Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[CH2:19][CH3:20])[C:5]1=[O:24])(=O)C.[N:25]1([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:36]/[C:18](=[C:6]3\[C:5](=[O:24])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[CH2:19][CH3:20])=[CH:37][CH:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(CC)OCC
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(/CC)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylene)-6-ethoxycarbonyl-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline Rf value: 0.9 (silica gel, methylene chloride/ethanol=5:1) C26H31N3O3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:10][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: COc1cccc(C2CO2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)COc2ccc(C=O)cc2)c1
Temperature: 78 °C
Yield: 122 %

Procedure:
To a stirring solution of 2-(3-methoxyphenyl)oxirane (5.60 g, 37.0 mmol) in toluene (65 ml) was added 4-hydroxybenzaldehyde (6.80 g, 5.60 mmol), 1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction mixture was allowed to cool to RT and extracted with EtOAc (2×150 ml). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed, eluting with 30-40% EtOAc/hexanes. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.86 g (18%) of the title compound as a clear colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.90 g (9%) the regioisomer as a nearly colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:21]/[N+:18]([O-:20])=[O:19])[CH:14]=[C:15]([F:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(F)cc(OCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
Heat 3-benzyloxy-5-fluoro-benzaldehyde (3.75 g, 16.29 mmol), nitromethane (4.08 g, 66.79 mmol), and ammonium acetate (3.47 g, 44.96 mmol) in acetic acid (54 mL) in 125° C. oil bath under nitrogen for 4 hours. Cool to room temperature and pour into ice/water. Extract with hexanes/ethyl acetate. Dry (magnesium sulfate), filter and concentrate. Purify on 120 g silica gel eluting with 100:0 to 80:20 hexanes:ethyl acetate to give 3.05 g (68.5%) of the desired compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].CS(O[CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17]1)(=O)=O>CC(N(C)C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17]1
Reactant: Oc1ccccc1Br
Reactant: CC(C)N1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCC(Oc2ccccc2Br)C1
Temperature: 150 °C

Procedure:
To a solution of 2-bromophenol (2.6 g) in dimethylacetamide (20 ml) was added sodium hydride (640 mg) portionwise. A solution of 1-isopropylpyrrolidin-3-yl methanesulphonate [Example 134 (c)] in dimethylacetamide (20 ml) was added and the mixture was heated to 150° C. for 18 h. The mixture was allowed to cool and partitioned between water and dichloromethane. The organic phase was extracted with 2N aqueous hydrochloric acid which was then neutralised and extracted with dichloromethane. The extracts were dried (MgSO4), the solvent removed under vacuum and the product purified by silica chromatography using dichloromethane/aqueous ammonia/methanol mixtures to yield the title compound as a brown oil (496 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CN1CCCC1)CO2

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), pyrrolidine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 0.4), 110 (4), 85 (8), 84 (bp), 63 (2), 55 (5).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]=[C:9]([C:18]#[N:19])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:15]=3)[N:10]=[C:9]([C:18]#[N:19])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1nc(NC2CCCC2)c2cc(O)ccc2n1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc2nc(C#N)nc(NC3CCCC3)c2c1

Procedure:
4-Cyclopentylamino-6-hydroxy-quinazoline-2-carbonitrile (0.4 mmol), (2-Chloro-ethyl)-dimethyl-amine hydrochloride (0.55 mmol) and cesiumcarbonate (3.5 mmol) are stirred in DMF (3 ml) at RT for 20 hours. The suspension is filtered, washed with little DMF and water is added to the filtrate until the solution gets turbide. The precipitate formed is filtered off and dried (vacuum). A white powder with mp. 158-160° C., Rf=0.51 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:20]([O-:22])=[O:21].Cl>ClCCl>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:20](=[O:21])[OH:22])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])Cl
Reactant: COc1cccc2sc(N)nc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2sc(NC(=O)O)nc12
Reaction time: 0.17 h

Procedure:
2-Amino-4-methoxybenzothiazol (23.6 g, 131 mmol) and pyridine (12.6 ml, 157 mmol) in dichloromethane (230 ml) are slowly treated with methyll chloroformate (10.6 ml, 137 mmol) at 0° C. After 10 minutes, further methyll chloroformate (1.0 ml, 13 mmol) and pyridine (1.0 ml, 12 mmol) are added. After 10 minutes, the mixture is poured into 200 ml 1M aqueous hydrochloric acid, the organic layer is separated, diluted with dichloromethane (250 ml) and washed with brine (50 ml). The organic phase is dried and the solvent evaporated in vacuo. 31.0 g (99.4%) white solid. MS: m/e=238 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([O:23]C(C)(C)C)=[O:22])[CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([OH:23])=[O:22])[CH:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: CCCSc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(CC(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCSc1c(C(=O)O)cnn1-c1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-butyl 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylate (Intermediate#36) was dissolved in DCM (10 mL). TFA (2 mL) was added and the mixture was stirred at ambient temperature for 5 h. Volatiles were then evaporated under reduced pressure and the residue dried under vacuum to afford 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylic acid as a light brown oil. (440 mg, 98%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: Cc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)c1
Temperature: 150 °C
Yield: 83.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(3-methylphenyl)-3-piperidinecarboxamide (90 mg, 0.209 mmol), 3 mL of EtOH, Hunig's base (0.11 ml, 0.627 mmol), and hydrazine anhydrous (0.026 ml, 0.836 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes in microwave. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (77 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 1H), 1.84 (m, 2H), 2.07 (m, 1H), 2.27 (s, 3H), 3.50 (m, 1H), 4.48 (m, 2H), 4.75 (m, 1H), 4.90-5.13 (m, 1H), 6.87 (s, 1H), 6.94-7.08 (m, 1H), 7.13-7.26 (m, 1H), 7.41 (m, 6H), 7.75 (s, 1H), 7.83-8.00 (m, 1H), 10.00 (s, 1H), 12.07 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[O:16]([C:18]#[N:19])[Na].[OH-].[Na+]>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:18](=[O:16])[NH:19][C:4]2=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: N#CO[Na]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2[nH]1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-amino-5-chlorobenzoic acid (10 g, 58.48 mmol, 1.00 equiv) in water (100 mL), acetic acid (8 g, 133.33 mmol, 2.24 equiv). This was followed by the addition of NaOCN (8.2 g, 126.15 mmol, 2.13 equiv). The mixture was stirred for 30 mins at 30° C. To this was added sodium hydroxide (86 g, 2.15 mol, 37.00 equiv). The resulting solution was stirred overnight at 30° C. The solids were collected by filtration. The residue was dissolved in water. The pH value of the solution was adjusted to 7 with hydrogen chloride (12 mol/L). The solids were collected by filtration. This resulted in 5 g (44%) of 6-chloroquinazoline-2,4(1H,3H)-dione as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][CH2:43]O>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:43][CH2:42][CH:38]3[CH2:39][CH2:40][CH2:41][N:37]3[CH3:36])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CN1CCCC1CCO
Reactant: CCOC(=O)c1ccc2cc(O)ccc2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2cc(OCCC3CCCN3C)ccc2n1
Temperature: 35 °C

Procedure:
A mixture of 0.400 g (0.002 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 0.966 g (0.004 mmol) of triphenylphospine (Fluka), 0.396 g (0.003 mmol) of 1-methyl-2-pyrrolidineethanol and 0.68 ml (0.004 mmol) di-tert.-butyl azadicarboxylate 40% in toluene in 40 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH/NH4OH from 97/3/0.5 to 90/10/0.5. The ]
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: C1CCNC1
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Product: COc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Yield: 46.9 %

Procedure:
The method described in Stage 12.1 is followed, starting from 5.4 g (28.64 mmol) of 2-chloro-4-methoxy-5-nitropyridine (WO2003/080610) and 4.53 g (63 mmol) of pyrrolidine. The product obtained is, in this case, purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate. In this way we isolate 3 g of the expected product.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[CH:31](OCC)=[O:32]>>[CH:31]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:32]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Reactant: CCOC=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC=O)c3ccccc32)cc1

Procedure:
A mixture of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) and ethyl formate (10 ml) is refluxed for 4 hours. The reaction solution is concentrated and the resulting residue is recrystallized from ethanol/petroleum ether to give 5-formylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless columnar crystal, m.p. 211-213° C.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].Cl.[NH2:7][C:8]1[N:9]=[C:10]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][CH3:29])[CH:20]=2)=[O:18])[N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12>N1C=CC=CC=1.C(OC(C)C)(C)C>[CH3:29][O:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26])[C:17]([C:10]1[N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[C:8]([NH:7][S:1]([CH3:4])(=[O:3])=[O:2])[N:9]=1)=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)c2nc(N)c3ccccn23)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: COc1cc(C(=O)c2nc(NS(C)(=O)=O)c3ccccn23)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
116 μl (1.49 mmol) of mesyl chloride are added, under a nitrogen atmosphere at a temperature of 5° C., to 0.473 g (1.36 mmol) of (1-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone hydrochloride obtained in example 76 in 14 ml of pyridine. On completion of the introduction, the mixture is allowed to return to ambient temperature and is stirred for 30 minutes. The reaction medium is poured under 95 ml of 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, separated by settling, dried over sodium sulfate and concentrated under reduced pressure. The solid residue obtained is taken up in isopropyl ether, filtered off, washed with isopropyl ether and then dried. 0.40 g of an orange solid is collected. Melting point: 231° C.; 1H NMR (d6-DMSO): 3.24 (3H, s), 4.02 (3H, s), 7.40-7.44 (1H, m), 7.49-7.53 (1H, m), 7.88-7.92 (1H, d), 8.00-8.07 (2H, m), 8.26 (1H, s), 9.75 (1H, d)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][C:64]([O:92][CH3:93])=[C:65]([O:87][CH2:88][CH2:89][O:90][CH3:91])[CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH3:93][O:92][C:64]1[CH:63]=[C:62]2[C:67]([C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)=[N:69][C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([NH:53][C:8](=[O:10])[CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:55]=3)=[N:61]2)=[CH:66][C:65]=1[O:87][CH2:88][CH2:89][O:90][CH3:91]
Reactant: O=C(O)CN1CCOCC1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(N)c3)nc2cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-morpholinoacetic acid (0.034 g, 0.24 mmol), DIEA (0.165 mL, 0.94 mmol) and PyBOP® (0.125 g, 0.24 mmol) in CH2Cl2 (1 mL) was stirred at RT for 10 minutes, upon which it was added to a solution of tert-Butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.260 g, 0.47 mmol) in CH2Cl2 (10 mL). the subsequent was stirred at RT for 1 hr upon which further aliquots of 2-morpholinoacetic acid (0.034 g, 0.24 mmol) and PyBOP® (0.125 g, 0.24 mmol) were added. The resulting mixture was stirred at RT overnight upon which the mixture was concentrated in vacuo and taken directly to the next step. HPLC retention time 5.35 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1.Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:26]([CH3:28])[CH3:27])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:20]([CH3:25])[CH:19]=2)=[O:17])[N:13]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)cc1C
Yield: 102.2 %

Procedure:
In methyl ethyl ketone (10 mL) were suspended the obtained 3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (209 mg, 0.50 mmol), ethyl 2-bromo-2-methylpropionate (489 mg, 2.50 mmol), and potassium carbonate (346 mg, 2.50 mmol). The suspension was refluxed for 40 hours. The suspension was then allowed to room temperature, filtered to remove insolubles, and washed with methyl ethyl ketone. The solvent was distilled off. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (7/1) to give the desired compound (272 mg) as colorless oil (quantitative yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[CH:9][C:8](O)=[C:7]([C:12]#[N:13])[C:6]2=[O:14])[CH2:3][CH2:2]1.O(Br)[Br:16].[P+3]>CN(C=O)C>[Br:16][C:8]1[CH:9]=[CH:10][N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6](=[O:14])[C:7]=1[C:12]#[N:13]
Reactant: N#Cc1c(O)ccn(CC2CC2)c1=O
Reactant: BrOBr
Agent: [P+3]
Solvent: CN(C)C=O
Product: N#Cc1c(Br)ccn(CC2CC2)c1=O
Temperature: 110 °C
Yield: 63.8 %

Procedure:
To a solution of intermediate 5 (10.4 g, 54.67 mmol) in DMF (250 ml) was added phosphorus(III) oxybromide (31.3 g, 109.3 mmol) and the mixture was heated at 110° C. for 1.5 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over MgSO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 8 (8.83 g, 64%).
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]#[CH:23]>C(O)C.O>[CH2:23]([O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][N:5]=[C:4]2[CH2:3][C@H:2]([OH:1])[CH3:14])[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: C[C@@H](O)Cc1n[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2[nH]nc(C[C@@H](C)O)c2c1
Temperature: 75 °C
Yield: 69.5 %

Procedure:
To a stirred mixture of the product from Step A (1.50 g, 7.81 mmol) in a mixture of ethanol in water (50 mL/10 mL) was added potassium carbonate (1.62 g, 11.7 mmol) and propargyl bromide (80% in toluene, 1.74 g, 1.30 mL, 11.7 mmol). The mixture was heated at 75° C. for 2 hours under nitrogen, evaporated to dryness, mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate. Chromatography on silica (gradient, 25% to 95% ethyl acetate in hexane) gave an oil (1.25 g, 69%): LC/MS (+APCI) m/z 231 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12]Br)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15]([NH2:18])(=[S:17])[CH3:16]>C(O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:18]=[C:15]([CH3:16])[S:17][CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(CBr)c1ccc(O)c(C(=O)O)c1
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc(-c2ccc(O)c(C(=O)O)c2)cs1
Yield: 86.3 %

Procedure:
A solution of 53 g (0.2 mol) of 2-hydroxy-5-(α-bromoacetyl) benzoic acid in 250 ml of slightly warm ethanol was dropped, for 15 minutes, in a solution of 15 g (0.2 mol) of thioacetamide in 60 ml of ethanol, while stirring vigorously. The reaction was slightly exothermic, and a white product gradually precipitated. Stirring was maintained for one hour, then the reaction mixture was diluted with 500 ml of water. The precipitate was filtered off, washed with water and the product was recrystallized from ethanol. 40.6 g of 2-hydroxy 5-(2-methyl thiazol-4-yl) benzoic acid, M.P. (K.B.) 250°-253° C, were obtained (yield 83%). A second yield of product was obtained by concentration of the ethanolic mother liquors. 3.1 g (0.0425 mol) of diethylamine was added to a suspension of 10 g (0.0425 mol) of the acid prepared above in 50 ml of ethanol. The mixture was stirred for 30 minutes then concentrated to dryness. The residue was recrystallized from benzene. 10.3 g of diethylammonium 2-hydroxy-5-(2-methyl thiazol-4-yl) benzoate are obtained, M.P. (M.K.) 128°-132° C with progressive recrystallization and second M.P. 249°-250° C (yield 78 %).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:48][O:49][C:50](=[O:55])[C:51]([NH2:54])([CH3:53])[CH3:52]>CN(C=O)C>[CH3:48][O:49][C:50](=[O:55])[C:51]([NH:54][C:13]([C:4]1[CH:3]=[C:2]([Br:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12])=[O:15])([CH3:53])[CH3:52]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cc(Br)c2ccccc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1cc(Br)c2ccccc2c1O
Reaction time: 24 h
Yield: 70.2 %

Procedure:
To a solution of 1.5 g 4-bromo-1-hydroxy-2-naphthoic acid in 20 ml abs. DMF under inert atmosphere 0.84 g 1-hydroxybenzotriazole, 1.18 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.1 ml of N,N-diisopropylethylamine were added. After 15 minutes 0.86 g of 2-amino-2-methyl-propionic acid methyl ester hydrochloride, followed by 1.1 ml of N,N-diisopropylethylamine were added. After 24 h at room temperature and 2 h at 50° C. the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 1.44 g of 2-[(4-bromo-1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.