Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[C:32]([O:37][CH3:38])[CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:13][C:3]1[C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:4]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Br
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c(Br)c3-c3ccccc3)CC2)ccc1Br

Procedure:
Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1.5) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.78–7.84 (d, 2H), 7.32–7.42 (m, 3H), 7.18–7.22 (d, 1H), 6.44–6.52 (d, 1H), 6.36–6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.84 (s, 3H), 3.76–3.82 (m, 4H), 3.12–3.18 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.6, 154.8, 150.2, 144.6, 130, 128.8, 128.6, 126.4, 109.2, 102, 56, 51, 50, 49.6, 45.6, 42.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[O:9][CH3:10].[OH-:11].[K+].CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.Cl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: COc1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1c(O)cccc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A reaction mixture of 1,3-dichloro-2-methoxybenzene (885 mg, 5 mmol), potassium hydroxide (280 mg, 5 mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.125 mmol) and tert-butyl X-Phos (159 mg, 0.375 mmol) in dioxane/water (1:1, 5 mL) was stirred at 100° C. for 2 hours. The reaction mixture was mixed with aqueous hydrochloride solution (1 N). The organic components were extracted with EtOAc. The combined EtOAc layers were washed with brine, and then concentrated. The residue was purified by chromatography. Elution with 10% EtOAc in hexane gave 3-chloro-2-methoxyphenol (22-1, 489 mg, 62% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.98-6.84 (m, 3H), 5.73 (br s, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]C)=O)[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>O>[CH2:1]([N:8]1[CH2:9][C@H:10]2[C@H:11]([C:14](=[O:16])[C:23]3[C:18]2=[CH:19][C:20]([Br:24])=[CH:21][CH:22]=3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCN(Cc2ccccc2)CC1c1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: O=C1c2ccc(Br)cc2[C@H]2CN(Cc3ccccc3)CC[C@@H]12
Temperature: 180 °C
Yield: 18.9 %

Procedure:
A mixture of methyl 1-benzyl-3-(3-bromophenyl)piperidine-4-carboxylate (3.7 g, 9.5 mmol) and polyphosphoric acid (37 g) was heated at 180° C. for 3 h then cooled to 0.20° C. To the reaction mixture H2O and saturated NH4Cl aqueous solution were added, successively then extracted with CH2Cl2. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to obtain the title compound (631 mg, 1.8 mmol) MS (ES) 356.1 (M+H) along with the regio-isomer example 2 as the less polar fraction.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][C:19]([F:23])([F:22])[CH2:20][CH3:21])[C:10]([O:12][C:13](C)(C)C)=[O:11])=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>>[OH:30][C:24]([C:26]([F:29])([F:28])[F:27])=[O:25].[NH2:8][C@@H:9]([CH2:17][CH2:18][C:19]([F:22])([F:23])[CH2:20][CH3:21])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCC(F)(F)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(F)(F)CC[C@H](N)C(=O)OC

Procedure:
(S)-tert-butyl 2-(tert-butoxycarbonylamino)-5,5-difluoroheptanoate (1 mmol) and TFA (5 mL) were stirred together at RT for 1 hr. The solvent was then removed and diethyl ether was added to precipitate out the solid, which was then filtered to give (S)-methyl 2-amino-5,5-difluoroheptanoate TFA salt.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:41][C@@H:42]2[O:44][CH2:43]2)(=O)=O)=CC=1>CC(N(C)C)=O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:41][C@H:42]5[CH2:43][O:44]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
Nitrogen was bubbled through a mixture of 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.07 g, 10 mmol), (prepared as described for the starting material in Example 107), potassium carbonate (4.14 g, 30 mmol) and (2R)-(−)-glycidyl tosylate (4.57 g, 20 mmol) in DMA (35 ml) for 5 minutes. The mixture was then stirred at 60° C. for 2 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica by gradient elution with dichloromethane/methanol (100/0 to 95/5), to give (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline as a yellow solid (1.92 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([O:41][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: COc1ccccc1O
Product: COc1ccccc1OC(CCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1F

Procedure:
Prepared by Procedure A and Scheme AN using 2-methoxyphenol and N-(3-[1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 547.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][NH:23][CH3:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:9]([N:23]([O:22][CH3:21])[CH3:24])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)N(C)OC
Yield: 81 %

Procedure:
2-Allyloxycarbonylamino-succinic acid 4-tert-butyl ester, 100, (43.4 g, 0.159 mol) is dissolved in CH2Cl2(900 mL). To this solution O,N-dimethyl-hydroxylamine hydrochloride (18.6 g, 0.191 mol), 4-Methyl-morpholine (21.0 mL, 19.3 g, 0.191 mol), and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.6 g, 0.191 mol) are added. After the consumption of the starting material, the solution is washed with 1.0 N HCl (2×400 mL) and brine (1×250 mL). The organic layer is concentrated in vacuo and the residue purified over silica (hexanes/ethyl acetate 65:35) to afford 40.8 g (81% yield) of the desired product as a clear oil.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Br:4][CH2:5][C:6]([C:8](=[N:34][OH:35])[C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[C:15]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10])=[O:7]>C(OCC)C.O1CCCC1>[Br:4][CH2:5][C:6]([C:8](=[N:34][O:35][CH3:3])[C:9]([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[C:15]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10])=[O:7]
Reactant: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12

Procedure:
A solution of diazomethane in diethyl ether was added little by little to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (0.9 g.) in tetrahydrofuran (30 ml.) under ice-cooling until the reaction terminated, and then acetic acid was added to the resultant solution to decompose excess diazomethane. The resultant solution was concentrated under reduced pressure to give the foamy product of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.9 g.)
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](CO)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:46]([Br:49])(Br)Br>C(Cl)Cl>[Br:49][CH2:46][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CO)cc3)cc2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CBr)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.5 g of 4'-(trans-4-pentylcyclohexyl)-4-biphenylmethanol and 2.9 g of triphenylphosphine in 150 ml of absolute methylene chloride was placed at -20° C. in a sulphonation flask while gassing with argon and treated portionwise within 10 minutes with 3.8 g of solid tetrabromomethane. Partially undissolved educt thereby dissolved slowly. The mixture was stirred for a further 2 hours while warming to room temperature. The mixture was subsequently concentrated on a rotary evaporator and the crystalline residue was suspended in 300 ml of warm hexane, freed by filtration from precipitated triphenylphosphine oxide (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.7 bar) of the residue on silica gel with toluene as the eluant gave 3.39 g (82%) of 4-(bromomethyl)-4'-(trans-4-pentylcyclohexyl)biphenyl as colourless crystals. This material was used in the following step without further purification. Rf value of the product [petroleum ether/ethyl acetate (97:3)]: 0.47.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)CCl)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of 2,4-dimethoxybenzylamine (1.50 mL, 10.0 mmol) and triethylamine (2.00 mL, 14.3 mmol) in tetrahydrofuran (20 mL) at 0° C. was added chloroacetyl chloride (0.80 mL, 10 mmol). The reaction was then stirred at 0° C. for three hours. The crude reaction mixture was partitioned between ethyl acetate and water, and the organic layer dried over brine and magnesium sulfate, filtered, and evaporated in vacuo to yield 2.2074 g (91%) of N-(2,4-Dimethoxy-benzyl)-2-chloro-acetamide which was carried forward without purification. LCMS (Method E, ESI): RT=1.43 min, m+H=244.2
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]=[C:15]([NH:17][CH2:18][C:19]#[C:20][CH3:21])[CH2:14][N:13]=[C:12]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:11]=2[CH:30]=1.[OH-].[Na+]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:19]([CH2:20][CH3:21])=[CH:18][N:17]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=3[F:28])[C:11]=2[CH:30]=1
Reactant: CC#CCNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1cnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 10 ml. of ice cold 50% (wt) sulfuric acid is added successively with stirring under nitrogen 0.01 mole of 7-chloro-5-(2,6-difluorophenyl)-2-(2-butynylamino)-3H-1,4-benzodiazepine (IV) and 0.132 g. of mercuric sulfate. The resulting mixture is stirred for about 18 hours, poured into ice water, neutralized with 15% aqueous sodium hydroxide solution and extracted with chloroform. The extract thus obtained is dried over potassium carbonate and concentrated in vacuo. The residue thus obtained is chromatographed on silica gel with chloroform containing 1% methanol. The eluates containing the desired product are combined, concentrated in vacuo and crystallized from ethyl acetate-hexanes to give 8-chloro-6-(2,6-difluorophenyl)-1-ethyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]([CH3:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])[CH2:20]3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([CH2:25][NH:24][CH:21]1[CH2:22][CH2:23][N:19]([C:16]2[CH:17]=[CH:18][C:13]([N:12]([CH3:26])[C:10](=[O:11])[C:9]3[CH:27]=[CH:28][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)=[CH:14][CH:15]=2)[CH2:20]1)(=[O:31])[CH3:30]
Reactant: CCCCOc1ccc(C(=O)N(C)c2ccc(N3CCC(NC)C3)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCOc1ccc(C(=O)N(C)c2ccc(N3CCC(NCC(C)=O)C3)cc2)cc1

Procedure:
4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was mixed with pyridine and acetic anhydride. Volatile fractions were removed after 2 hours. This resulted in the product with the molecular weight of 423.56 (C25H33N3O3); MS (ESI): 424 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:41])[C@@H:13]([NH:23]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(S)CCCCCCC.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:41])[C@@H:13]([NH2:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: CCCCCCCCS
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CNC(=O)OC(C)(C)C)CC1

Procedure:
A solution of 1.71 g 4-[(S)-3-tert-butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionyl]-piperazine-1-carboxylic acid ethyl ester in 50 ml THF was stirred in the presence of 4 ml 1-octanethiol and 90 μl DBU. After 12 h the mixture was concentrated, the residue dissolved in dichloromethane and extracted with 0.1 M HCl. The aqueous phase was brought to pH9 by adding aqueous NaHCO3 before being extracted with dichloromethane. The product was obtained after evaporation of the solvent and was used in the subsequent reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]([C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)c1ccccc1)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccccc1)c1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 5-(benzoyl-methyl-amino)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (500 mg) and MnO2 (5 g) in toluene (20 mL) was heated at 80° C. for 1 h. Additional MnO2 (5 g) was introduced and the resulting mixture was stirred at 80° C. for 1 h. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated. The product was purified by chromatography (30% EtOAc-hexanes) to give 5-(benzoyl-methyl-amino)-indole-1-carboxylic acid tert-butyl ester (372 mg, 75%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[N+:1]([C:12]1[CH:11]=[C:10]([S:13]([Cl:16])(=[O:14])=[O:15])[CH:9]=[CH:8][C:7]=1[O:6][CH3:5])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
350 ml of fuming nitric acid (8.3 mol) was added very carefully in 25 ml aliquots to the crude product of Example 1 in a one-liter flask. To maintain control over the very vigorous reaction which immediately commenced, each portion of the nitric acid was allowed to react completely (i.e., until no fumes were evolved) before the next portion was added. When addition was complete, the solution was allowed to stand at room temperature for 30 minutes and then carefully poured over ice (1000 g). The resulting slurry was extracted with CH2Cl (3×250 ml) and the organic extracts were combined, dried over MgSO4 and filtered. The solvent was removed in a rotary evaporator and the yellow crystals thus obtained were recrystallized from 50% Et2O/hexane to yield pure 3-nitro-4-methoxy-benzenesulfonyl-chloride (161.3 g, 89% yield) as faintly yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([OH:22])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:25]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]O)[CH2:30][CH2:29]1)(=[O:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][O:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[O:23][CH3:24])[N:15]=[CH:14][N:13]=[C:12]3[O:11][C:10]2[C:2]([F:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[CH:4]3)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCN(CCO)CC1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCCN1CCN(C(C)=O)CC1
Yield: 67.8 %

Procedure:
A mixture of 4-[(4-fluoro-1H-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline (260 mg, 0.80 mmol), (prepared as described for the starting material in Example 10), 2-(4-acetylpiperazin-1-yl)ethanol (165 mg, 0.96 mmol), (prepared as described for the starting material in Example 28), and triphenylphosphine (252 mg, 0.96 mmol) in dichloromethane (15 ml) was stirred and cooled in an ice/water bath. Diisopropyl azodicarboxylate (189 μl, 0.96 mmol) was added. The mixture was stirred for 3 hours and then a further 0.5 mole equivalent of 2-(4-acetylpiperazin-1-yl)ethanol, triphenylphosphine and diisopropyl azodicarboxylate were added. The mixture was stirred for a further 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 6-[2(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline (260 mg, 68%) as a white solid.
Reaction SMILES: N[C@@H:2]([C@H:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7])[C:3]([OH:5])=[O:4].N([O-])=[O:17].[Na+].[OH-].[Na+].C(OCC)(=O)C>S(=O)(=O)(O)O.O>[CH2:9]([O:8][C@H:6]([CH3:7])[C@H:2]([OH:17])[C:3]([OH:5])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=N[O-]
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](OCc1ccccc1)[C@H](O)C(=O)O
Temperature: -5 °C
Reaction time: 6 h

Procedure:
To a solution of (2S,3R)-2-amino-3-benzyloxy-butyric acid (1.1 g) in 2M sulfuric acid (6.31 mL) was added dropwise over 2 h a solution of sodium nitrite (0.65 g) in water (6 mL), keeping the internal temperature of the reaction below 0° C. The reaction mixture was stirred at −5° C. for 6 h then allowed to warm to room temperature overnight. The mixture was adjusted to pH 4 with 50% aqueous sodium hydroxide then ethyl acetate was added. The mixture was stirred vigorously and acidified to pH 2 with concentrated sulfuric acid. The layers were separated and the aqueous layer extracted with further ethyl acetate (×2). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated to give the subtitle compound as a yellow crystalline solid which was used without further purification. Yield: 0.84 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.C([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)C.Cl.C(N=C=NCCCN(C)C)C.N1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN1CCOCC1
Reactant: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c21
Reaction time: 24 h

Procedure:
A solution of 4-[(3-chlorophenyl)amino]-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (25.0 g) in dry dimethylformamide (300 ml), was treated with 1-hydroxybenzotriazole (14.00 g), N-ethylmorpholine (42 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.03 g) and morpholine (14.4 ml) at 23° C. under argon with stirring. After 24 h, the solution was evaporated in vacuo and treated with aqueous saturated sodium carbonate (200 ml) and water (300 ml). The mixture was extracted with ethyl acetate (5×200 ml), and the combined, dried (Na2SO4) organic extracts were evaporated in vacuo. The residue was purified by column chromatography on a Biotage silica column (800 g) eluting with ethyl acetate-hexane (1:1 to 7:3) to give the free base of the title compound (26.9 g). A portion of the free base (21.9 g) in methanol (250 ml) was treated with 1.0M hydrochloric acid in diethyl ether to pH1 and then evaporated in vacuo. Trituration of the residue with ether followed by filtration yielded the title compound (22.75 g).