Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.C[CH:17]1[CH2:40][C:39]2[C:19](=[CH:20][C:21]3[N+:26]([O-:27])=NC(NCCCN4CCOCC4)=[N:23][C:22]=3[CH:38]=2)[CH2:18]1.C(O)(C(F)(F)F)=[O:42]>C(Cl)Cl.N>[N+:26]([C:21]1[CH:20]=[C:19]2[C:39]([CH2:40][CH2:17][CH2:18]2)=[CH:38][C:22]=1[NH:23][C:10](=[O:11])[CH3:12])([O-:27])=[O:42]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1Cc2cc3nc(NCCCN4CCOCC4)n[n+]([O-])c3cc2C1
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.72 mL, ca. 14.3 mmol) was added dropwise to a stirred solution of TFAA (2.0 mL, 14.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 98 (490 mg, 1.4 mmol) and TFA (0.55 mL, 7.1 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 98 (280 mg, 57%) and (ii) 1,4-dioxide 99 (88 mg, 17%) as a red solid: mp (MeOH/DCM) 161-163 DC; 1H NMR δ 8.30 (br s, 1H, NH), 8.08 (br s, 2H, H-5, H-9), 3.82 (br t, J=4.5 Hz, 4H, 2×CH2O), 3.58-3.63 (m, 2H, CH2N), 3.15-3.25 (m, 2H, CH2), 2.61-2.74 (m, 3H, CH, CH2), 2.57 (br t, J=6.1 Hz, 2H, CH2N), 2.47-2.53 (m, 4H, 2×CH2N), 1.83-1.90 (m, 2H, CH2), 1.18 (d, J=6.2 Hz, 3H, CH3); 13C NMR δ 155.2, 149.5, 145.2, 138.1, 129.5, 115.8, 111.7, 66.9 (2), 57.7, 53.8 (2), 41.6, 41.4, 40.4, 34.9, 24.5, 20.2. Anal. calcd for C18H25N5O3: C, 60.2; H, 7.0; N, 19.5. Found: C, 60.6; H, 7.0; N, 18.3%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:32][CH2:31][CH2:30][CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CN1CCN(CCCN)CC1
Reactant: COC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)cc12

Procedure:
A stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methyl ester (440 mg, 1.30 mmol) in 1,4-dioxane (10 mL) is treated with 3-(4-methyl-piperazin-1-yl)- propylamine (610 mg, 3.90 mmol) and diisopropylethylamine (500 mg, 3.90 mmol), the resultant mixture is heated at 90° C. under nitrogen for 16 hours. After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 1-10%, the title compound is isolated as a solid (310 mg, 51% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[O:3][CH2:4][CH2:5][C:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1.C([Li:17])CCC.CCCCCC.CCCC>CCOCC>[CH3:11][Si:2]([CH3:1])([CH3:12])[O:3][CH2:4][CH2:5][C-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Li+:17]
Reactant: C[Si](C)(C)OCCC1=CC=CC1
Reactant: [Li]CCCC
Solvent: CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)OCC[c-]1cccc1
Product: [Li+]
Reaction time: 3 h
Yield: 82 %

Procedure:
To 7.33 g of (2-trimethylsiloxy-ethyl)-cyclopentadiene in ether, 16 ml of a 2.5 M butyllithium solution in hexane (40 mmol) is added. The addition is realised at −78° C. The immediate formation of a white solid and butane evolution are observed. It is maintained reacting for 3 hours. Then it is dried; the resulting solid washed with hexane, leaving a powdery white solid. (6.19 g, 33 mmol, Yield: 82%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]3[CH2:26][CH2:25][C@:24]([CH2:33][C:34]([OH:37])([CH3:36])[CH3:35])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:23][C:22]3=[O:38])[CH3:20])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[NH2:12]>O.C(O)(=O)C>[N:12]1[C:11]2[CH:10]=[CH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]([N:21]4[CH2:26][CH2:25][C@:24]([CH2:33][C:34]([OH:37])([CH3:35])[CH3:36])([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[O:23][C:22]4=[O:38])[CH3:20])=[CH:17][CH:18]=3)=[CH:7][C:6]=2[NH:5][N:1]=1
Reactant: O=N[O-]
Reactant: C[C@@H](c1ccc(-c2ccc(N)c(N)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(-c2ccc3nn[nH]c3c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
A solution of NaNO2 (0.16 g) in water (2 mL) was added dropwise to an ice-cold solution of 3-[(S)-1-(3′,4′-diamino-biphenyl-4-yl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.43 g) in acetic acid (10 mL). The resulting mixture was stirred with cooling for 2 h and at room temperature for another 1 h. Then, water (100 mL) was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NaHCO3 solution, water, and brine and dried (Na2SO4). The solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate/MeOH 98:2→80:20) to afford the title compound as a foam-like solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH3:22])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19].FC(F)(F)C(O)=O.[OH-].[K+]>ClCCl.[Pt]=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH3:22])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: O=[Pt]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Yield: 91.4 %

Procedure:
A mixture of 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (19.45 g, 61.39 mmol), prepared as described in Example 46, platinum oxide (10.00 g) and trifluoroacetic acid (200 mL) was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for 2 days. The reaction mixture was filtered through CELITE filter aid. The filtrate was concentrated under reduced pressure to provide a dark oil. The oil was chilled in an ice bath, ice was added, and the mixture was made basic (pH 14) by the addition of 1 N potassium hydroxide. The resulting solid was isolated by filtration and then dissolved in dichloromethane. The solution was washed sequentially with 1 N potassium hydroxide, water, and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dried under vacuum for 2 days to provide 18.0 g of 1-(4-chlorobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@@H:18]([OH:19])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:24]I>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@@H:18]([O:19][CH3:24])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CI
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1CCN2N=C(c3ccc(C#N)c(Cl)c3C)[C@@H](OC)[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile as obtained in example 1 (50 mg, 0.16 mmol) in THF (3 mL) at 0° C. was added sodium hydride (13 mg, 0.33 mmol) for 10 min, followed by the addition of methyl iodide (0.015 mL, 0.245 mmol). The reaction mixture was stirred at room temperature for 2 h. Once the starting material had disappeared (monitored by TLC) reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate, organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 30% EtOAc in Hexane) provided the title compound (10 mg, 20%).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11](NC2C(F)=CN=C(C)C=2C2C3C(=NC=C(Cl)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)[C@H:10]1[OH:44])(C(C)(C)C)(C)C.[Si](O[C@]1(C)CCC[C@H]([NH:59][C:60]2[C:65]([F:66])=[CH:64][N:63]=[C:62]([C:67]3[C:75]4[C:70](=[N:71][CH:72]=[C:73]([Cl:76])[CH:74]=4)[N:69](S(C4C=CC(C)=CC=4)(=O)=O)[CH:68]=3)[N:61]=2)[C@H]1O)(C(C)(C)C)(C)C.[F-].[CH2:90]([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:76][C:73]1[CH:74]=[C:75]2[C:67]([C:62]3[N:61]=[C:60]([NH:59][C:9]4([OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]4([CH3:90])[OH:44])[C:65]([F:66])=[CH:64][N:63]=3)=[CH:68][NH:69][C:70]2=[N:71][CH:72]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@](C)(O[Si](C)(C)C(C)(C)C)[C@@H]4O)n3)c3cc(Cl)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)ncc(F)c3N[C@H]3CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]3O)c3cc(Cl)cnc32)cc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(O)CCCCC1(O)Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Reaction time: 1.5 h

Procedure:
To a stirred solution of (1R,2R,6S)-2-[tert-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5-chloro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4-yl]amino]cyclohexanol, 50f, (0.11 g; 0.16 mmol) in THF (2 mL) at room temperature, was added tetrabutylammonium fluoride (1.5 equiv) and the reaction mixture stirred for 1.5 h, at which point HPLC-analysis revealed no starting material but the de-tosylated product was observed with minor desilylation. An additional equivalent of TBAF was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was suspended in ethyl acetate (10 mL), washed with H2O (2×4 mL), aqueous saturated NH4Cl solution (2 mL) and brine (2 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to provide 139 mg of crude. The crude residue was purified by reverse phase HPLC (5-95% MeOH/water w/HCl buffer over 15 minutes). to afford 15 mg of desired product, 860. LCMS M+1=392.34
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].I[CH2:11][CH3:12].C(N(CC)CC)C>C(#N)C>[CH2:11]([S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:12]
Reactant: Fc1ccc(S)c(F)c1
Reactant: CCI
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCSc1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To thick-walled, reaction pressure tube was added 2,4-difluorobenzenethiol (1500 mg, 10.26 mmol), iodoethane (1.095 mL, 13.34 mmol), acetonitrile (20 mL), and triethylamine (1.860 mL, 13.34 mmol). The vessel was capped and heated at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Methylene chloride was added and the mixture was washed with water three times. The organic layer was concentrated to provide crude 4-(ethylthio)-1,3-difluorobenzene which was used without further purification. To this material (1700 mg, 9.76 mmol) in acetic acid (10 mL) was added hydrogen peroxide (30% in H2O, 4.7 mL, 48.8 mmol). The mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was added to methylene chloride and washed with water three times. The organic layer was dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/hexane) to give 1-(ethylsulfinyl)-2,4-difluorobenzene (1.2 g, 6.31 mmol) as white oil. 1H NMR (CDCl3, 500 MHz) δ 7.69-7.86 (m, 1H), 7.03-7.17 (m, 1H), 6.80-6.94 (m, 1H), 3.05 (dd, J=13.75, 7.15 Hz, 1H), 2.83 (dd, J=13.75, 7.15 Hz, 1H), 1.22 (t, J=7.42 Hz, 3H); MS (ESI) 191.1 (M+H). To a solution of 1-(ethylsulfinyl)-2,4-difluorobenzene (1100 mg, 5.78 mmol) in 2-propanol (10 mL) was added water (10 mL) and OXONE® (4622 mg, 7.52 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated. The resulting crude material was dissolved in ethyl acetate and was washed with saturated aqueous sodium chloride twice. The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue obtained was then purified by flash chromatography (silica gel, 0-100% ethyl acetate/hexane) to give Intermediate 9 (600 mg, 50% yield) as a white oil. 1H NMR (CDCl3, 500 MHz) δ 7.90-8.02 (1H, m), 6.90-7.12 (2H, m), 3.30 (2H, q, J=7.3 Hz), 1.30 (3H, t, J=7.4 Hz); MS (ESI) 207.1 (M+H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][C:14](OCC)=[O:15]>>[CH2:19]([C:12]1[CH:13]=[C:14]([OH:15])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(Cc3ccccc3)cc2O)c1
Yield: 53 %

Procedure:
The title compound was prepared in 53% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxo-4-phenylbutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O, 277; Found, 277.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([OH:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C=[CH:9][CH:8]=1.[N:21]1C2C(=CC=CC=2)C(C=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([OH:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:21]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(O)c2cccc3ccccc23)c1
Reactant: O=Cc1ccnc2ccccc12
Product: COc1cccc(C(O)c2ccnc3ccccc23)c1

Procedure:
The compound 26 was prepared by following the synthesis procedure as described for compound 1, but substituting 1-naphtaldehyde for 4-quinolinecarboxaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([OH:29])=O)[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH:66]1[C:70]([CH2:71][CH2:72][CH2:73][NH2:74])=[N:69][N:68]=[N:67]1.Cl>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:74][CH2:73][CH2:72][CH2:71][C:70]4[N:66]=[N:67][NH:68][N:69]=4)=[O:29])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Reactant: NCCCc1nnn[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCc5nn[nH]n5)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (Compound F1) (100 mg, 0.23 mmol) in 10 ml of anhydrous acetonitrile were added HATU (95 mg, 0.25 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol). The mixture was stirred at room temperature for 20 minutes, followed by addition of 3-(1H-tetrazol-5-yl)propan-1-amine hydrochloride (57 mg, 0.35 mmol). The mixture was stirred at room temperature for another 40 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 8˜12% methanol in chloroform containing 0.5% of triethylamine to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide as white solid. Yield: 50 mg, 40%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26].C(N)C(C)C>>[NH2:28][C:25]([CH3:27])([CH3:26])[CH2:24][NH:23][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(N)CN
Solvent: CC(C)CN
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Yield: 73.6 %

Procedure:
7-Benzyloxy-4-chloro-3-nitroquinoline (14.5 g, 46.0 mmol) was treated using the general method described in Part E of Example 1. 1,2-Diamino-2-methylpropane (5.29 mL, 50.6 mmol) was used in lieu of isobutylamine. After the work-up, the crude product was passed through a layer of silica gel (eluting sequentially with chloroform and 96:4 chloroform:methanol) to provide 12.4 g of (2-amino-2-methylpropyl)-(7-benzyloxy-3-nitroquinolin-4-yl)amine as a yellow solid.
Reaction SMILES: C[O-].[Na+].C(O[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10][CH:9]=1)C.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].Cl>O.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:16](=[O:18])[CH2:17][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10][CH:9]=1)[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccc(C)nc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(C)nc1
Temperature: 20 °C
Yield: 33.6 %

Procedure:
35.8 g (0.52 mol) of sodium methylate and 200 ml of toluene were put in a 750-ml sulfonation flask. The reaction mixture was heated to reflux temperature. A mixture of 55.7 g (0.33 mol) of 6-methyl nicotinic acid ethyl ester (produced according to Swiss Pat. No. 654 577) and 60.3 g (0.68 mol) of ethyl acetate was added drop by drop to the stirred suspension over 7 hour period. The suspension was stirred at reflux temperature for 22 hours and then cooled to 20° C. 200 ml of water and 25 ml of concentrated hydrochloric acid were added and the phases were separated. The water phase was extracted with toluene and the combined organic phases were evaporated. Then the evaporation residue was distilled under vacuum. 25.9 g of 6-methyl nicotinoyl acetic acid ethyl ester, having a boiling point of 112°-130° C./0.2-0.4 mbar and a content according to HPLC of 89.7 percent, was obtained (yield 33.6 percent, in relation to the 6-methyl nicotinic acid ethyl ester).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Mg]Br)C.O1CCCC1.[CH3:19][C:20]1([CH3:28])[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25](Cl)=[O:26]>ClCCl.[Cl-].[Cl-].[Zn+2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:25]([CH:21]2[C:22]([CH3:24])([CH3:23])[C:20]2([CH3:28])[CH3:19])=[O:26])=[CH:2]1.[CH3:19][C:20]1([CH3:28])[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:26]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)C(C(=O)c2c[nH]c3ccccc23)C1(C)C
Product: CC1(C)C(C(=O)n2ccc3ccccc32)C1(C)C
Reaction time: 0.5 h
Yield: 42 %
Yield: 27 %

Procedure:
To a solution of indole (Aldrich, 11 g, 95 mmol) in 30 mL dichloromethane at ambient temperature was added 105 mL of a 1 M solution of ethyl magnesium bromide in tetrahydrofuran (THF) (105 mmol) dropwise via syringe pump. After the addition was complete, the solution was stirred for 15 min at which time ZnCl2 (14 g, 105 mmol) was added. The mixture stirred for an additional 30 min then the product of Example 1A (95 mmol) in 50 mL dichloromethane was added via cannula. The mixture was stirred for 6 h then was quenched with 50 mL saturated aqueous NH4Cl and diluted with 50 mL dichloromethane. The layers were separated and the aqueous layer was extracted with 3×30 mL dichloromethane. The combined organics were washed with 1×20 mL H2O then were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (SiO2, 50% ethyl acetate:hexanes) to give 9.7 g of the major regioisomer 1H-indol-3-yl(2,2,3,3-tetramethylcyclopropyl)methanone (40 mmol, 42% yield) and 6.1 g of the minor regioisomer of 1-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole (25 mmol, 27% yield). MS (major and minor regioisomers) (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CO.O.[Fe]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)c(F)c1Nc1ccccc1
Yield: 99.4 %

Procedure:
(2,3-Difluoro-6-nitro-phenyl)-phenylamine (4.2 g, 16.9 mmol), iron powder (3.8 g, 67.6 mmol), and ammonium chloride (5.2 g, 101.4 mmol) in methanol (60 mL) and water (15 mL) were heated at 90° C. for 3 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a red solid (3.7 g, 100%). 1H NMR 400 MHz δ (CDCl3): 7.25-7.16 (2H, m), 6.94-6.82 (2H, m), 6.70-6.64 (2H, m), 6.47 (1H, ddd, J=12.0, 6.1, 3.0 Hz), 5.23 (1H, br s), 3.71 (2H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.Cl.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:18]=1[F:25])[CH3:15]>>[ClH:1].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:24])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:19][C:18]=1[F:25])[CH3:15]
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CCOc1ccc(NC)cc1F
Agent: Cl
Product: CCOc1ccc(N(C)c2nc(C)nc3ccccc23)cc1F

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (78 mg, 0.44 mmol) and (4-ethoxy-3-fluoro-phenyl)-methyl-amine hydrochloride (81 mg, 0.39 mmol) by a procedure similar to Example 251. 1H NMR (CDCl3) δ 8.57 (m, 1H), 7.74 (m, 1H), 7.19 (m, 1H), 7.10 (dd, J=2.6, 10.6 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.98 (ddd, J=1.5, 2.8, 8.5 Hz, 1H), 6.81 (m, 1H), 4.19 (q, J=6.9 Hz, 2H), 3.77 (s, 3H), 2.98 (s, 3H), 1.53 (t, J=7.0 Hz, 3H); LC-MS (ESI+; 312 ([M+H]+)).