Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:7]([CH3:19])([CH3:18])[O:8][C:9]1[CH2:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:4][CH2:5][CH3:6])([CH3:3])[CH3:2].[Li][CH2:21][CH2:22][CH2:23][CH3:24].[CH3:25][Si:26]([CH3:29])(Cl)Cl>CCOCC.CCCCCC>[CH3:25][Si:26]([CH3:29])([CH:21]1[C:16]2[C:24](=[CH:11][CH:10]=[CH:9][CH:17]=2)[CH:23]=[C:22]1[O:8][Si:7]([C:1]([CH2:4][CH2:5][CH3:6])([CH3:2])[CH3:3])([CH3:19])[CH3:18])[CH:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:8][Si:7]([CH3:19])([CH3:18])[C:1]([CH2:4][CH2:5][CH3:6])([CH3:3])[CH3:2]
Reactant: CCCC(C)(C)[Si](C)(C)OC1=Cc2ccccc2C1
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC(C)(C)[Si](C)(C)OC1=Cc2ccccc2C1[Si](C)(C)C1C(O[Si](C)(C)C(C)(C)CCC)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
To a solution of 2-(t-hexyldimethylsiloxy)indene (35.58 g, 129.6 mmol) in Et2O (120 mL) at 0° C. was added dropwise n-BuLi (52.4 mL of a 2.5 M solution in hexane, 130.9 mmol) and the reaction mixture was stirred overnight at room temperature. The resulting solution was then added dropwise to a solution of dimethyldichlorosilane (7.9 mL, 64.8 mmol) in Et2O (50 mL) at 0° C. The reaction mixture was stirred overnight at room temperature and washed with saturated ammonium chloride solution (300 mL), water (2×200 mL) and dried over sodium sulfate. Evaporation of the solvents left a red oil that was dissolved in a 4:1 mixture of MeOH and acetone. Concentration and cooling to −30° C. gave 11.67 g (29.7%) of the title compound as a white powder. The crystalline first crop consisted exclusively of the racemic diastereomer. EIMS (calcd/found): m/e 604.3588/604.3585. 1H NMR (CDCl3, δ): 7.22-7.13 (m, 6H); 6.98 (td, 3J=7.3 Hz, 4J=1.4 Hz, 2H); 5.85 (s, 2H); 3.99 (s, 2H); 1.72 (sept, 3J=6.9 Hz, 2H); 0.94 (s, 6H); 0.94 (s, 6H); 0.90 (d, 3J=6.9 Hz, 6H); 0.89 (d, 3J=6.9 Hz, 6H); 0.38 (s, 6H); 0.34 (s, 6H); −0.23 (s, 6H). 13C NNR (CDCl3, δ): 164.87; 144.49; 137.53; 125.13; 122.86; 121.38; 118.84; 104.26; 43.15; 33.76; 25.19; 20.17; 20.08; 18.54; 18.45; −2.30; −2.75; −6.73. The oily residue was washed with cold MeOH (3×100 mL) and dried in vacuo to yield 14.02 g (35.8%) of the fairly pure meso diastereomer as a red oil (total yield 65.5%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7]2.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[C:9]1(=[O:13])[C:10]2[C:6](=[CH:5][C:4]([O:3][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)[CH2:7][NH:8]1
Reactant: O=C1NCc2cc(O)ccc21
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0° C. was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70° C. for 3 h. The mixture was cooled to 0° C. and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf0.35.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.C(N(C(C)C)CC)(C)C.N1([C:42](=[O:44])[CH3:43])CCNCC1>C(#N)C>[C:42]([N:3]1[CH2:7][CH2:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=2)=[O:9])[CH2:4][CH2:2]1)(=[O:44])[CH3:43]
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CC(=O)N1CCNCC1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCN(C(=O)/N=c2\sc(C)cn2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial were combined a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (45 mg, 0.09 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) and diisopropylethylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added 1-(piperazin-1-yl)ethanone (13 mg, 0.1 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to supply the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:12][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:4]([NH2:5])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
4-Bromo-3-fluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 3-fluoro-6-nitroaniline (500 mg, 3.2 mmol) in dry DMF (15 mL) under N2 was added dropwise a solution of N-bromosuccinimide (626 mg, 3.2 mmol) in dry DMF. The reaction was allowed to stir 48 h. The solution was then poured into 100 mL H2O. The cloudy yellow suspension which formed was then extracted with 4×25 mL of methylene chloride. The combined organic extracts were washed with 4×25 mL of H2O and 25 mL sat'd NaCl solution. The organic phase was dried (MgSO4) and the drying agent removed by vacuum filtration. The solvent was rotary evaporated to yield a yellow orange oil which crystallized on standing. 1H NMR showed this solid to be a mixture of mono- and dibrominated products in a 3.8:1 ratio. The mixture was separated by flash chromatography (2:1 hexanes:ethyl acetate) to yield 324 mg of a yellow solid (43%). 1H NMR (CDCl3) δ6.19(br s, 2H, NH2); 6.58(d, 1H, JHF =9.6, ArH); 8.39(d, 1H, JHF =6.9, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20](N)[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:29]=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:26]([Cl:25])[CH:27]=2)[CH:19]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Clc1ccc(COc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)cc1Cl

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 3,4-dichlorobenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 491.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.F[C:28](F)(F)[C:29]([OH:31])=[O:30].BrCC(OCC)=O.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>C(O)(C)(C)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([CH2:28][C:29]([OH:31])=[O:30])[C@H:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: O=C(O)CN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 50 mg, 0.14 mmol, 1 equiv) in a 1:1 mixture of dichloromethane and trifluoroacetic acid (10 mL) was stirred for 30 minutes, then concentrated. The residue was partitioned between aqueous saturated sodium bicarbonate solution (60 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. A solution of the residue, ethyl bromoacetate (16 μL, 0.14 mmol, 1.0 equiv) and N,N-diisopropylethylamine (29 μL, 0.17 mmol, 1.2 equiv) in DMP (5 mL) was heated at 70° C. for 3 hours. The reaction mixture was partitioned between water (125 mL) and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. A solution of the residue and sodium hydroxide (1N, 280 μL, 0.28 mmol, 2.0 equiv) in tert-butanol (10 mL) was heated at 45° C. for 20 hours. The reaction mixture was then partitioned between water and ethyl ether. The aqueous layer was acidified to pH 4 with aqueous HCl solution, then extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide [(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]acetic acid (28-1) as a colorless oil. LRMS m/z (M+H) 316.3 found, 316.1 required.
Reaction SMILES: [C:1](=[N:14][OH:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]2[CH:27]=[C:28]([C:33]3([O:39][CH3:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:29]=[C:30]([F:32])[CH:31]=2)=[CH:21][CH:20]=1)[CH3:18]>>[F:32][C:30]1[CH:29]=[C:28]([C:33]2([O:39][CH3:40])[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:27]=[C:26]([S:25][C:22]2[CH:21]=[CH:20][C:19]([CH:17]([O:15][N:14]=[C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH3:18])=[CH:24][CH:23]=2)[CH:31]=1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ON=C(c4ccccc4)c4ccccc4)cc3)c2)CCOCC1
Temperature: 60 °C
Yield: 38 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, benzophenone oxime was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give benzophenone O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl}-oxime as an oil in 38% yield.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16](CCCN)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:27]([NH2:35])(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C[N:43](C)[C@@H:44]1CCC[CH2:46][C@H:45]1N>[Cu](I)I.O1CCOCC1>[CH2:44]([NH:43][C:16]1[C:17]2[S:22][CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:35][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[N:15]=1)[CH2:45][CH3:46]
Reactant: NCCCc1nc(N2CCN(c3ccc(I)cc3)CC2)nc2c1SCC2
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Reactant: NC(=O)c1ccncc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCNc1nc(N2CCN(c3ccc(NC(=O)c4ccncc4)cc3)CC2)nc2c1SCC2

Procedure:
0.170 g (0.4 mmol) of {2-[4-(4-iodophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine (VIII), 0.054 g (0.4 mmol) of isonicotinamide, 0.100 g (0.7 mmol) of potassium carbonate, and 0.004 g (0.02 mmol) of copper iodide are taken, and under an argon atmosphere 1 mL of anhydrous/degassed dioxane and 0.006 mL (0.04 mmol) of trans-N,N-dimethyl-1,2-cyclohexanediamine are added. The reaction mixture is reacted for 2 hours at 140° C. in the microwave, then filtered through silica gel with petroleum ether/ethyl acetate (1/1) and then ethyl acetate/methanol (8/2), and concentrated by evaporation. The residue is purified by chromatography (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:12][CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.C1C=CC=CC=1.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Clc1cccc(C2NCCS2)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCSC1c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
Five (5) grams of 2-m-chlorophenyl thiazolidine was dissolved in 50 ml. of benzene and 2.6 g. of triethylamine and the mixture was stirred in a room temperature water bath, while 3.7 g. of dichloroacetyl chloride was added dropwise. After standing for about 30 minutes, the mixture was washed with water, separated and dried over magnesium sulfate and the benzene stripped under vacuum. There was obtained a yield of 7.2 g. of an oil, the title compound, ND30 =1.5805.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)=[CH:3][C:2]=1[C:25]1[CH:24]=[N:23][CH:22]=[C:21]([F:20])[CH:26]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3cncc(F)c3)c2)c1=O
Yield: 59 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine, in the same way as in Example 1, to give 1-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyl]-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one as an off-white solid (62 mg, 59%): δH (400 MHz, d6-DMSO) 3.69 (3H, s), 6.36 (1H, s), 7.23 (1H, d, J 7), 7.40-7.56 (3H, m), 7.68-7.69 (1H, m), 7.94 (1H, s), 8.57 (1H, d, J 3), 8.66 (1H, d, J 1); m/z (ES+) 339 [MH+].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[CH2:14][C@:13]4([CH:19]5[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]5)[CH2:15]4)[O:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[Br:22]Br>CN(C=O)C.C(Cl)(Cl)Cl>[Br:22][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]1[CH:7]=[C:8]2[CH2:14][C@:13]3([CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[O:12][C:9]2=[N:10][CH:11]=1
Reactant: c1cc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)co1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Brc1occc1-c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
(2′R)-5′-(Furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (102 mg, 0.37 mmol), was stirred with bromine (65 mg, 0.41 mmol) in DMF (3 ml) at room temperature for 1 h. Vaccum was applied, and the mixture was stirred for a further 30 min. The reaction mixture was diluted with chloroform, and washed with aqueous sodium hydroxide, then the organic layer was dried, filtered and evaporated. The compound was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound (28 mg) as a pale solid; m/z 361, 363 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCNC(=O)c3ccc(-c4ccccc4)cc3)c2c1
Yield: 63.9 %

Procedure:
N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-methoxy-1H-indol-3-yl)ethanamine (0.100 g, 0.515 mmol), biphenyl-4-carbonyl chloride (0.120 g; 0.541 mmol), and triethylamine (0.087 mL; 0.616 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent with 10% ethyl acetate in dichloromethane) furnished 0.122 g (64%) of N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1)[CH3:2].C1C(=O)N([Br:20])C(=O)C1>C(Cl)Cl>[Br:20][C:8]1[C:9]([NH2:12])=[N:10][CH:11]=[C:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:7]=1
Reactant: CCOCCc1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOCCc1cnc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(2-ethoxyethyl)pyrazin-2-amine (45 mg, 0.269 mmol) in DCM (897 μL) was added NBS (43.1 mg, 0.242 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. After quenched with sat. NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 246.0 (MH+), 0.59 min.
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:13]=[CH:14]/[N:15](C)C)=[C:4]([N+]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(OCC)(=O)C.[H][H]>[Ni].O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:15][CH:14]=[CH:13][C:3]=12
Reactant: [H][H]
Reactant: COc1ncc(Br)c(/C=C/N(C)C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(Br)c2cc[nH]c12
Yield: 56 %

Procedure:
(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added to Ra-Ni 2800 (pre-washed with ethanol), water slurry (6.9 g, 118 mmol) in a stainless steel pressure bottle and stirred for 30 minutes at 30 psi of hydrogen and room temperature. The reaction mixture was filtered, and concentrated. The residue was triturated with dichloromethane, and the solid collected by filtration to provide 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (5.82 g). The mother liquor was evaporated and the residue triturated again with dichloromethane and filtered to provide an additional 1.63 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine. Total yield=7.45 g, 72% yield.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl[CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33].[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>O>[CH2:33]([O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2)[CH2:32][CH2:31][CH2:30][C:29]#[CH:28]
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Reactant: C#CCCCCCl
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C#CCCCCON=C1CC(c2ccccc2-c2ccccc2)Cc2nc(N)nc(C)c21

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (50 mg, 0.145 mmol), 6-chloro-1-hexyne (21 μl, 0.174 mmol) and sodium hydride (60% dispersion in oil) (11 mg, 0.465 mmol), following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88), except after addition of water the solvent was removed under reduced pressure. The crude material was taken up in methanol (20 ml) and the resulting solution was filtered. The solvent was removed under reduced pressure. The title compound was purified by preparative HPLC (mass directed fraction collection).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]#N)=[CH:14][C:15]([O-:17])=[O:16])=[CH:9][CH:8]=1.[K+]>C(O)=O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18](=[O:2])[O:16][C:15](=[O:17])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC(=CC(=O)[O-])c1ccc(Cl)cc1
Agent: [K+]
Solvent: O=CO
Product: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Temperature: 50 °C

Procedure:
With stirring, 80 ml of concentrated sulfuric acid were added dropwise to 1.38 g (0.57 mol) potassium 3-(4-chlorophenyl)-3-cyanoacrylate in 1.2 1 of 88% strength formic acid. During the addition, the temperature increased to 50° C. The mixture was refluxed for 3 h and, after cooling; put into 10 l of ice-water and then stirred for 1 h, and the product was filtered off, washed with water and dried under reduced pressure. Yield: 86.0 g of m.p. 144-145° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([OH:19])=O)[S:16][C:3]1=2.O=S(Cl)Cl.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])[S:16][C:3]1=2
Reactant: C1COCCN1
Reactant: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)O)sc21
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)N3CCOCC3)sc21
Reaction time: 1 h

Procedure:
280 mg of (68) was added to 25 ml of THF, 0.5 ml of SOCl2 was added, and the reaction left with stirring for 1 hour. 1 ml of morpholine was added in portions, and stirring continued. The precipitated morpholine hydrochloride was filtered off, and the solvent evaporated. The residue was purified by column chromatography on silica gel, using MeOH in CH2Cl2, 1+9 as the eluent. MeOH was added to the pooled fractions to precipitate the product, giving after filtration and drying 50 mg of (69). M.p. 250°-2° C.
Reaction SMILES: [CH:1]([Si:4]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:6]1)([CH3:3])[CH3:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C.O>O1CCCC1>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([Si:4]([CH:1]([CH3:2])[CH3:3])([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26])[CH:6]=3)=[CH:20][CH:19]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(N)cc2)c2cccnc21
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenylamine (113, 70.0 mg, 0.184 mmol) was dissolved in tetrahydrofuran (12 mL) and 3-trifluoromethyl-phenyl isocyanate (41 mg, 0.22 mmol) and triethylamine (28 mg, 0.28 mmol) were added under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated to give crude compound 114 used in the next step.