Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=[O:3].C(=O)=O.C(OC[C@@H:17]([CH2:28][N:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31][C:30]1=[O:36])[C@H:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl>ClCCl>[NH2:35][C:32]1[CH:33]=[CH:34][N:29]([CH:28]([OH:3])[CH2:17][CH:18]([OH:20])[CH3:19])[C:30](=[O:36])[N:31]=1
Reactant: CC(C)=O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1ccc(N)nc1=O
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: ClCCl
Product: CC(O)CC(O)n1ccc(N)nc1=O
Reaction time: 10 h
Yield: 82 %

Procedure:
To a cold (˜−77° C., acetone/dry ice bath) solution of 19 (1.2 g, 2.87 mmol) in 50 ml of anhydrous dichloromethane was added via syringe 19 ml (19 mmol) of 1 M BCl3/CH2Cl2. The reaction was stirred for 10 hrs and quenched with a mixture of methanol (27 ml) and pyridine (13 ml). The reaction was warmed up, concentrated, co-evapoarated with a triethylamine/MeOH mixture to remove pyridine and chromatographed on C18 (5×25 cm) column eluting with a gradient of acetonitrile (0-15%). Concentration of the pure product fractions afforded 0.5 g (82%) of nucleoside 20 as a white solid. 1H NMR (DMSO-d6): δ 7.52 (d, J=7.2 Hz, 1H), 7.01 (br s, 2H), 5.65 (d, J=7.2 Hz), 4.70 (d, J=4.8 Hz, 1H), 4.62 (t, J=5.4 Hz, 1H), 3.84 (m, 1H), 3.63 (m, 2H), 3.34 (m, 1H), 3.25 (m, 1H), 1.68 (m, 1H), 1.08 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[F:14][C:15]([F:32])([F:31])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25]3)=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:32][C:15]([F:14])([F:31])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:26][CH2:25]3)=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 25 °C

Procedure:
1.25 g of commercially available 4-cyano-benzenesulfonyl chloride were dissolved in 35 ml dichloromethane. Then 760 mg 5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole hydrochloride were added followed by 2.14 ml triethylamine. The mixture was stirred at room temperature for fifteen minutes. Then 100 ml of dichloromethane were added, the mixture washed with 40 ml water and brine and then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 517 mg of 4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile as amorphous lyophilisate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14].[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH:12]=1
Reactant: O=Cc1cccn1-c1ccncc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cn1-c1ccncc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 29.4 %

Procedure:
To a solution of 2.95 g of 1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde in 20 ml of N,N-dimethylformamide was added 2.66 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.2 g of 4-bromo-1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].C(Cl)Cl.Cl.[CH3:11][NH:12][O:13][CH3:14]>O>[CH3:14][O:13][N:12]([CH3:11])[C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: CNOC
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 2-methoxyacetyl chloride (10 g, 92.1 mmol) and DCM (100 mL) cooled to 0° C. was added N,O-dimethylhydroxylamine hydrochloride (9.89 g, 101 mmol) and TEA (38.5 mL, 276 mmol) and the reaction warmed to RT and stirred for 18 h. The reaction mixture was poured into H2O and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by SiO2 chromatography eluting with DCM/MeOH (500:50) to afford 12 g (97.8%) of N,2-dimethoxy-N-methylacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:24][C:18]=4[N:17]=3)=[N:9]2)=[CH:5][CH:4]=1>[Fe].O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[C:10]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([CH2:25][N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[CH:24][C:18]=4[N:17]=3)=[N:9]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Agent: [Fe]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(N)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Yield: 93.7 %

Procedure:
To a mixture of 2-[1-(4-methoxy-benzyl)-4-nitro-1H-pyrazol-3-yl]-5-morpholin-4-ylmethyl-1H-benzimidazole (1.6 g, 3.57 mmol), Fe powder (2 g, 35 mmol) and FeSO4.7H2O (0.496 g, 1.78 mmol) was added 1,4-dioxane:water (5:1, 120 ml). The mixture was refluxed for 3 h, filtered through celite, washing with MeOH, and reduced in vacuo azeotroping with toluene. EtOAc (100 ml) was added and insoluble material removed via filtration. The filtrate was reduced in vacuo to give 1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine as a dark brown solid (1.4 g, 94%). (LC/MS: Rt 1.72, [M+H]+ 419).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[C:13]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:14]=3[N:15]=[C:16](Cl)[N:17]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[OH-].[NH4+].[CH3:34][CH:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[C:45]([O:50][CH3:51])[CH:44]=2)[CH2:39][CH2:38]1)[CH3:36]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[C:13]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:14]=3[N:15]=[C:16]([NH:47][C:46]3[CH:48]=[CH:49][C:43]([N:40]4[CH2:41][CH2:42][N:37]([CH:35]([CH3:34])[CH3:36])[CH2:38][CH2:39]4)=[CH:44][C:45]=3[O:50][CH3:51])[N:17]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(Br)cc4C(N)=O)nc(Cl)nc32)cc1
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2ccc(Br)cc2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Yield: 73.1 %

Procedure:
According to General Protocol III/Step A & B, 5-bromo-2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (1.5 g, 3.69 mmol), 27% aqueous ammonium hydroxide, and 4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (0.550 g, 3.32 mmol) were combined to afford 5-bromo-2-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide as a pale yellow solid (1.78 g). An aliquot of 5-bromo-2-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (0.340 g) was detosylated according to the General Protocol III/Step C to afford 5-bromo-2-[(2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (0.204 g, 58% yield, 3 steps); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.41 Hz, 6H), 2.56 (s, 4H), 2.63 (d, J=6.23 Hz, 1H), 3.07 (s, 4H), 3.26 (s, 3H), 6.19 (dd, J=3.30, 1.83 Hz, 1H), 6.45 (d, J=8.97 Hz, 1H), 6.59 (d, J=2.01 Hz, 1H), 6.91 (d, J=2.20 Hz, 1H), 7.41 (s, 1H), 7.51 (dd, J=9.06, 2.29 Hz, 1H), 7.75-7.84 (m, 2H), 7.96 (d, J=2.20 Hz, 1H), 8.35 (s, 1H), 8.88 (d, J=8.97 Hz, 1H), 11.26 (s, 1H), 11.85 (s, 1H). ESIMS (M+H)+=580.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].[Cl:10]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl>[Cl:10][CH2:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)nc(CCl)c1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A solution of 121.18 g (1 mole) of 2,4,6-collidine in 400 ml of chloroform was heated at reflux while adding in portions 140 g (0.6 mole) of trichloroisocyanuric acid (min. 90% available chlorine) over 4 hours and stirring was continued for another 30 minutes and then cooled and filtered. The filtrate was admixed with 150 ml of 10% HCl to transform the product into the aqueous phase. The decanted acid aqueous phase was mixed with 150 ml of ethyl acetate and was made alkaline with sodium hydroxide. The decanted aqueous phase was extracted with 100 ml of ethyl acetate. The organic phase was dried and evaporated to dryness under reduced pressure to obtain 45 g (28.9%) of 2-chloromethyl-4,6-dimethyl pyridine with a Cl content of 22.78% (theoretical 22.78%) and a boiling point of 64° to 70° C. at 1 mm Hg.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N#N>CCN(CC)CC.O.[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>[C:24]1([C:30]#[C:31][C:2]2[CH:23]=[CH:22][C:5]3[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]4[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=4[C:4]=3[CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(C#Cc3ccccc3)ccc12)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (150 mg, 0.040 mmol) in Et3N (3.0 mL) was added the phenylacetylene (50 mg, 0.05 mmol), CuI (10 mg) and PdCl2(PPh3)2 (10 mg). The mixture was stirred under reflux and N2 atmosphere for 12 h. After cooling to room temperature, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated to a crude residue that was purified by preparative TLC to afford 9-(phenylethynyl)-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H-NMR (300 MHz, MeOH): δ 10.03 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H) 7.39 (m, 1H), 6.62 (m, 4H), 3.30 (s, 1H), 1.27 (d, J=6.9 Hz, 2H), 1.03 (s, 9H). LRMS calculated for C26H25N3O [M+H]+, 396; found 396.
Reaction SMILES: [F:1][C:2]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.O.Cl>C(#N)C>[CH3:34][O:33][C:31]1[N:30]=[C:29]([O:35][CH3:36])[N:28]=[C:27]([NH:26][C:25]([NH:17][S:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:2]([F:1])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5])(=[O:16])=[O:15])=[O:24])[N:32]=1
Reactant: NS(=O)(=O)c1sccc1C(F)=C(F)C(F)(F)F
Reactant: COc1nc(NC(=O)Oc2ccccc2)nc(OC)n1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COc1nc(NC(=O)NS(=O)(=O)c2sccc2C(F)=C(F)C(F)(F)F)nc(OC)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
According to steps (1) to (4) in Preparation Examples 1, 3-(1,2,3,3,3-pentafluoropropen-1-yl)-2-thiophenesulfonamide was prepared. A portion (0.3 g) of this substance and 0.311 g of phenyl-N-(4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate were dissolved in 4 ml of dry acetonitrile. To the solution, 0.175 g of 1,8-diazabicyclo-(5,4,0)-7-undecene was added dropwise, and the mixture was subjected to reaction under stirring for 2.5 hours at room temperature. After completion of the reaction, the resulting product was poured into water and acidified with hydrochloric acid. The precipitated crystals were filtered, washed with water and dried to obtain 0.47 g of the object compound having a melting point of 149° to 153° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:27][C:25]1[CH:24]=[CH:23][C:19]([C:20]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:21])=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1ccc(F)cc1C(F)(F)F
Reaction time: 48 h

Procedure:
30.7 g (0.22 mol) of ethyl glycinate hydrochloride were suspended in CH2Cl2. At 0° C., 86.3 g (0.854 mol) of triethylamin and 50 g (0.22 mol) of 2-trifluoromethyl-4-fluorobenzoylchlorid dissolved in 250 ml of CH2Cl2 were successively added dropwise. After 48 h at RT, the solution was washed and dried, and the solvent was removed. This gave 62.2 g (97% of theory) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[N:46]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[C:34](=[O:36])[NH:54][CH2:53][CH2:52][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:4][N:3]=1
Reactant: NCCN1CCCCC1
Reactant: COc1cc(-c2csc3c(/C=C/C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2csc3c(/C=C/C(=O)NCCN4CCCCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A mixture of Example 271 (30.6 mg, 0.044 mmol), N,N-diisopropylethylamine (35 μL, 0.20 mmol), 2-piperidin-1-ylethylamine (14.3 μL, 0.10 mmol), and DMF (1 mL) was treated sequentially with 0.5M (0.09 mL) of HBTU in DMF and 0.5M (0.09 mL) of HOBT in DMF. The reaction was stirred for 24 hours at ambient temperature and partitioned between 1N NaOH and ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product (20.4 mg, 0.034 mmol). LCMS m/e 609.2; retention time: 2.93 min.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[C:12]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCc2ccccc2C1
Solvent: CCOCC
Product: c1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.6 g. of 2-tetralone, 20 g. of phenyl magnesium bromide, and 200 ml. of diethyl ether is stirred for 4 hours and then refluxed for one hour. The mixture is acidified with the addition of 200 ml. of 1 N hydrochloric acid, filtered, and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, filtered, dried and evaporated; unchanged 2-tetralone is removed by distillation. The residue, containing 2-phenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5 percent palladium-on-charcoal catalyst; the resulting mixture is heated to 200° C for 6 hours, cooled, diluted with 250 ml. of chloroform, filtered, and evaporated to give 2-phenylnaphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cncc(Br)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.44 g (2.2 mmol) 5-bromonicotinic acid, 0.30 g (2.2 mmol) 5-fluoroindoline, 0.75 g (2.3 mmol) TBTU and 0.60 mL (4.3 mmol) TEA were combined in 3.0 mL DMF and stirred overnight at RT. Then the reaction mixture was added to water, the precipitate formed was suction filtered and dried.
Reaction SMILES: [CH:1]1([CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:26].[Na+]>CO.O>[CH:1]1([CH2:5][C:6]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:24])=[O:26])=[CH:21][CH:22]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
A solution of 2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (90 mg, 0.266 mmol) in methanol (6 mL) was added a sodium metaperiodate (171 mg, 0.798 mmol) solution in water (3 mL). The resulting mixture was stirred for 12 h at room temperature, extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to afford 2-cyclobutyl-1-(4-methanesulfinyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (94.2 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C20H22N2O2S [M+H]+ 355.47, observed 355.4.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH2:3].Cl.[C:16](=O)(O)[O-].[Na+]>CO>[CH3:16][O:13][C:12](=[O:14])[CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1NCC(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCc1ccccc1NCC(=O)OC

Procedure:
A solution of 0.06 mol of N-(2-allylphenyl)glycine, prepared as described by A. Padwa, R. Lim, J. G. MacDonald, H. L. Gingrich, and S. M. Kellar in J. Org. Chem., 1985, 50, 3816-3823, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(2-allylphenyl)glycine methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>C(N(CC)CC)C.[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>[CH2:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]([CH2:25][C:24]([O:23][CH3:22])=[O:33])=[CH:27][CH:28]=3)=[CH:4][C:5]=2[CH2:20][CH3:21])[CH2:11][CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 107.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 110.0 mg, 0.39 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 130.0 mg (79%) of the title compound as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7]C(=O)[C:5]2=[O:15].[OH:16]O.Cl>[OH-].[Na+]>[NH2:7][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[C:5]([OH:15])=[O:16]
Reactant: OO
Reactant: O=C1Nc2c(cc(Br)cc2[N+](=O)[O-])C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a slurry of 5-bromo-7-nitro-1H-indole-2,3-dione (5.5 g, 20.3 mmol) in aqueous 5N NaOH solution (23.2 mL) was added an aq. solution of 33% hydrogen peroxide solution (4.96 mL) slowly at 0° C. After completion of the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with 2N HCl and the solid the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (5 g, 94.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:31]([C:30]3[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=3)=[O:32])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=469.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.CN(C=O)C>S(Cl)(Cl)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=c1[nH]cnc2ccccc12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: c1ccc2ncncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 293.9 %

Procedure:
A solution of 6-methoxy-7-(2-(N-methyl-N-(3-morpholinopropylsulphonyl))amino)ethoxy)-3,4-dihydroquinazolin4-one (176 mg, 0.4 mmol) in thionyl chloride (4 ml) containing DMF (100 μl) was stirred at 45° C. for 1 hour. The volatiles were removed by evaporation and by azeotroping with toluene. The residue was partitioned between methylene chloride and water, the aqueous phase was adjusted to pH8 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methanol/methylene chloride (a gradient from 3/100 to 10/90). The purified product was triturated with ether, collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(N-methyl-N-(3-morpholinopropylsulphonyl)]amino)ethoxy)quinazoline (153 mg, 71%).