Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][C:33]2=[O:38])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][C:33]2=[O:38])=[CH:39][CH:40]=1
Reactant: O=C1COCCN1CCCOc1ccc(Br)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4=O)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 36.3 %

Procedure:
A mixture of of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.311 mmol), 4-(3-(4-bromophenoxy)propyl)morpholin-3-one (100 mg, 0.373 mmol), 2 N potassium carbonate (0.5 mL, 2 mmol), and Pd(dppf)Cl2 (30 mg, 0.03 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by preparative TLC to give the title compound (50 mg, 50% yield) as a white solid.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][NH:20][C@H:21]1[CH2:40][N:25]2[C:26]3[C:31]([C:32]([CH2:33][C:34]([O:36]CCC)=[O:35])=[C:24]2[CH2:23][CH2:22]1)=[CH:30][CH:29]=[CH:28][CH:27]=3>>[CH3:19][N:20]([C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:11]=1)[C@H:21]1[CH2:40][N:25]2[C:26]3[C:31]([C:32]([CH2:33][C:34]([OH:36])=[O:35])=[C:24]2[CH2:23][CH2:22]1)=[CH:30][CH:29]=[CH:28][CH:27]=3
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 3-(piperidin-1-ylsulfonyl)benzoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 510.
Reaction SMILES: [CH3:1][C:2]1[S:26][C:5]2=[N:6][C:7]([CH3:25])=[C:8]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20]C)=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[CH:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[S:26][C:5]2=[N:6][C:7]([CH3:25])=[C:8]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([OH:20])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[CH:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of methyl 2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.135 g; 0.367 mmol) in methanol (8 mL) and ethanol (4 mL) was added a 5% sodium hydroxide solution (10.5 mL; 13.125 mmol). The reaction mixture was heated under reflux for 4.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.107 g (82%) of the title compound as a white powder.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[CH:23][C:22]([F:26])=[C:21]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:32])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[CH:23][C:22]([F:26])=[C:21]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:32]
Reactant: CCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN=[N+]=[N-])c(F)c3)cc(=O)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
438 mg (0.984 mmol) of the above 2-[4-(3-azidopropylamino)-3-fluorophenyl]-5-butylamino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 25 mL of tetrahydrofuran, 389 mg (1.48mmol) of triphenylphosphine was added under ice-cooling and the mixture was stirred at room temperature for 1 hour. 25 mL of water was added thereto and the mixture was further stirred for 5.5 hours. The mixture was extracted twice with ethyl acetate, and the organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=9:1:1) to give 380 mg of Compound 126 (yield: 92%), which was converted to hydrochloride according to the conventional method.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][C:13]([N:20]([CH3:22])[CH3:21])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][NH2:15].[OH-].[Na+]>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:15][CH2:14][C:13]([CH3:12])([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCCCC(C)(CN)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCC(C)(CNC(=O)c1ccc(Cl)c(Cl)c1)N(C)C

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (2.1 g.,) in dry benzene (25 ml.) was added to a solution of 2-methyl-2-dimethylamino-hexylamine (1.58 g.,) in dry benzene (25 ml.) and the mixture heated under reflux for 1.5 hrs.. The mixture was diluted with water, basified with 2N sodium hydroxide solution, and extracted with benzene (4 × 100 ml.). The combined benzene extracts were washed with water (4 × 50 ml.), dried (Na2SO4) and evaporated affording 3,4-dichloro-N-[2-methyl-2-dimethylamino-hexyl]benzamide as a colourless oil (3.6 g., ca 100%) which slowly crystallised.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:14][C:13]=1[CH:25]=[O:26].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:25]([OH:26])[C:13]3[CH:14]=[C:15]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])[CH:16]=[CH:17][C:12]=3[F:11])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 170.0 mg, 0.86 mmol) in methanol (7.0 mL) were added propane-1-sulfonic acid (4-fluoro-3-formyl-phenyl)-amide (672, 220.0 mg, 0.90 mmol) and potassium hydroxide (0.50 g, 0.0089 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water, acidified with 1N HCl to pH=5, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in methylene chloride to give the compound (673, 55.0 mg, 14.0%). MS (ESI) [M+H+]+=442.1, 444.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:46]1([CH2:51][C@@H:52]2[CH2:56][CH2:55][CH2:54][NH:53]2)[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O>[N:46]1([CH2:51][CH:52]2[CH2:56][CH2:55][CH2:54][N:53]2[CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[N:13]=[C:12]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCN4CCCC4CN4CCCC4)cccc32)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and (S)-(+)-2-(pyrroldin-1-ylmethyl)pyrrolidine (28.7 mg, 0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: [Br-].[Na+].C(N(CC)CC)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH3:28][N:29]([CH3:32])[CH:30]=[O:31]>>[C:10]([O:14][C:15]([NH:17][CH2:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]1)=[O:16])([CH3:13])([CH3:11])[CH3:12].[C:10]([O:14][C:15]([NH:17][CH2:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]1)=[O:16])([CH3:13])([CH3:11])[CH3:12].[OH:14][CH:15]([OH:16])[C:30]([N:29]([CH3:32])[CH3:28])=[O:31]
Reactant: CN(C)C=O
Agent: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Br-]
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(O)O
Reaction time: 4 h

Procedure:
Sodium bromide (10.2 g; 0.1 mol) and 1,1-dichloro-N,N-dimethylacetamide (7.8 g; 0.05 mol) was added to dry dimethylformamide (100 ml) and the mixture was stirred for 4 h. Triethylamine (20.7 g; 0.2 mol) and trans-4-(tert.-butyloxycarbonylaminomethyl)cyclohexanecarboxylic acid (25.7 g; 0.1 mol) dissolved in dimethylformamide was added. The mixture was stirred for 84 h at 50° C. The solvent was evaporated and the residue was taken up into diethylether and washed, dried and evaporated. The oily residue was stirred with pentane. Yield 7 g, m.p. 110° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH3:6][CH:5]([CH3:7])[CH2:4][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:2]=[O:1]
Reactant: CC(C)CC(CO)NC(=O)OC(C)(C)C
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CC(C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (2.7 g) in DMSO (60 mL) was added 2-iodoxybenzoic acid (3.5 g), and the mixture was stirred at room temperature for 3 hr. Water was added thereto, the resulting insoluble matter was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After the dessicant was filtered off, the filtrate was concentrated under reduced pressure to afford a crude product of tert-butyl (4-methyl-1-oxopentan-2-yl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:16]([P:19](Cl)(Cl)=[O:20])([CH3:18])[CH3:17]>>[CH:16]([P:19]1(=[O:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: Cc1cccc(NCc2ccccc2)c1
Reactant: CC(C)P(=O)(Cl)Cl
Product: Cc1cccc(N2Cc3ccccc3P2(=O)C(C)C)c1
Yield: 20 %

Procedure:
The procedure of Example 1 was employed utilizing N-(3-methylphenyl)-N-benzylamine and isopropyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation was distilled at 150° C. and 0.8 mm to yield a pale yellow glass. The yellow glass was crystallized from methylcyclohexane to yield 1-isopropyl-2-(3-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (3.5 g, 20% yield) as a white crystalline solid having a melting point of 112°-113° C. and the following analysis:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([Cl:23])=[N:18][N:17]=[C:16]3Cl)=[O:12])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].[O:29]1CCOCC1.Cl>O>[F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([Cl:23])=[N:18][NH:17][C:16]3=[O:29])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (350 mg, 0.87 mmol), 2N NaOH (4.4 mL, 8.70 mmol) and dioxane (4 mL) was heated to 50° C. for 3 h. The reaction was diluted with water, acidified with conc. HCl to ˜pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (14 mg) as a white solid, 1H NMR (400 MHz, d6-DMSO) δ: 7.14 (m, 1H), 7.52 (t, 1H), 7.82 (d, 1H), 7.95 (s, 1H), 8.14 (d, 1H), 8.53 (dd, 1H), 8.89 (s, 1H), 10.88 (s, 1H), 13.04 (s, 1H) ppm; m/z (M+1) 384.05; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (20 mg) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 7.06 (d, 1H), 7.44 (t, 1H), 7.70 (d, 1H), 7.85 (s, 1H), 8.34 (m, 2H), 8.39 (s, 1H), 10.87 (s, 1H), 12.92 (s, 1H) ppm; m/z (M+1) 384.05.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:11][CH2:12][OH:13])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C)C=O>[CH3:3][N:4]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH2:11][CH2:12][O:13][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN(CCO)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1ccc([N+](=O)[O-])cc1)c1ccncc1
Reaction time: 0.3 h

Procedure:
Sodium hydride (0.16 g of a 50% dispersion in mineral oil) was added portionwise to a stirred solution of the product of part (i) (0.45 g) in dry N,N-dimethylformamide (30 ml) and the mixture was stirred at 50° for 0.3 hour and then cooled to 5°. 4-Chloronitrobenzene (0.47 g) was added portionwise and the mixture was then stirred at room temperature for 2 hours and evaporated. Water was added and the mixture was extracted several times with dichloromethane. The combined extracts were dried (Na2SO4) and evaporated to give a yellow solid which was washed with hexane to remove mineral oil. The solid was chromatographed on silica gel using dichloromethane/methanol (10:1) as eluant. The product fractions were combined and evaporated to give pure product, (0.60 g), m.p. 88°-89° (from ethyl acetate/hexane).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.CN(C=O)C>S(Cl)(Cl)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=c1[nH]cnc2ccccc12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: c1ccc2ncncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 293.9 %

Procedure:
A solution of 6-methoxy-7-(2-(N-methyl-N-(3-morpholinopropylsulphonyl))amino)ethoxy)-3,4-dihydroquinazolin4-one (176 mg, 0.4 mmol) in thionyl chloride (4 ml) containing DMF (100 μl) was stirred at 45° C. for 1 hour. The volatiles were removed by evaporation and by azeotroping with toluene. The residue was partitioned between methylene chloride and water, the aqueous phase was adjusted to pH8 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methanol/methylene chloride (a gradient from 3/100 to 10/90). The purified product was triturated with ether, collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(N-methyl-N-(3-morpholinopropylsulphonyl)]amino)ethoxy)quinazoline (153 mg, 71%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14](Cl)[CH3:15].[OH-].[Na+].C(N(CCCC)CCCC)CCC>ClC1C=CC=CC=1Cl>[CH2:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:15]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Clc1ccccc1Cl
Product: CCn1c2ccccc2c2ccccc21
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A 0.5-liter autoclave equipped with a stirrer was charged with carbazole (82.4 g), o-dichlorobenzene (100 g), ethyl chloride (40.2 g), 48% sodium hydroxide (55.8 g) and tributylamine (9.2 g). After the atmosphere in the autoclave was replaced with nitrogen gas, the autoclave was heated to the reaction temperature of 100° C. and the reaction mixture was stirred at the same temperature for 9 hours, while keeping the temperature. After completion of the reaction, the mixture was cooled to 50° C. The same procedures as those described in Example 1 gave 275.9 g of an o-dichlorobenzene solution of N-ethylcarbazole. The analysis of this solution by chromatography revealed that the content of N-ethylcarbazole was 32.9% and the yield thereof was 94.3%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]([F:13])[F:12])[C:3]=1[O:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[O:36][CH2:35]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:12][CH:11]([F:13])[O:10][C:4]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:2]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[O:36][CH2:35]3)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: COCOc1c(Br)ccc(OC)c1OC(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC(F)F
Temperature: 80 °C
Yield: 57 %

Procedure:
A stirring solution of 1-bromo-3-(difluoromethoxy)-4-methoxy-2-(methoxymethoxy)benzene (1.5 g, 4.79 mmol) in dimethylformamide (30 mL) was purged with argon gas for 1 h, to this cesium carbonate (4.7 g, 14.37 mmol), tetrakis(triphenylphosphine) palladium (0) (553 mg, 0.479 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (1.49 g, 5.74 mmol) were added and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 5-(3-(Difluoromethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one as a solid (1 g, 56.8%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:38](=[O:40])[CH3:39])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(C)=O)C3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.3 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), acetic anhydride (0.040 mL, 0.423 mmol) was added. The mixture was stirred at room temperature for 4 h. It was then purified by HPLC to give the titled compound (5 mg). MS 426.5 (M+H); UV 248.6 nm.
Reaction SMILES: CC(C)CC[N+]([O-])=O.N(OCCC(C)C)=O.[Br:17]Br.N[C:20]1[S:24][N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]=1[C:29]#[N:30]>C(Cl)Cl>[Br:17][C:20]1[S:24][N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]=1[C:29]#[N:30]
Reactant: BrBr
Reactant: N#Cc1c(C(F)(F)F)nsc1N
Agent: CC(C)CCON=O
Agent: CC(C)CC[N+](=O)[O-]
Solvent: ClCCl
Product: N#Cc1c(C(F)(F)F)nsc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask, was placed 3-methyl-1-nitrobutane (14.4 g, 122.92 mmol, 6.00 equiv), isopentyl nitrite (30 mL), Br2 (32.4 g, 202.74 mmol, 10.00 equiv). This was followed by the addition of 5-amino-3-(trifluoromethyl)-1,2-thiazole-4-carbonitrile (4.0 g, 20.71 mmol, 1.00 equiv), in portions at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:4). The resulting solution was diluted with 30 mL of DCM. The resulting mixture was washed with 2×50 mL of Na2SO3/H2O. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 4.5 g (85%) of 5-bromo-3-(trifluoromethyl)-1,2-thiazole-4-carbonitrile as yellow crude oil.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:32])[CH2:14][C:15]2[C:16]([CH3:31])=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:33]([F:36])([F:35])[F:34])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:32][N:13]([CH2:14][C:15]1[C:16]([CH3:31])=[N:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])=[C:8]([C:33]([F:34])([F:35])[F:36])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CN(C)c1ccc(OCC(=O)O)c(C(F)(F)F)c1
Reaction time: 3.5 h

Procedure:
0.046 g (0.087 mmol) of the above prepared [rac]-(4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester was dissolved in 0.52 ml of THF/EtOH=1/1, treated with 0.26 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 3.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after recrystallisation from AcOEt/hexane, 0.039 g of the title compound as off-white solid.