Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19]O>>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:19][CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1
Reactant: O=c1[nH]ncc2scc(Br)c12
Reactant: OCCc1ccccn1
Product: O=c1c2c(Br)csc2cnn1CCc1ccccn1
Yield: 76.3 %

Procedure:
The title compound was prepared in analogy to the process described in Example 3.4 starting from 3-bromo-5H-thieno[2,3-d]-pyridazin-4-one and 2-pyridin-2-yl-ethanol. Yield: 76.3%.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[K+].[C:14](=[O:16])=[O:15]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 185 °C
Yield: 30 %

Procedure:
p-Acetaminophenol 15 g, and potassium hydroxide 60 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 2.0 MPa and heated to 185° C., maintained for 14 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the yield is 30%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)([C:14]([NH2:23])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccccn2)CC1

Procedure:
Prepare by the method of example 20.8 using 1-tert-butoxycarbonyl-4-(pyridin-2-yl)-piperidine-4-carboxylic acid (4 mmol) and NH3 (gas). Purify to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[C:1]([NH:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([O:13][CH2:22][CH3:23])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)Nc1ccc(OC(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Yield: 80 %

Procedure:
To a solution of 2-(4-acetamidophenoxy)propionic acid (0.5 g, 2.2 mmol) in ethanol (10 mL) is added a drop of concentrated sulfuric acid and refluxed for 4 hours. The reaction is concentrated to dryness to give a residue. The residue is partitioned between water and ethyl acetate. The ethyl acetate layer is collected, dried (MgSO4), and concentrated to give ethyl 2-(4-acetamidophenoxy)propanoate (0.44 g) (yield 80%): 1H NMR (CDCl3) delta 1.27 (t, J=7.0 Hz, 3H), 1.60 (d, J=7.0 Hz, 3H), 4.25 (q, J=7.0 Hz, 2H), 4.76 (q, J=7.0 Hz, 1H), 6.84 and 7.46 (dd, J=9.0 Hz, 4H), and 8.02 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.O.NN.Cl>C(O)COCCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCCC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: CCCCCc1ccc(Br)cc1
Temperature: 200 °C

Procedure:
A mixture of compound 15 (24.87 g, 0.103 mol), hydrazine hydrate (15.45 g, 55% hydrazine content), and diethylene glycol (200 ml), was heated at 130° to 160° C. for 1 hour and water and the excess of hydrazine hydrate were distilled off. The solution was cooled to below 60° C. and potassium hydroxide pellets (17.37 g, 0.309 mol) were added and the solution heated at 200° C. for 2 hours (glc analysis revealed a complete reaction) cooled, and poured into crushed ice (200 g) and hydrochloric acid (200 ml, 6M). The product was extracted into ether (2×200 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was distilled to give a colourless liquid.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]4[C:18]([CH3:21])=[N:19][N:20]=[C:13]4[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=[C:9]2[C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=CC=1.FC(F)(F)C(O)=O>>[CH3:21][C:18]1[N:14]2[C:15](=[O:17])[C:16]3[NH:8][C:9]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[N:10][C:11]=3[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]2=[N:20][N:19]=1
Reactant: CCCCCn1c2nc(-c3nccs3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Solvent: O=C(O)C(F)(F)F
Product: CCCCCn1c2nc(-c3nccs3)[nH]c2c(=O)n2c(C)nnc12
Temperature: 55 °C
Reaction time: 8 h

Procedure:
The mixture of 6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1,3-thiazol-2-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.22 mmol) in trifluoroacetic acid (5 mL, 65 mmol) was stirred at 55° C. overnight. The reaction solution was concentrated and purified using preparative LCMS to yield the desired product. LCMS calculated for C15H18N7OS: 344.1; found: 344.1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([N:11]=[C:12]=[O:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH:17][CH2:18][CH:19]=[O:20])[C:15]#[CH:16]>C1C=CC=CC=1>[CH2:14]([N:17]([CH2:18][CH:19]=[O:20])[C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1)=[O:13])[C:15]#[CH:16]
Reactant: O=C=Nc1nc2cccc(Br)c2s1
Reactant: C#CCNCC=O
Solvent: c1ccccc1
Product: C#CCN(CC=O)C(=O)Nc1nc2cccc(Br)c2s1
Reaction time: 1 h

Procedure:
7-Bromobenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-propargylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(7-bromobenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[O:31]=[S:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3)CC2)nc1C
Yield: 81.7 %

Procedure:
Using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (218 mg) described in Preparation Example 120 and [1,2]thiazinane 1,1-dioxide (68 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (181 mg) was obtained.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]#[N:22].C[O-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[C:21]=1[NH2:22]
Reactant: COc1ccc(N=[N+]=[N-])cc1
Reactant: N#CCc1ccc(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(F)cc3Cl)c2N)cc1
Temperature: 0 °C
Yield: 66.4 %

Procedure:
To a stirred and ice-cooled solution of 1-azido-4-methoxy-benzene (1.000 g, 6.7046 mmol) and 2-chloro-4-fluoro phenyl acetonitrile (1.758 g, 10.0569 mmol) in absolute ethanol (15 ml), an ice-cooled solution of sodium methoxide (0.435 g, 8.0455 mmol) in absolute ethanol (10 ml) is added drop-wise. The resulting reaction mixture is evaporated and the residue is dissolved in methylene chloride and washed with water, brine, dried over MgSO4, filtered and evaporated to afford ˜2.2 g of crude material as brownish solid. This material is purified by crystallization from methylene chloride and petroleum ether, to obtain the title compound as yellowish solid (1.42 g, 66% yield). M.p. 175-176.8° C. LC-ESI-HRMS of [M+H]+ shows 319.0745 Da. Calc. 319.076192 Da, dev. −5.3 ppm.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1.[CH3:14][CH2:15][O-:16].[Na+]>CCO>[CH2:15]([O:16][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1)[CH3:14]
Reactant: CC[O-]
Reactant: Oc1nc(Cl)nc2ccc(I)cc12
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(O)c2cc(I)ccc2n1
Temperature: 20 °C
Yield: 84.2 %

Procedure:
2-Chloro-6-iodoquinazolin-4-ol (3.5 g, 11.42 mmol) was suspended in EtOH and treated with an ethanolic solution of NaOEt (21%, 12.8 ml, 34.3 mmol). The mixture was irradiated at 150° C. in a microwave for 2 h, then was cooled to 20° C. The precipitated product was collected by filtration, and washed with aqueous HCl (1 N) and water. After drying under vacuum, the title compound (3.04 g, 84%) was obtained as a yellow solid. LCMS (ES+) m/z 317 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH3:14]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH3:14])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCn1ccc([N+](=O)[O-])n1
Yield: 66.6 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (37 mg, 0.93 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 10 min, the 1-bromo-propane (91 μL, 1.00 mmol) was added. The mixture was continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-propyl-1H-pyrazole (92 mg, 67%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ0.89 (3H, t, J=7.6 Hz), 1.90 (2H, sextet, J=7.2 Hz), 6.82 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=2.4 Hz).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:16])[CH:12]=2)[O:7][CH2:6]1)C.Cl.[NH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])N.C(O)(=O)C>C(O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:18]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:16])[CH:10]=[CH:9][C:8]=3[O:7][CH2:6][C:5]=2[CH:4]=[N:2]1)[CH3:25]
Reactant: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CO2
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cn1ncc2c1-c1cc(C)ccc1OC2
Yield: 40 %

Procedure:
A solution of crude 3-Dimethylaminomethylene-6-methyl-chroman-4-one b (1.34 g, 6.16 mmol), ethyl hydrazinoacetate hydrochloride (0.95 g, 6.16 mmol), and a catalytic amount of acetic acid were heated at refluxed in absolute ethanol (10 mL) for overnight. The reaction mixture was concentrated and the residue was purified by column chromatography to get the pure compound c (675 mg; 40% yield, for two steps): LC MS (Method B): 273 (M+1); 1H NMR (400 MHz, CDCl3/TMS):δ 7.37 (s, 1H), 7.02-7.01 (m, 2H), 6.90 (d. J=8.5 Hz, 1H), 5.20 (s, 2H), 5.15 (s, 2H), 4.22 (q, J=7.6 Hz, 2H), 2.36 (s, 3H), 1.22 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][C:12]2=[O:22])[N:4]=1.CN1C=CN=C1.[F:29][CH:30]([F:35])[S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[F:29][CH:30]([F:35])[S:31]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:22])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1nc(OC)nc(C2C(=O)Nc3c(F)cc(F)cc32)n1
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3c(F)cc(F)cc32)n1

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5,7-difluoro-1,3-dihydro-2H-indol-2-one (1.0 g), 1-methyl-1H-imidazole (0.74 g) and difluoromethanesulfonyl chloride (1.09 g) are reacted in 8 ml of dichloromethane analogously to Example 5. For the work-up, water is added and stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 97% (1.08 g, 82% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [CH:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][Mg]Cl)=[CH:10][CH:9]=1.Cl>CCOCC>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][CH:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:10][CH:9]=1
Reactant: Cl[Mg]Cc1ccc(Cl)cc1
Reactant: CC(C)(C)C=O
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)C(O)Cc1ccc(Cl)cc1
Yield: 98.7 %

Procedure:
A 10 ml quantity of ether solution of 4.3 g of (0.05 mole) of pivalaldehyde was added dropwise to a solution of p-chlorobenzylmagnesium chloride (0.055 mole) in 100 ml of ether with cooling and stirring. The mixture was thereafter stirred at room temperature for 1 hour and then placed into 5% aqueous solution of hydrochloride acid containing pieces of ice. After separating off the oily layer, the aqueous layer was subjected to extraction with ether. The ethereal extract and the oily layer were combined together, washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and distilled to remove the solvent, affording 10.5 g of the above-identified desired compound in the form of a white solid.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:8]2C=[CH:12][C:11](C(O)=O)=[CH:10][CH:9]=2)C=[CH:6][CH:7]=1.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cc1cccc(-c2ccc(C(=O)O)cc2)c1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCOC(=O)c1ccc(Br)cc1

Procedure:
Preparation of 3′-methyl-4-biphenylcarboxylic acid with OXO-C10 alcohols (NGP-87): Decyl 4-bromobenzoate was Prepared from the Condensation of 4-bromobenzoic acid and OXO-C10 alcohols by Refluxing in Benzene with Water Removal via a Dean-Stark Trap
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[C:29](OC(=O)C)(=[O:31])[CH3:30].CCN(CC)CC>CC#N>[C:29]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([CH2:18][N:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])=[C:2]([Cl:1])[C:3]3=[O:28])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1)(=[O:31])[CH3:30]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2[nH]ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)n1ccc2cc(Cn3ccc(OCc4ccc(F)cc4F)c(Cl)c3=O)ccc21
Temperature: 86 °C
Reaction time: 6 h

Procedure:
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one (Step 5, synthesis of Example 86) (0.22 g, 0.57 mmol) in CH3CN (10 mL) was added acetic anhydride (0.06 mL, 0.58 mmol) and Et3N (2 mL), and the reaction mixture was stirred at 86° C. for 6 h. The reaction mixture was cooled to room temperature, and partitioned between 1 N HCl and EtOAc. The organic solution was separated, washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, MeOD) δ 8.35 (d, J=9 Hz, 1H), 7.77 (d, J=9 Hz, 1H), 7.70 (d, J=3 Hz, 1H), 7.54 (s, 2H), 7.31 (d, J=9 Hz, 1H), 7.01-6.99 (m, 2H), 6.66 (d, J=3 Hz, 1H), 6.59 (d, J=9 Hz, 1H), 5.29 (s, 4H), 2.63 (s, 3H). ES HRMS m/z 443.0965 (M+H C23H18ClF2N2O3 requires 443.0969).
Reaction SMILES: [NH2:1][CH:2]([P:7]([OH:10])(=[O:9])[OH:8])[P:3]([OH:6])(=[O:5])[OH:4].[OH-].[Na+].[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15].Cl>O>[C:13]([CH2:14][CH2:15][NH:1][CH:2]([P:7]([OH:10])(=[O:8])[OH:9])[P:3]([OH:6])(=[O:4])[OH:5])([OH:17])=[O:16]
Reactant: NC(P(=O)(O)O)P(=O)(O)O
Reactant: C=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNC(P(=O)(O)O)P(=O)(O)O
Reaction time: 0.5 h
Yield: 78 %

Procedure:
47.8 g. of aminomethane diphosphonic acid and 50 g. of sodium hydroxide are dissolved in 200 cc. of water. 19 g. Of acrylic acid dissolved in 50 cc. of water are added drop by drop thereto at a temperature between 20° C. and 40° C. while stirring vigorously. After the acrylic acid solution has been added, the reaction mixture is kept at a temperature of 90° C. for 30 minutes and is then neutralized with dilute hydrochloric acid. The neutralized solution is passed through a cation exchange agent and the resulting solution is concentrated by evaporation. After allowing the concentrated solution to stand for several days, N-(2-carboxy ethyl) amino methane diphosphonic acid is obtained in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#N)=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.S(=O)(=O)(O)[OH:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:23])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Cl)nc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a cooled (5° C.), stirred solution of 2-chloro-5-cyanopyridine (25.0 g) in anhydrous toluene (540 mL) was added a 1 M solution of diisobutylaluminum hydride (189 mL) over a 30-min period. The resulting red-colored solution was treated with methanol (50 mL) and 2M sulfuric acid (150 mL), sequentially. The resulting biphasic solution was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The organic phase was stirred over activated charcoal for 20 min, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 23.5 g of the title compound (I-2a) as a light-yellow colored solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=2)=[CH:4][C:5]([C@@:9]2([CH2:48][C:49]([CH3:51])=[CH2:50])[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:66]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=2)=[CH:4][C:5]([C@:9]2([CH2:48][C:49]3([CH3:51])[CH2:50][O:66]3)[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc([C@@]3(CC4(C)CO4)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 25 (52 mg, 63 μmol) in anhydrous DCM (1 mL) was added 3-chlorobenzoperoxoic acid (21 mg, 95 μmol, 1.2 equiv). The reaction was stirred overnight, directly loaded onto a preparatory TLC plate, and eluted with 15% EtOAc in petroleum ether to give 50 (41 mg, 77% yield). LC/MS m/z 862 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[NH:30][CH2:31][CH2:32][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2C(CCN2C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2NCCC2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a mixture of tert-butyl 5-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.64 g) in the mixture solvent of CH2Cl2 and MeOH was added a solution of HCl in EtOAC (30 mL). The reaction mixture was stirred at room temperature for another 4 h and filtered to give the title compound as a solid (0.33 g, 62.00%), HPLC: 98.69%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.45 (m, 2H), 1.78 (m, 3H), 1.80 (m, 2H), 2.10 (m, 1H), 2.42 (m, 5H), 2.72 (m, 3H), 4.03 (s, 3H), 4.10 (m, 2H), 6.76 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 8.54 (s, 1H) ppm.
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].O>COCCOC>[C:18]([C:17]1[O:22][C:7](=[NH:8])[N:6]([CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: N#CNCC1CCC1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cn(CC2CCC2)c(=N)o1
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of N-(cyclobutylmethyl)cyanamide (0.40 g, 3.6 mmol), cesium carbonate (2.4 g, 7.3 mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.50 mL, 3.6 mmol, Aldrich) in 1,2-dimethoxyethane (20 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to provide the title compound (0.6 g). LCMS (APCI+) m/z 209 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:24][NH:25][O:26][CH3:27].N1C=CC=CC=1>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH3:24])[O:26][CH3:27])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
16.25 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.05 mol) and 5.36 g of N,O-dimethyl hydroxylamine hydrochloride (0.055 mol, 1.1 eq) are dissolved in 100 mL of dichloromethane. The reaction mixture is cooled to 0° C. and 9.25 g of pyridine (0.11 mol, 2.2 eq) is added. The mixture is heated to room temperature and it is stirred for 1 hour. The solvent is evaporated in vacuum and 30 mL of brine and 30 mL of dichloromethane are added to the residue. After 15 min stirring the phases are separated and the organic phase is dried on sodium sulfate, the solvent is evaporated and the residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 11.9 g of the title compound (VIc) (68%) as a brown solid.