reactant: O=S(=O)(O)Cl
Solvent: CCOCC
Product: CCCCCCCCc1cccc(S(=O)(=O)Cl)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Octyltoluene (50 g. - 0.245 mole) as prepared in Table 1 was added slowly at 5°-10° C. with stirring over 1/2 hour (some exotherm) to 81 g. (.69 mole) chlorosulfonic acid in a 250 ml. round bottom flask fitted with air stirrer, thermometer, addition funnel, reflux condenser, scrubber and ice bath. The reaction mixture was allowed to stir for 3 hours at 25°-30° C. and then stand overnight. It was poured onto 900 g. ice, 500 ml. diethyl ether was added and the mixture was stirred until the ice melted. The resulting organic phase was washed with water, 30% aqueous Na2CO3, again with water, dried over Na2SO4 and the solvent was evaporated. Thirty nine g. of octylmethylbenzenesulfonyl chloride was obtained.