Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:24])[O:4][N:3]=1.[H-].[Na+].[CH3:27]I>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:27])[C:11](=[O:16])[C:10]3([CH3:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(3,5-Dimethyl-isoxazol-4-yl)-3-methyl-3-phenyl-1,3-dihydro-indol-2-one (54 mg, 0.196 mmol) and NaH (5.5 mg, 0.203 mmol) in THF (10 mL) is stirred at room temperature for 1.5 h. MeI (48 mg, 0.338 mmol) is added to the mixture and stirred overnight. The solvent is removed in vacuo. The residue is purified by chromatography (ethyl acetate:petroleum ether=1:2) to give the desired compound.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([NH:18]C(OC(C)(C)C)=O)[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>>[NH2:18][CH:4]([CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Agent: Cl
Product: NC(C(=O)O)C(c1ccccc1)c1ccccc1

Procedure:
Reaction was carried out in a similar manner to Example 26, except that 2.5 g of N-Boc-glycine methyl ester was used in place of 1-dimethylethyl-(2R)-(2,6-dichlorophenyl)-5-oxo-3-((1′R)-phenylethyl)tetrahydro-1H-1-imidazolecarboxylate to obtain 640 mg of 2-(N-Boc-amino)-3,3-diphenylpropionic acid methyl ester as a colorless oily material (yield: 14%). Further, 354 mg of 2-(N-Boc-amino)-3,3-diphenylpropionic acid methyl ester was mixed with a 6 M solution of aqueous hydrochloric acid, and the mixture was refluxed for 5 hours. Thereafter, the mixture was washed with toluene, and neutralized with a 30% aqueous solution of sodium hydroxide to obtain a white solid of 2-amino-3,3-diphenylpropionic acid. The retention time of the respective isomers was confirmed by using the product.
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2N=N1.C(N)C1C=CC=CC=1.[CH2:51]([NH:53][C:54]([CH:56]1[CH2:60][CH:59]([N:61]2[C:65]3[N:66]=[C:67]([S:80][CH2:81][CH2:82][CH3:83])[N:68]=[C:69]([NH:70][CH:71]4[CH2:73][CH:72]4[C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=4)[C:64]=3[N:63]=[N:62]2)[CH:58]([OH:84])[CH:57]1[OH:85])=[O:55])C>CN(C=O)C>[OH:85][CH:57]1[CH:58]([OH:84])[CH:59]([N:61]2[C:65]3[N:66]=[C:67]([S:80][CH2:81][CH2:82][CH3:83])[N:68]=[C:69]([NH:70][CH:71]4[CH2:73][CH:72]4[C:74]4[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=4)[C:64]=3[N:63]=[N:62]2)[CH2:60][CH:56]1[C:54]([NH:53][CH2:51][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:55]
Reactant: On1nnc2ccccc21
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: NCc1ccccc1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCc4ccccc4)C(O)C3O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (3 eq) was added to a solution of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.5 eq), 1-hydroxybenzotriazole hydrate (1.5 eq), benzylamine (2 eq) and the product of Example 1, step c) (1 eq) in DMF (20 ml). The reaction mixture was stirred at room temperature for 2 hours then added dropwise to stirred acidic ice-water. The subtitle compound was isolated by filtration.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11](=[O:16])[N:10]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21](C(OC(C)(C)C)=O)[CH:22]=[N:23][C:19]=2[CH:18]=1.[F:33][CH:34]([F:40])[C:35]([F:39])([F:38])[CH2:36]I>>[F:38][C:35]([F:39])([CH:34]([F:40])[F:33])[CH2:36][O:15][C:12]1[C:11](=[O:16])[N:10]([C:17]2[CH:32]=[CH:31][C:20]3[NH:21][CH:22]=[N:23][C:19]=3[CH:18]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[C:13]=1[CH3:14]
Reactant: FC(F)C(F)(F)CI
Reactant: CC1=C(O)C(=O)N(c2ccc3c(c2)ncn3C(=O)OC(C)(C)C)C1c1cccc(F)c1F
Product: CC1=C(OCC(F)(F)C(F)F)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cccc(F)c1F

Procedure:
The compound was synthesized starting from tert-butyl 5-(2-(2,3-difluorophenyl)-4-hydroxy-3-methyl-5-oxo-2H-pyrrol-1(5H)-yl)-1H-benzo[d]imidazole-1-carboxylate (0.441 g, 1 mmol), 1,1,2,2-tetrafluoro-3-iodopropane (0.17 ml, 1.5 mmol) and P1-tBu (0.38 ml, 1.5 mmol) according to the method described above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][C:28]([NH2:30])=[S:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]=[C:28]([CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:29][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)CCc1ccccc1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ccc(-c2sc(CCc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, Step 3)(0.115 g, 0.340 mmol) in ethanol (4 mL) in a 10 mL round bottom flask was added 3-phenylthiopropionamide from Step 1 (0.059 g, 0.357 mmol) and the mixture was heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with Na2CO3 (10% solution), brine, dried over Na2SO4, filtered and concentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-(2-phenylethyl)thiazole (0.090 g, 65%) as oily crystals: mp 97°-99° C.; 1HNMR (CDCl3) 300 mHz 7.50 (d of d, J=5.38 and 8.80, 2 H), 7.35-7.15 (m, 9H), 6.99 (t, J=8.80, 2H), 3.35 (t, J=8.80, 2 H), 3.19 (t, J=8.56 Hz, 2H), 2.49 (s, 3H); MS (EI) m/z 405.10 (MH+), HRMS (M+) Δ=0.0 mmu.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.C(N(C(C)C)CC)(C)C.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CO>CN(C=O)C.[Cl-].[Na+].O.C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CNCCN1CCSc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)CC(=O)OC(C)(C)C

Procedure:
A solution of N-methyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (0.95 g, 3.75 mmol), diisopropylethyl amine (1.960 mL, 11.25 mmol), and tert-butyl bromoacetate (0.61 mL, 4.13 mmol) in DMF (20 mL) was heated at 55° C. for 17 hours (overnight). The yellow solution was diluted with brine (40 mL) and extracted with EtOAc (100 mL). The organic extract was separated and rinsed with brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to give a yellow residue. This residue was subjected to flash chromatography on silica gel using 2.5:97.5 MeOH:CH2Cl2 to give a yellow brown residue. Two fractions were collected, with the latter containing a non-polar yellow spot (950 mg, 68.9%). 1H-NMR (CDCl3) δ 7.96 (d, J=2.7 Hz, 1H), 7.88 (d, J=2.7, 9.3 Hz, 1H), 6.65 (d, J=9.3 Hz, 1H), 3.88-3.83 (m, 2H), 3.55 (t, J=7.2 Hz, 2H), 3.20 (s, 2H), 3.02-2.99 (m, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.44 (s, 3H), 1.46 (s, 9H); ESI-MS (m/z, %): 368 (MH+, 20), 312 (100).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([N+:29]([O-])=O)=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CCO.O.CC(O)=O.[Fe]>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([NH2:29])=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc([N+](=O)[O-])cc3n2)cc1
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(N)cc3n2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
[2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (182 mg, 4.18.10−4 mol) is dissolved in a mixture EtOH/water/AcOH (25/10/1, 36 mL) and the reaction is heated at 90° C. Iron powder (93 mg) is added and the mixture is stirred at 90° C. for 4 hours, cooled to room temperature and filtered through a pad of celite. The pad is washed with methanol and the combined filtrate is concentrated in vacuo. The residue is purified by flash chromatography (SiO2, DCM/MeOH gradient) to give the desired [2-(4-acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:9](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:10].O.O.O.O.O.[N+]([O-])([O-])=O.[Bi+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(OCC)(=O)C>C(Cl)Cl.O>[O:8]=[C:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:10][C:9](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2]1
Reactant: O=C1C=CCCCC1
Reactant: CC(C)(C)OC(N)=O
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a stirring mixture of cyclohept-2-enone (26.96 g, 245.0 mmol) and tert-butyl carbamate (28.7 g, 245 mmol) in DCM (245 mL) was added bismuth nitrate pentahydrate (22.79 g, 47.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was diluted reaction with ethyl acetate (500 mL) and water (300 mL) and the biphasic mixture was filtered through a bed of Celite. The bed of Celite was washed well with ethyl acetate and water, and layers of the filtrate separated. The organic layer was concentrated to an oil that was purified by silica gel chromatography (0-40% ethyl acetate in hexanes). Product containing fractions were concentrated to afford the title compound (31.09 g, 137 mmol, 55.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (d, J=7.03 Hz, 1H), 3.60 (d, J=8.59 Hz, 1H), 2.55-2.69 (m, 1H), 2.26-2.45 (m, 2H), 1.69-1.93 (m, 3H), 1.44-1.61 (m, 2H), 1.37 (d, J=5.08 Hz, 11H). MS (ESI) m/z 228.5 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.CC(O)=O>O.CCOC(C)=O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[CH:9][C:8]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2sncc2c1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc2sncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
5-Nitrobenzo[d]isothiazole (305 mg, 1.69 mmol), 5% AcOH (aq.) (12 mL) and EtOAc (12 mL) at 65° C. was treated with iron powder (325 mesh, 473 mg) and stirred rapidly for 1 h. The mixture was cooled to ambient temperature, diluted with water and EtOAc and filtered through dicalite. The organic layer was separated and the aqueous layer extracted with further EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid (220 mg, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:9]([C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([F:24])([F:23])[F:12])[CH:7]=[CH:6][C:5]=1[NH2:8])([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
A solution of 4-bromo-2-nitro-phenylamine (5.00 g, 0.0230 mol) in DME (100 mL) was treated with (2-trifluoromethylphenyl) boronic acid (5.25 g, 0.0277 mol), LiCl (0.976 g, 0.0230 mol), and 2M aqueous Na2CO3 (92.1 mL, 0.184 mol). The resulting mixture was heated to 80° C. under a stream of Argon, treated with Pd(PPh3)4 (2.66 g, 0.00230 mol) and heated to 80° C. overnight. The cooled mixture was diluted with water and extracted thrice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 200-g Sepra Si 50 SPE column (Isco system: flow rate=40 mL/min; eluting with EtOAc/hexanes, 5:95 v/v, over 10 min, 5:95 to 20:80, v/v over 25 min, and 20:80 to 40:60 v/v over 35 min) to yield 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine as an orange solid
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]4)=[CH:48][CH:47]=2)=[CH:39][CH:38]=1>>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]4)=[CH:50][CH:51]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(OC)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: COc1ccc(NC(=S)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)O)C(C)C)C4=O)cc2)cc1
Yield: 63 %

Procedure:
The compound of example 261 was prepared analogous to compound of example 257 by hydrolysis of compound of example 260.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].C(O[CH:9](OCC)[CH2:10][Br:11])C>Cl>[Br:11][CH2:10][CH:9]1[NH:5][S:1](=[O:3])(=[O:2])[NH:4][CH:9]([CH2:10][Br:11])[NH:5][S:1](=[O:3])(=[O:2])[NH:4]1
Reactant: NS(N)(=O)=O
Reactant: CCOC(CBr)OCC
Agent: Cl
Product: O=S1(=O)NC(CBr)NS(=O)(=O)NC(CBr)N1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
0.01 mole of sulphamide in 5 ml of concentrated hydrochloric acid is added to 0.012 mole of bromoacetaldehyde-diethylacetal, at room temperature whilst stirring. After 5 minutes, the precipitate which has formed is filtered off and washed with ice water, dried and recrystallised from acetone/petroleum ether. 3,7-Di-(bromomethyl)-1,5-dithia-2,4,6,8-tetra-aza-cyclooctane-1,1,5,5-tetraoxide is obtained as colourless needle-shaped crystals of melting point 172° C (decomposition) in a yield of 60%.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: C#C[Si](C)(C)C
Reactant: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1-(methylsulfonyl)-4-(4-bromophenyl)piperazine (4.79 g, 15 mmol, prepared as in example 3), trimethylsilylacetylene (4.15 mL, 30 mmol), Copper (I) iodide (31 mg, 0.17 mmol) and triphenylphosphine (80 mg, 0.3 mmol) in piperidine (60 mL) at 20° C. was added dichlorobis(triphenylphosphine)palladium(II) (31 mg, 45 μmol). The reaction was warmed to 105° C. and stirred for 8 hours under an inert atmosphere. After cooling, the suspension was filtered and washed with toluene. The solid was dissolved in CH2Cl2, washed with water and filtered through silica, washing with CH2Cl2. The filtrate was concentrated and the resulting suspension filtered, washing well with CH2Cl2/iHexane to give 1-(methylsulfonyl)-4-[4-(trimethylsilylethynyl)phenyl]piperazine as a white powder (3.05 g, 9.06 mmol, 60
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[C:7]=1[F:25])[CH3:2].I[C:28]1[CH:29]=[N:30][N:31]([CH2:33][CH2:34][CH3:35])[CH:32]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][CH3:35])[CH:32]=3)[C:14]=2[CH3:24])[C:7]=1[F:25])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F
Reactant: CCCn1cc(I)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-phenyl]-acetic acid ethyl ester and 4-iodo-1-propyl-1H-pyrazole.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:21]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[C:26]1([C:22]2[CH:21]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:5]3[CH:4]=[C:3]([OH:2])[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:6]=3)[CH:25]=[CH:24][CH:23]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccccc2-c2cccc(-c3ccccc3)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccccc2-c2cccc(-c3ccccc3)c2)nn1-c1ccccn1
Yield: 82 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 33 of Example C-7 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]Cl)=[CH:8][N:7]=1)=[O:5])[CH3:2].[C-:14]#[N:15].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:14]#[N:15])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CCl)cn1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CC#N)cn1

Procedure:
10.5 g (52.6 mmol) 5-(chloromethyl)pyridine-2-carboxylic acid ethyl ester [preparation according to H. Barth et al., Liebigs Ann. Chem. 1981, 2164-2179] are initially introduced into 75 ml anhydrous DMF and 2.58 g (52.6 mmol) sodium cyanide are added in portions at RT in the course of 3 h. The mixture is then introduced on to 500 ml saturated ammonium chloride solution and extracted with methylene chloride (four times with 100 ml each time). The combined organic phases are dried over sodium sulfate and concentrated and the residue is purified by chromatography over silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 1:4). 3.80 g (38% of th.) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH3:28]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH3:28])[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: CCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 1-iodoethane.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([CH3:30])([CH3:29])[CH2:9][N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[C:5]2=[CH:4][C:3]=1[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C([Sn]([C:50]#[N:51])(CCCC)CCCC)CCC>CN1C(=O)CCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:5]4[C:6](=[N:7][C:2]([C:50]#[N:51])=[C:3]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:4]=4)[C:8]([CH3:29])([CH3:30])[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2nc(Br)c(N3CCOCC3)cc21
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2nc(C#N)c(N3CCOCC3)cc21
Temperature: 140 °C

Procedure:
To a stirred solution of 4-(5-bromo-3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline (61 mg, 0.111 mmol) in NMP (1.5 mL) was added tri-n-butyltin cyanide (35.2 mg, 0.111 mmol), XPhos precatalyst (16.3 mg, 0.022 mmol) and heated at 140° C. for 2 h in the microwave. After this time the reaction was partitioned between EtOAc (60 mL) and water (30 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile water) gave 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile. 1H NMR (400 MHz, chloroform-d) δ ppm 8.68-8.80 (1H, m), 7.84-7.99 (3H, m), 7.67 (1H, dd, J=9.2, 5.9 Hz), 7.44 (1H, ddd, J=6.9, 4.9, 1.9 Hz), 7.35 (1H, ddd, J=9.2, 8.0, 2.5 Hz), 5.74 (1H, s), 3.87 (2H, s), 3.79 (4H, t, J=4.7 Hz), 2.94-3.11 (4H, m), 2.40 (3H, s), 1.59 (3H, s), 1.53 (3H, s). Mass Spectrum (ESI) m/e=495.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1N.N([O-])=[O:14].[Na+].O>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[OH:14]
Reactant: O=N[O-]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1O
Temperature: 0 °C

Procedure:
2,6-Dimethyl-3-nitrobenzenamine (10.4 g, 62.6 mmol) was dissolved in 75% sulfuric acid (200 ml). Mixture cooled to 0° C. and treated with a solution of sodium nitrite (4.53 g, 65.7 mmol) in concentrated sulfuric acid (25.0 ml). After the mixture had been stirred for 1 hour at this temperature, water (200 ml) was added and the mixture warmed to 60° C. until the evolution of gas ceased. The mixture was allowed to cool to room temperature and then filtered to afford 2,6-dimethyl-3-nitrophenol. MS m/z=168 (M+H)+. Calc'd for C8H9NO3: 169.18.