Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38])[CH3:33].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:38][CH2:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:39])=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COC)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a mixture of 4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methyl}amino)benzoic acid (200 mg) synthesized above, β-alanine ethyl ester hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (112 mg), triethylamine (203 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (207 mg, 83%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:27])=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:30][CH2:31][CH3:32])[C:12]=1[OH:33])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([NH:23][C:22]1[C:24]([CH3:27])=[CH:25][CH:26]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:28]=[CH:29][C:11]([C:8](=[O:10])[CH3:9])=[C:12]([OH:33])[C:13]=2[CH2:30][CH2:31][CH3:32])[CH:21]=1)=[O:5]
Reactant: COC(=O)C(=O)Cl
Reactant: CCCc1c(OCCCOc2ccc(C)c(N)c2)ccc(C(C)=O)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2ccc(C)c(NC(=O)C(=O)OC)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 1.9 ml (21 mmol) of chloro-oxalic acid methyl ester in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 7.5 g (21 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-6-methylaniline and 3.0 g (21 mmol) of triethylamine in 60 ml of methylene chloride. The reaction mixture is stirred for 90 minutes at room temperature, is poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-6-methylphenyl}-oxamic acid methyl ester having a melting point of 125°-127°.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:25][O:26][NH2:27]>O>[CH3:25][O:26][N:27]=[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON
Reactant: O=C(COCc1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=C(COCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To 50 ml of pyridine were added 0.0434 mole (9.77 g) of 2-benzyloxyacetophenone prepared in the first and second paragraphs in Referential Example 1 (Table 1, No. 1) and 4.35 g (0.0521 mole) of O-methylhydroxylamine hydrochloride. The mixture was stirred at room temperature for 2 hours and then at 100° C. for 1 hour. The reaction liquid was cooled down to room temperature, 300 ml of water was added thereto, and the oil layer was separated off. The aqueous layer was extracted with chloroform and the extract was combined with said oil layer, washed with water, dried and distilled under reduced pressure to obtain 10.77 g of 2-benzyloxyacetophenone O-methyloxime.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2OC)CCC(NCCO)CC3)ncc1Cl
Yield: 38 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine were combined to yield 2-{2-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino}-ethanol (146.19 mg, 38% yield) as a beige foam. 1H-NMR (CDCl3) δ 8.25 (d, J=7.5 Hz, 1H), 8.03 (m, 2H), 7.54 (s, 1H), 7.37 (s, 1H), 6.83 (d, J=6.9 Hz, 1H), 6.54 (m, 2H), 3.91 (br s, 6H), 3.72 (s, 3H), 3.63 (s, 2H), 3.17 (m, 5H), 2.85 (m, 4H), 2.68 (m, 1H), 2.47 (m, 1H), 2.14 (m, 2H), 1.31 (m, 3H). LC/MS (ESI+)=569 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)=[O:23])[N:21]=2)[CH:18]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3-(trifluoromethyl)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6](N)=[N:5][CH:4]=1.[C:9]([Cu])#[N:10]>>[CH3:1][O:2][C:3]1[S:7][C:6]([C:9]#[N:10])=[N:5][CH:4]=1
Reactant: COc1cnc(N)s1
Reactant: N#C[Cu]
Product: COc1cnc(C#N)s1
Yield: 30 %

Procedure:
5-methoxythiazol-2-amine (2.6 g, 20 mmol) was reacted with CuCN (4 g, 44 mmol) according to the procedure as described in Example 61, Step A to give the title compound as brownish oil (0.84 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)c(N)c1
Yield: 96.9 %

Procedure:
To a solution of 3-nitro-4-hydroxybenzonitrile (3.28 g, 20 mmol) in ethyl acetate was hydrogenated over 5% Pd/C, at an initial pressure 20 psi in a Parr shaker. After 3 h the reaction mixture was filtered (Celite). The solvent was removed under reduced pressure and the residue oil 3-Amino-4-hydroxybenzonitrile (2.6 g, 97% yield) used in the next step without further purification: 1H NMR (400 MHz; DMSO-D6): 6.85 (m, 2H); 6.73 (d, 1H); 5.0 (br s, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)=[O:39])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Product: Cc1ccc(NC(=O)Nc2nc3nc(NCCCN4CCN(C)CC4)ncc3cc2-c2c(Cl)cccc2Cl)cc1

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 36 was reacted with 0.29 g of 4-tolyl isocyanate according to the general procedure of Example 37 to give 0.9492 g of the title compound. ESMS (20/80 MeOH/CH3CN+0.1% ACOH): M+ +H=579;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[C:17](Cl)(Cl)=[O:18]>>[C:4]1([N:1]=[C:17]=[O:18])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=C(Cl)Cl
Solvent: Nc1ccccc1
Product: O=C=Nc1ccccc1

Procedure:
The process of claim 18 in which the nitrobenzene is converted to an aniline compound and then reacted with phosgene to form a phenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:30]2[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=2)=[C:4]([F:14])[CH:3]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
617 mg (2.82 mmol) of the compound from Example 156A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT overnight, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 155 mg (14% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[CH:1]1([C:4]([C:31]2[C:30]3[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=3)[NH:33][CH:32]=2)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: COc1ccc(C(C)(O)C2CC2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)(c2c[nH]c3c(CSC)cccc23)C2CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.48 mmol) of the compound from Example 140A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 84 mg (0.48 mmol) of the compound from Example 8A in 2.5 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified directly by preparative HPLC (mobile phase: acetonitrile/water gradient). 63 mg (361% of theory) of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[C:8]([NH:12][C:13]1[N:14]=[C:15]2[CH2:37][CH2:36][NH:35][CH2:34][C:16]2=[N:17][C:18]=1[N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[CH2:21][CH2:20]1)([CH3:11])([CH3:10])[CH3:9].[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:8]([NH:12][C:13]1[N:14]=[C:15]2[CH2:37][CH2:36][N:35]([C:40]([N:39]([CH3:43])[CH3:38])=[O:41])[CH2:34][C:16]2=[N:17][C:18]=1[N:19]1[CH2:20][CH2:21][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[CH2:23][CH2:24]1)([CH3:11])([CH3:9])[CH3:10].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N1CCc2nc(NC(C)(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1

Procedure:
A solution of N-(tert-butyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (16 mg, 0.030 mmol), dimethylcarbamic chloride (3.2 mg, 0.030 mmol), and DIPEA (5.3 μL, 0.030 mmol) in DCM (151 μL) was stirred at room temperature overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (10 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4) δ ppm 1.48 (s, 9H), 1.87-1.97 (m, 2H), 2.07-2.17 (m, 2H), 2.82 (t, J=5.9 Hz, 2H), 2.90 (s, 6H), 2.95 (ddd, J=12.2, 8.5, 3.3 Hz, 2H), 3.29-3.35 (m, 2H), 3.53 (t, J=5.8 Hz, 2H), 4.25 (s, 2H), 4.46 (tt, J=7.5, 3.8 Hz, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+489.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2cccnc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Methyl 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoate (231 mg, 0.5286 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10 ml) and 1,4-dioxane (10 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (170 mg, 0.4018 mmol, 76%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:7])(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:16]1[C:12]2[CH:13]=[N:14][S:15][C:11]=2[CH:10]=[CH:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-5-carboxylic acid tert-butyl ester (445 mg, 0.95 mmoL) in DCM (20 mL) was added water (0.1 mL), the mixture cooled to 0° C. and TFA (20 mL) added. The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo and the residue azeotroped with toluene (×2) to give the title compound as a beige solid (392 mg, 100%). LCMS (Method B): RT=3.97 min, [M+H]+=415.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10]COC.C(O)(=O)C.S(=O)(=O)(O)O>O>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:5][C:4]=1[CH2:3][CH2:2][OH:1]
Reactant: COCOc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1CCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)c(CCO)c3)nc2c1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol), 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol), sodium hydrogensulfite (0.146 g, 1:4 mmol) and p-toluenesulfonic acid (0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure. Water (70 mL) was added to obtain a solid. The yellow solid was filtered off, washed with water and dried under vacuum to provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which was used as such in the next step. A solution of 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.18 g), 50% acetic acid solution (4 mL) and catalytic amount of concentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h. After cooling to room temperature the reaction mixture was diluted with water (30 mL) to obtain a solid. The solid was filtered off, washed with water and dried under high vacuum to provide crude solid (0.135 g, 85%). The crude was purified by flash column chromatography to give pure 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP 249-250.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])N.N([O-])=O.[Na+].[BrH:18]>C(O)(=O)C.S(=O)(=O)(O)O.O.[Cu]Br>[Cl:1][C:2]1[CH:3]=[C:4]([Br:18])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: Br
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc(Br)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro4-trifluoromethoxyaniline (5.1 g) in acetic acid (31 ml) was stirred and treated with sodium nitrite (2.16 g) in concentrated sulphuric acid (14 ml) at below 18° C. After an additional 1 hour at 10° C., the solution was added to a mixture of copper (I) bromide (7.7 g) and hydrobromic acid (24.5 ml) in water at 40-50° C. The reaction was completed by heating at 50° C. for 2 hours, water was added and the mixture filtered. The filtrate was extracted with ether, washed with sodium bicarbonate, dried (magnesium sulphate) and evaporated to give 3-chloro-4-trifluoromethoxy-bromobenzene (6.05 g) as a brown oil, NMR (CDCl3) 7.10(m,1H), 7.35(m,1H), 7.55(d,1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>CN(C=O)C.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)ccc1Cl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Cl)ccc1-n1cncn1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
To a solution of 2,5-dichlorobenzonitrile (10 g, 58.1 mmol) in DMF (100 ml) is added cesium carbonate (22.7 g, 69.8 mmol) and 1,2,4-triazole (4.8 g, 69.8 mmol) and the reaction mixture is stirred at 65° C. for 5.5 h, at 75° C. for 16 h, at 85° C. for 7 h. More 1,2,4-triazole (5 g) is added and the reaction mixture is stirred at 85° C. for 18 h and at 100° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The combined organic layer is washed with aqueous LiCl, dried on sodium sulfate, concentrated in vacuo to give 5-Chloro-2-[1,2,4]triazol-1-yl-benzonitrile as a white solid which is used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][C:2]1[C:1](=[O:10])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C=Cc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(Br)=Cc2ccccc21

Procedure:
The indenone compound of formula 16 prepared in Step 3 is dissolved in CCl4, N-bromosuccinimide (1 to 1.2 eq) and 2,2′-azobisisobutyronitrile (10 to 15 wt %) are added thereto. The resulting mixture is allowed to reflux for 2 to 3 h with stirring, to obtain the 2-bromoindenone of formula 17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])=[CH:4][CH:3]=1.C[Si]([C:20]#[N:21])(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]#[N:21])[CH:11]=[CH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc[n+]([O-])c1-c1ccc(F)cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)nc1-c1ccc(F)cc1
Yield: 66.7 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-methylpyridine 1-oxide (24 g, 0.118 mol) in tetrahydrofuran (200 mL) were added trimethylsilyl cyanide (19.2 mL, 0.153 mol) and dimethylcarbamoyl chloride (14.1 mL, 0.153 mmol), and the mixture was heated under reflux for 2 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (16.7 g, 67%) as a white solid. Under reduced pressure, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9) to give the title compound (3.0 g, 12%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([O:11][CH3:12])[CH:4]=1)#[N:2].Cl.[C:14]([O:18][C:19](=[O:23])[CH2:20][NH:21][CH3:22])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:21]([CH3:22])[CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23])=[C:5]([O:11][CH3:12])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1CBr
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Product: COc1cc(C#N)ccc1CN(C)CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyano-2-methoxybenzyl bromide (Carbocore) and sarcosine tert-butyl ester hydrochloride. It was isolated as a colorless oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.53 (d, J=7.7 Hz, 1H), 7.45-7.40 (m, 2H), 3.83 (s, 3H), 3.69 (s, 2H), 3.20 (s, 2H), 2.27 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 291.0 (M+H)+. HPLC (Method A) Rt 2.52 min (Purity: 93.5%).