Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH2:14][NH:15]C(=O)OC(C)(C)C)=[CH:12][C:11]([C:23]([F:26])([F:25])[F:24])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:27]>O1CCOCC1>[ClH:27].[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:23]([F:25])([F:24])[F:26])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)nn1-c1cc(F)cc(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc(C(F)(F)F)nn1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In 4 mL of dioxane, tert-butyl (1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (214 mg, 0.567 mmol, 1 equiv.) was dissolved and hydrogen chloride in dioxane (0.923 mL, c=4 mol/L, 3.69 mmo, 6.5 equiv.) was added. The reaction mixture was stirred overnight at room temperature, the precipitate was filtered out, washed with dioxane (2×15 mL) and dried to give (1-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (139 mg, 78%).
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]1[C:12]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)=[CH:11][CH:10]=[C:9]([CH2:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:5]=1[C:6]([OH:8])=[O:7]>CO>[C:22]1([S:19]([CH2:18][C:9]2[C:5]3[C:6](=[O:8])[O:7][CH2:1][NH:3][C:4]=3[C:12]([C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)=[CH:11][CH:10]=2)(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Reactant: C=O
Solvent: CO
Product: O=C1OCNc2c(-c3ccoc3)ccc(CS(=O)(=O)c3ccccc3)c21

Procedure:
Formaldehyde (0.138 ml) was added dropwise to a solution of 2-amino-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoic acid (Intermediate 211, 0.116 g) in methanol (4 ml) at 60° C. and the resultant mixture was stirred at that temperature for 0.5 hours. After cooling, the mixture was filtered through a phase separator and the filtrate was evaporated to dryness. The residue was triturated with diethyl ether and the solid was collected by filtration to give 5-(benzenesulphonylmethyl)-8-(furan-3-yl)-1,2-dihydro-benzo[d][1,3]oxazin-4-one (0.118 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH:21](Br)([CH3:23])[CH3:22]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH:21]([CH3:23])[CH3:22])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(O)(c2ccc(F)c(F)c2)C1
Temperature: 120 °C
Yield: 39.6 %

Procedure:
In a sealed tube a mixture of 3-(3,4-difluorophenyl)pyrrolidin-3-ol (0.192 g, 0.963 mmol), acetonitrile (3 mL), potassium carbonate (0.133 g, 0.963 mmol) and isopropylbromide (0.118 g, 0.963 mmol) was heated under microwave irradiation at 120° C. for 25 minutes. The mixture was filtrated and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1 to 1:1) and by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 55:45) gave the title compound (0.092 g). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 143-147° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 11), 226 (bp), 182 (46), 85 (53), 84 (31).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:30])=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([OH:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].CS(OC[CH:37]1[CH2:51][C@@H:40]2[CH2:41][N:42]([C:44]([O:46][C:47](C)(C)C)=[O:45])[CH2:43][C@@H:39]2[CH2:38]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C.CO.C(OCC)(=O)C>[CH2:41]1[CH:40]2[CH2:51][CH2:37][CH2:38][CH:39]2[CH2:43][N:42]1[C:44]([O:46][CH2:47][O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[C:10]=3[F:30])=[N:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[O:27][CH3:28])=[O:45]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(COS(C)(=O)=O)C[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1OCOC(=O)N1CC2CCCC2C1

Procedure:
A solution of 4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (0.22 g, 0.47 mmol), 1,1-dimethylethyl (3aR,6aS)-5-{[(methylsulfonyl)oxy]methyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.16 g, 0.51 mmol), K2CO3 (0.33 g, 2.36 mmol) in N,N-dimethylacetamide (5 mL) was heated in a sealed reaction tube at 90° C. for 12 h. The crude reaction mixture was diluted with 100 mL 10% methanol in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1×30 mL), water (1×30 mL) and brine (1×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 3:2 hexanes:acetone) provided 1,1-dimethylethyl (3aR,6aS)-5-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxymethyl) hexahydrocyclopenta-[c]pyrrole-2(1H)-carboxylate which was used directly in the next step. MS (EI) for C28H31Cl2FN4O4: 577, 579 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=O)(C)(C)C.[ClH:15].O1CCOC[CH2:17]1>CO>[ClH:15].[CH3:17][O:14][C:12]([CH:10]1[CH2:9][NH:8][CH2:11]1)=[O:13]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNC1

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (8.00 g, 39.8 mmol) in MeOH (60 mL) was added 4 M HCl in dioxane (60 mL, 240.0 mmol). The mixture was refluxed for 2 hours. The mixture was concentrated to afford INT 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl.[OH-].[Ca+2].[OH-]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8](=[O:27])[C:7]=2[CH:18]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)c1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.63 G. 3-cyano-10,11-dihydro-11-oxodibenzo[b,f]thiepin is dissolved in 100 cc. methylene chloride and 1.12 g. m-chloroperbenzoic acid is added and the solution stirred for one hour at room temperature. The reaction mixture is diluted with methylene chloride, excess powdered calcium hydroxide is added, and the mixture stirred for five minutes and filtered through celite. The organic filtrate is evaporated to dryness and the residue chromatographed on silica gel and eluted with a 1:1 mixture of benzene: chloroform to yield 937 mg. (54%) of the desired pure sulfoxide, m.p. 219°-221° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CS([C:26]1[N:31]=[C:30]([N:32]2[C:40]3[C:35](=[C:36]([CH2:41][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])[CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH:29]=[CH:28][N:27]=1)=O>CN1C(=O)CCC1>[CH3:47][O:46][CH2:45][CH2:44][N:42]([CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:35]=1[CH:34]=[CH:33][N:32]2[C:30]1[CH:29]=[CH:28][N:27]=[C:26]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]2)[N:31]=1)[CH3:43]
Reactant: COCCN(C)Cc1cccc2c1ccn2-c1ccnc(S(C)=O)n1
Reactant: CN(C1CCC(N)CC1)S(C)(=O)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)Cc1cccc2c1ccn2-c1ccnc(NC2CCC(N(C)S(C)(=O)=O)CC2)n1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
N-(4-amino-cyclohexyl)-N-methyl-methanesulfonamide (567 mg, 2.12 mmol) and DIEA (0.44 mL) were stirred in NMP (0.7 mL) at RT for 1 h. [1-(2-Methanesulfinyl-pyrimidin-4-yl)-1H-indol-4-ylmethyl]-(2-methoxyethyl)-methyl-amine (305 mg, 0.85 mmol) in NMP (0.8 mL) was added, and the tube sealed and heated to 130° C. for 1 h. The mixture was then cooled to RT, decanted into water, stirred at RT overnight, and the filtrate filtered off and dried in vacuo, dissolved in DCM/ether, the precipitate filtered off, and the residue concentrated and crystallized from DCM/ether to yield N-{4-[4-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide (Compound 203).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:36][CH2:37][O:38]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:38][CH2:37][CH2:36][C:26]2[N:27]=[C:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:29][C:25]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)c1

Procedure:
Standard Procedure (B): A mixture of 3-(4-hydroxy-phenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester (0.095 g, 0.030 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (0.108 g, 0.030 mmol) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 0.134 g of crude product which was purified by LCMS to give 0.036 g (25%) of analytically pure 2-methyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-m-tolyloxy-propionic acid.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([CH2:25][CH3:26])[C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][C:12]=2[CH2:11]1)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([CH2:25][CH3:26])[C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][C:12]=2[CH2:11]1)=[S:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC(O[Si](C)(C)C(C)(C)C)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Solvent: Cc1ccccc1
Product: CCC(O[Si](C)(C)C(C)(C)C)C(=S)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
680.00 mg (1.70 mmol) 2-(tert-butyl-dimethyl-silanyloxy)-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-butan-1-one and 1.40 g (3.46 mmol) Lawesson's reagent are placed in 35 mL toluene and stirred overnight at 90° C. The solvent of the reaction mixture is eliminated in vacuo and the residue is purified on silica gel. (Eluant: cyclohexane/EA).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C1(C(C)[CH:18]=[O:19])C=CC=CC=1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:18]=[O:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C=O)c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(CC=O)cc1

Procedure:
This compound was prepared from 4-cyanobenzaldehyde using a modification of a procedure previously used in the multi-step synthesis of 2-phenylpropanal [Allen, C. F. H.; van Allan, J. Org. Syn. Coll. Vol 3, 733-734 (1955)].
Reaction SMILES: CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=1[OH:27])=[O:4].[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[N:15]3[C:7](=[CH:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([OH:27])=[C:5]([C:3]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])[C:17]2=[O:18])=[CH:21][CH:22]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc3ccccc3n2n(Cc2ccc(F)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc3ccccc3n2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: B1C2CCCC1CCC2.[C:10]([O:14][C:15](=[O:34])[NH:16][C:17]1([CH2:31][CH:32]=[CH2:33])[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[OH-:35].[Na+].OO>C1COCC1>[C:10]([O:14][C:15](=[O:34])[NH:16][C:17]1([CH2:31][CH2:32][CH2:33][OH:35])[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CCCO)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
16.2 mL (8.12 mmol) of a 0.5M solution of 9-BBN in THF were added to a solution of 1.00 g (2.71 mmol) of [1-allyl-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-carbamic acid tert-butyl ester (31) in 5 mL THF at 0° C. The reaction mixture was allowed to warm to room temperature over night, before being cooled to 0° C. Then, 20 mL of 3M aqueous sodium hydroxide and 20 mL of 30% aqueous hydrogen peroxide were added slowly, and the mixture was stirred for 12 h. The mixture was extracted twice with ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 0.85 g of the title compound 32 could be isolated as mixture of diastereoisomers in a purity sufficient for further conversion. Rt=2.03 min, 2.10 min (Method C). Detected mass: 388.3 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26]>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:24][N+:25]([O-:27])=[O:26]
Reactant: O=[N+]([O-])/C=C/c1ccccc1F
Reactant: c1cc2ccc(N3CCOCC3)cc2[nH]1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CC(c1ccccc1F)c1c[nH]c2cc(N3CCOCC3)ccc12
Temperature: 150 °C
Yield: 43.6 %

Procedure:
A mixture of 4-(1H-indol-6-yl)morpholine (0.300 g, 1.483 mmol) and (E)-1-fluoro-2-(2-nitrovinyl)benzene (0.372 g, 2.225 mmol) in toluene (8 mL) was heated in a pressure tube at 150° C. for 2 days. The solvent was removed under vacuum, and the residue was subjected to ISCO (80 g silica gel, solid loading, 30-60% ethyl acetate/hexane) to provide the desired product (0.239 g, 0.647 mmol, 43.6% yield) as a tan solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH:25][CH2:26][C:27](Cl)=[O:28])=[O:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C(Cl)Cl>[O:28]=[C:27]1[C:21]2[C:22]3[CH:13]([CH2:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:14][CH2:15][O:16][C:17]=3[CH:18]=[CH:19][C:20]=2[C:23](=[O:24])[NH:25][CH2:26]1
Reactant: O=C(Cl)CNC(=O)c1ccc2c(c1)C(CCNC(=O)Cc1ccccc1)CCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: O=C(Cc1ccccc1)NCCC1CCOc2ccc3c(c21)C(=O)CNC3=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step B (3 mmol), dissolved in 1,1,2,2-tetrachloroethane (30 ml), is added dropwise to a solution of aluminium chloride (10 mmol) in the same solvent (20 ml) under nitrogen. The reaction mixture is heated at 60° C., with stirring, until the reaction has ceased. The solution is then poured into a mixture of ice (10 g)/concentrated HCl (0.3 ml) and stirring is carried out for one hour. The aqueous phase is extracted twice with chloroform; the combined organic phases are then dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a12) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O)=[O:17]>[Pd].CN(C=O)C>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:16]([NH:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1)=[O:17]
Reactant: COc1cc2ncnc(NC(=O)Nc3ccccc3[N+](=O)[O-])c2cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(NC(=O)Nc3ccccc3N)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 1-(6,7-dimethoxyquinazolin-4-yl)-3-(2-nitrophenyl)urea (0.18 g), 10% palladium-on-charcoal catalyst (0.023 g) and DMF (10 ml) was stirred at ambient temperature under an atmosphere of hydrogen for 16 hours. The reaction mixture was filtered and the filtrate was evaporated. The resultant gum was triturated under ethyl acetate and there was thus obtained the title compound as a solid (0.137 g); NMR Spectrum: (DMSOd6) 3.85-3.95 (br s, 8H), 6.63 (t, 1H), 6.81 (d, 1H), 6.91 (t, 1H), 7.25 (s, 1H), 7.47 (d, 1H), 8.05 (s, 1H), 8.64 (s, 1H), 10.28 (br s, 1H), 11.74 (br s, 1H); Mass Spectrum: M+H+ 340.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](Cl)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 14 h
Yield: 60 %

Procedure:
To a solution of 7-((3-chlorobenzyl)oxy)quinoline-3-carbonyl chloride in THF (1.5 mL) was added tert-butyl (2-aminoethyl)carbamate (38 mg, 0.23 mmol) and triethylamine (0.044 mL, 0.32 mmol). The reaction was stirred for 14 h. The crude reaction was loaded directly onto a column and purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a white solid (44 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 9.31-9.20 (m, 1H), 8.61-8.51 (m, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.49 (s, 2H), 7.40-7.29 (m, 4H), 5.20 (s, 2H), 5.09-4.92 (m, 1H), 3.68-3.59 (m, 2H), 3.50-3.43 (m, 2H), 1.44 (s, 9H). [M+H]=456.3
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([F:18])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:13]=[C:14]([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CN(C)c1ccnc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CN(C)c1ccnc(-c2cc(F)cc(F)c2)c1
Temperature: 90 °C
Yield: 47.4 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (2.68 g, 10.8 mmol), 3,5-difluorophenylboronic acid (2.56 g, 16.2 mmol) and K2CO3 (6.7 g, 48.6 mmol) in toluene (60 ml) and water (10 ml) were degased with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated to afford a brown oil. The following oil was dissolved in Et2O and extracted with 10% HCl solution (3×50 ml). The combined aqueous fractions were washed with Et2O (2×100 ml) and neutralized with concentrated NaOH solution. The resulting mixture was extracted with EtOAc (4×100 ml), the combined organic fractions were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The obtained residue was then purified by column chromatography (SiO2, EtOAc) to afford 1.2 g (46%) of the titled compound as a colorless oil, which solidify upon standing. The crude compound was purified by column chromatography (SiO2, CHCl3 then CHCl3/MeOH, 97/3) to afford 1 g (40%) of the titled compound as a colorless oil, which solidify upon standing.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22](O)=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:34][C@H:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([C:8]1([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22]([NH:34][C@H:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)CCc1ccc(O)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.8 %

Procedure:
A mixture of 3-(2-(5-(tert-butoxycarbonyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoic acid (214 mg), di-tert-butyl L-aspartate hydrochloride (161 mg), WSC (89 mg), HOBt (77 mg), triethylamine (0.080 mL), and DMF (2 mL) was stirred at room temperature for 3 days. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (154 mg).