Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[C:16]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:25][CH3:26])(=[O:11])=[O:10].[N+:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1>[CH3:26][O:25][C:13]1[CH:14]=[CH:15][C:16]([S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1)(=[O:37])=[O:38])(=[O:10])=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
To a solution of N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide (2 mmol, prepared as in Example A) in DCM (4 mL) and pyridine (4 mL), 3-nitrobenzenesulfonyl chloride (2.2 mmol) was added at RT and the reaction mixture was then allowed to stir at RT. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 1.04 g of 2-methoxy-N-[2-(3-nitrobenzenesulfonylamino)phenyl]-5-trifluoromethanesulfonylbenzenesulfonamide. LC: Tr 1.17 min, MS: 596.6 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.27 (s, 3H), 6.76 (d, 1H), 6.78(bs, 1H), 7.05 (m, 1H), 7.16 (m, 2H), 7.34 (d, 1H), 7.68 (bs, 1H), 7.72 (t, 1H), 8.01 (dd, 1H), 8.20 (dd, 1H), 8.25 (d, 1H), 8.46 (dd, 1H), 8.55 (d, 1H) ppm.
Reaction SMILES: [C:1]([C:4]1[C:31]([CH3:32])=[CH:30][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH2:22][C:23]4([CH3:29])[CH2:28][O:27][CH2:26][O:25][CH2:24]4)[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])(O)=[O:34].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)Cl.O>[C:1]([C:4]1[C:31]([CH3:32])=[CH:30][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH2:22][C:23]4([CH3:29])[CH2:24][O:25][CH2:26][O:27][CH2:28]4)[CH:16]=[CH:15][N:14]=3)=[O:34])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: COc1c(OCC2(C)COCOC2)ccnc1CSc1nc2cc(C(C)=O)c(C)cc2[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1c(OCC2(C)COCOC2)ccnc1CS(=O)c1nc2cc(C(C)=O)c(C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred mixture of 5-acetyl-6-methyl-2-[[(3-methoxy-4-(5-methyl-1,3-dioxan-5-yl-methoxy)-2-pyridinyl)methyl]thio]-1H-benzimidazole (87 mg, 0.19 mmol) in 20 ml CH2Cl2 and NaHCO3 (32 mg, 0.38 mmol) in 5 ml H2O was cooled to 0° C. and treated with 3-chloro-perbenzoic acid (47 mg 70%, 0.19 mmol). After reacting for 10 min the layers were separated (the aqueous layer was washed once more with 5 ml CH2Cl2) and the organic layer extracted with 10 ml H2O containing NaOH (15 mg, 38 mmol). The alkaline aqueous layer was collected and treated with several portions of methyl formate (each 23 μl, 38 mmol) until the solution turned opaque. The aqueous layer was extracted with 25+10 ml CH2Cl2. The two latter organic layers were combined, dried over MgSO4 and evaporated. The residue was chromatographed (SiO2, CH2Cl2 /MeOH saturated with NH3(g), 93/7) yielding 40 mg (44%) pure solfoxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:30])[CH3:29].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:30][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: CC(N)c1ccc(F)cc1-c1cc(F)ccc1F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2cc(F)ccc2F)c1
Yield: 100 %

Procedure:
The title compound was prepared from 3-methoxybenzenesulfonyl chloride (153 mg, 0.74 mmol), 1-(-2′,5′,5-trifluoro-1,1′-biphenyl-2-yl)ethylamine (177 mg, 0.70 mmol), and triethylamine (147 uL, 1.1 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (295 mg, 100%) as a white solid;
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>ClCCl>[Cl:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Clc1c[nH]c2ccncc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)n1cc(Cl)c2cnccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 128.9 %

Procedure:
To a stirred solution of 3-chloro-1H-pyrrolo[3,2-c]pyridine (1 g, 6.55 mmol) in dichloromethane (10 mL), triethylamine (2.3 ml, 16.38 mmol) was added. The mixture was cooled to 0° C. and benzyl chloroformate (2.3 mL, 50% solution in dichloromethane, 9.83 mmol) was added drop wise. After complete addition, the reaction mixture was stirred at room temperature for about 1 hour. On completion, the reaction was quenched by addition of saturated aq. sodium bicarbonate solution and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.42 g, 100%) as viscous liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][C:5]=1[NH2:9])([O-:3])=[O:2].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[C:5]3[N:9]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cc(-c2ccnc3c([N+](=O)[O-])cnn23)ccc1Cl)S(C)(=O)=O
Yield: 37.6 %

Procedure:
A mixture of 0.050 g (0.39 mmol) of 4-nitro-2H-pyrazol-3-ylamine and 0.124 g (0.39 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-methanesulfonamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 56 mg of N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 77%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2CC[C@@H]1O[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-1H-isoindole (step L) and cyclopentane-1,3-dione according to the procedure of Example 7. 1H-NMR (CDCl3): rotamers δ: 7.64 (1H, s), 7.18 (2H, s), 7.04–6.97 (4H, m), 4.74, 4.53 (1H, s), 4.42 (1H, m), 3.68, 3.43 (1H, m), 3.50 (1H, m), 3.06 (1H, m), 2.93 (2H, m), 2.86, 2.76 (1H, m), 2.57 (1H, m), 2.40 (2H, m), 2.28 (3H, s), 2.20 (1H, m), 2.17 (1 H, m), 2.10–1.94 (3H, m), 1.58 (1H, m), 1.40(1H, m), 1.28 (3H, d, J=6.0 Hz). MS: (MH)+552.43
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[F:9].[CH3:10][S:11]([O-])(=[O:13])=[O:12].[Na+]>CN(C)C(=O)C.[Cu](I)I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:11]([CH3:10])(=[O:13])=[O:12])[C:3]=1[F:9]
Reactant: CS(=O)(=O)[O-]
Reactant: Fc1cccc(I)c1F
Agent: I[Cu]I
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(F)c1F
Yield: 72.5 %

Procedure:
1,2-Difluoro-3-iodobenzene (1.70 g; 7.08 mmol), 2.17 g (21.2 mmol) of sodium methanesulfonate and 4.03 g (21.2 mmol) of copper iodide were heated with stirring at 111° C. for 20 hours in 50 ml of N,N-dimethylacetamide. The reaction solution was filtered, chloroform was added to the filtrate and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=2:1) to give 987 mg (yield: 72%) of 1,2-difluoro-3-methanesulfonylbenzene as a colorless transparent solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24]1[O:32][C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][C:24]2[O:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: c1cnc2cc(CC3CCCCN3)oc2c1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ncccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared using the method of Example 4, from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (120 mg, 0.5 mmol) and (RS)-2-piperidin-2-ylmethyl-furo[3,2-b]pyridine, D47 (108 mg, 0.5 mmol), as a colourless solid (95 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][C:3]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14].CO.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:24][N:23]=[N:22][CH:9]=2)=[CH:4][C:3]=1[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc(Cl)c(CNC(=O)OC)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)NCc1cc(-c2cnn[nH]2)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of methyl N-[(2-chloro-5-ethynylphenyl)methyl]carbamate (i.e. the product of Step D) (0.43 g, 1.92 mmol) in N,N-dimethylformamide (3.9 mL) and methanol (0.4 mL) was added trimethylsilyl azide (0.38 mL, 2.89 mmol) and copper(I) iodide (0.019 g, 0.1 mmol). The reaction mixture was heated in a CEM Discover microwave apparatus at 100° C. for 8 h and then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium chloride, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water (3×), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound, a compound of the present invention, as a brown solid (0.30 g).
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13](/[CH:12]=[CH:11]/[CH2:10][CH2:9][OH:8])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(C)(C)[Si](C)(C)OCC/C=C/c1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To solution of Intermediate 2A (2.2 g, 5.2 mmol) in THF (50 mL) cooled to 0° C. was added TBAF (6.3 mL, 6.3 mmol) via dropwise addition. The reaction mixture was stirred at 0° C. for 1 h, then diluted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL), dried over Na2SO4 and dried in vacuo. The product was purified by silica gel chromatography (80 g silica gel; linear gradient 0-25% ethyl acetate for 30 min) to obtain 917 mg (97% yield) of Intermediate 2B. HPLC/MS (Method D) RT=1.00 min, [M−H2O+1]+ 199.1.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]([C:16]1[N+:21]([O-])=C(C)[CH:19]=[CH:18][CH:17]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:5]([O:4][CH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:21]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C(=O)c2ccccc2)[n+]1[O-]
Product: CC(=O)OCc1cccc(C(=O)c2ccccc2)n1
Reaction time: 1 h

Procedure:
Acetic anhydride (6.6 ml) is heated to 115°, after which 6-benzoyl-2-methylpyridine N-oxide is added in portions over 1 hour. The mixture is then held at 115° for 1 hour after the addition. The reaction is poured onto ice and extracted with ether (3×). The combined ether phases are washed with sat. NaHCO3 (2×) and water until neutral, dried and stripped. The product is preparatory thin layer chromatographed, the least polar band giving 2-(acetoxymethyl)-6-benzoylpyridine.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(F)n2)CC1
Agent: [Ni]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(F)n2)CC1

Procedure:
A solution of tert-butyl 4-cyano-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (250 mg, 0.82 mmol) in methanol (20 mL) with triethylamine (1 mL) was reacted with Raney nickel (0.5 mL of 50% slurry in water) under 40 psi hydrogen for 5 hours. The catalyst was filtered off and washed thoroughly with methanol. Evaporation of the solvent afforded the desired product: tert-butyl 4-(aminomethyl)-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate: m/z (ES) 310 (M+H).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[CH3:15][C:16]1([CH3:35])[CH2:21][CH2:20][C:19](=[O:22])/[C:18](=[CH:23]/[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])/[CH2:17]1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH3:15])([CH3:35])[CH2:17]/[C:18]/2=[CH:23]\[O:24][Si:25]([CH:26]([CH3:28])[CH3:27])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)[Si](O/C=C1\CC(C)(C)CCC1=O)(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[Si](O/C=C1\CC(C)(C)CCC1(O)c1ccc(Cl)cc1)(C(C)C)C(C)C
Temperature: -2.5 °C
Reaction time: 1 h

Procedure:
To EXAMPLE 2 (26 g, as a solution in toluene) was added to anhydrous tetrahydrofuran (65 mL). The resulting mixture was cooled to −5 to 0° C. A separate flask was charged with anhydrous tetrahydrofuran (65 mL) and a 1 M solution of (4-chlorophenyl)magnesium bromide (172 mL, 2.05 equiv). The reagent mixture was cooled to −5 to 0° C. The mixture of EXAMPLE 2 in toluene was slowly added to the Grignard reagent, maintaining a reaction temperature below 5° C. The reaction was monitored by HPLC and was determined to be complete in about one hour. The reaction mixture was quenched slowly with methanol (91 mL), maintaining an internal temperature below 5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (26.1 g) in N,N-dimethylformamide (350 ml) were added potassium tert. butoxide (9.2 g) and ethyl bromoacetate (13.7 g) at room temperature. The mixture was stirred overnight. After neutralization with diluted hydrochloric acid, the mixture was evaporated and chromatographed on silica gel using chloroform. Fractions containing the object compound were evaporated and the residue was triturated in ethanol to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethoxycarbonylmethyl-methyl-4(2,4,6-trimethylphenylimino)-2(1H)pyrimidinone (15.3 g). mp. 112°-113° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[C:21]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)(=[O:23])[CH3:22]>>[C:21]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:30]1)(=[O:23])[CH3:22]
Reactant: CC(=O)CNCCCC1CCCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Product: CC(=O)CNCCCC1CCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1

Procedure:
Prepared analogously to Example 8 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[3-[(acetyl)methylamino]-propyl]piperidine. Purification is carried out by chromatography on silica gel (Baker) using methylene chloride to which increasing amounts of methanol are added.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[NH:50][C:51]([C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[CH:58][CH:59]=2)=[CH:52][CH:53]=1>CN(C=O)C>[N:49]1[NH:50][C:51]([C:54]2[CH:55]=[C:56]([NH:60][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:57]=[CH:58][CH:59]=2)=[CH:52][CH:53]=1
Reactant: Nc1cccc(-c2ccn[nH]2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccn[nH]2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 7.1 %

Procedure:
DIEA (0.011 mL, 0.062 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.057 mmol) and HATU (0.024 g, 0.062 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2H-pyrazol-3-yl)-phenylamine (0.009 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.0014 g of product in 7% yield: LCMS (ESI) m/z 348 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Yield: 96.6 %

Procedure:
Reaction of benzoate 3 (1.96 g, 5.1 mmol) and 6 M HCl (50 mL) gave acid 4 (1.83 g, 97%) as a white solid: mp (H2O) 242-245° C.; 1H NMR δ 13.16 (br s, 1H, CO2H), 8.05 (ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.92 (ddd, J=8.6, 1.9, 1.5 Hz, 2H, H-3, H-5), 7.67 (br d, J=8.3 Hz, 2H, H-2′, H-6′), 7.42 (br d, J=8.3 Hz, 2H, H-3′, H-5′), 4.63 (s, 2H, CH2SO2), 2.40 (s, 3H, CH3), 2.13 (s, 3H, CH3); MS m/z 372.8 (MH+, 100%). Anal. calcd for C19H17NO5S: C, 61.44; H, 4.61; N, 3.77. Found: C, 61.67; H, 4.57; N, 3.79%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=2)[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1ccccn1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccc(C(F)(F)F)cc3c2=O)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccn3)c3ccc(C(F)(F)F)cc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 55 mg (0.16 mmol) of 3-(3,4-dimethyl-benzoyl)-6-trifluoromethyl-1H-quinolin-4-one, 18 mg of 60% sodium hydride, 52 mg of 2-bromomethylpyridine hydrobromide and 1 mL of N,N-dimethylformamide. Yield: 49 mg of a white solid: LC-MSD, m/z for C25H19F2N2O2 [M+H]+=437.5; HPLC retention time: 2.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:27]=[CH:26]C3C(=CC=C(C=O)C=3)N=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C[Mg]Br.O.C([O:37][CH2:38][CH3:39])(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:5]3[C:4](=[CH:3][CH:2]=[C:7]([CH:38]([OH:37])[CH3:39])[CH:6]=3)[N:17]=[CH:26][N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=Cc1ccc2nc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncc2c1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
In 30 mL of tetrahydrofuran was dissolved 620 mg of 4 (3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1), the solution was cooled to 0° C. under the nitrogen atmosphere, and 4.9 mL of methylmagnesium bromide (0.93M tetrahydrofuran solution) was added dropwise. After the reaction at 0° C. for 1 hour under the nitrogen atmosphere, water and ethyl acetate were added to separate the layers. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the resulting crystal was washed with chloroform to obtain 330 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-hydroxyethan-1-yl)quinazoline (VI-1).