Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:24](Cl)(Cl)=[S:25]>>[Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:24]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:9]=1)=[S:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N′-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline (80 mg, 0.308 mmol) and NaHCO3 in CHCH3:H2O (2.5:1, 7 mL) with thiophosgene at 0° C. The solution was allowed to warm to 23° C. and the reaction was continued overnight. The CHCH3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline (100 uL) at 23° C. for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexanes) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-145° C.; 1H NMR (CD3OD/CDCl3): d 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C@@H:6]1[C@@H:14]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:13]([CH3:20])[O:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23](=[O:33])[C:24]2[C:29]([OH:30])=[C:28]([O:31][CH3:32])[CH:27]=[CH:26][N:25]=2)[CH2:9][O:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].[CH3:34][O:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][O:35][CH2:36][CH2:37][C:38]([O:30][C:29]1[C:24]([C:23](=[O:33])[NH:22][C@H:10]2[CH2:9][O:8][CH2:7][C@H:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C@@H:14]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:13]([CH3:20])[O:12][C:11]2=[O:21])=[N:25][CH:26]=[CH:27][C:28]=1[O:31][CH3:32])=[O:39]
Reactant: COCCC(=O)Cl
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCC(C)C)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCC(=O)Oc1c(OC)ccnc1C(=O)N[C@H]1COC[C@H](OCC(C)C)[C@@H](OCC(C)C)[C@H](C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A reaction flask was charged with N-((3S,7S,8S,9S)-7,8-diisobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (97 mg, 0.207 mmol), DMAP (40.1 mg, 0.328 mmol), and DCM. 3-Methoxypropanoyl chloride (22.5 μl, 0.207 mmol) was added and the colorless solution was stirred at room temperature under N2 overnight. The reaction mixture was concentrated and purified by column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (108.5 mg, 94% yield) as a sticky orange oil: IR (thin film) 3375, 2955, 2873, 1753, 1677, 1507, 1088 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J=8.2 Hz, 1H), 8.38-8.30 (m, 1H), 7.00 (dd, J=5.7, 1.8 Hz, 1H), 5.08-4.98 (m, 1H), 4.93 (ddt, J=12.2, 8.4, 4.1 Hz, 1H), 4.00 (tt, J=7.2, 3.4 Hz, 1H), 3.93-3.84 (m, 3H), 3.85-3.64 (m, 5H), 3.64-3.55 (m, 1H), 3.41 (d, J=1.5 Hz, 3H), 3.33-3.12 (m, 5H), 2.97 (t, J=6.6 Hz, 2H), 1.82 (tt, J=12.9, 6.0 Hz, 2H), 1.43 (dd, J=6.3, 1.7 Hz, 3H), 0.97-0.85 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 170.85, 169.37, 162.67, 159.42, 146.81, 141.19, 137.38, 109.88, 84.82, 83.75, 80.56, 77.70, 74.88, 74.07, 72.99, 67.58, 58.80, 56.32, 52.13, 34.61, 29.11, 28.87, 19.58, 19.46, 19.37, 18.63; ESIMS m/z 555 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([F:22])[CH:9]=2)=[N:6][CH:7]=1.[Na+].[CH3:24][S:25]([O-:27])=[O:26].[OH-].[Na+].O>CS(C)=O>[F:22][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][N:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)[O-]
Reactant: Fc1cc(-c2ccc(Br)cn2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCc3ccccc3)c(F)c2)nc1
Yield: 33.6 %

Procedure:
2-{3-Fluoro-4-[(phenylmethyl)oxy]phenyl}-5-(methylsulfonyl)pyridine (0.168 g, 34%) was prepared as a white solid from 5-bromo-2-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}pyridine (0.50 g, 1.40 mmol), methanesulfinic acid sodium salt (0.72 g, 80%, 5.58 mmol) Cul (0.80 g, 4.19 mmol), NaOH (67 mg, 1.68 mmol) and water (0.4 mL) in DMSO (15 mL) in a manner similar to Example 83, Step 2. The crude product was triturated with hot MeOH containing 5% of CHCl3. 1H NMR (400 MHz, CDCl3): δ 9.14 (d, 1H, J=2.4 Hz), 8.22 (dd, 1H, Ja=8.3 Hz, Jb=2.5 Hz), 7.91 (d, 1H, J=2.2 Hz), 7.90-7.70 (m, 2H), 7.50-7.30 (m, 5H), 7.11 (t, 1H, J=8.6 Hz), 5.23 (s, 2H), 3.13 (s, 3H); LRMS (ESI), m/z 358 (M+H).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH:1]([CH3:3])[CH3:2])[C:21]#[N:22])=[CH:16][CH:15]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: CC(C)Br
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)C(C)C)cc1

Procedure:
A mixture comprising: isopropyl bromide, sodium hydroxide pels, and optionally the catalyst triethylamine (i.e., approximately 0.5 to 12 mol or weight percent) is stirred and heated to 50°-60° C. Over approximately a 30-minute period 4-methoxyphenylacetonitrile is added to the reaction mixture. Following this addition, the mixture is stirred and heated at reflux for several hours. After cooling, water is added to the reaction mixture which is then stirred briefly. The organic phase containing the product is then separated. This solution can be used in subsequent reaction steps or the product can be isolated by removal of the solvents.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(SCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(SCCCI)cc1
Yield: 92.4 %

Procedure:
A solution of N-[4-(3-chloro-1-propylthio)phenyl]methanesulfonamide (4.0 g, 0.014 mol) and sodium iodide (6.4 g 0.043 mol) in acetone (55 mL) was heated under reflux for 18 hours. The mixture was concentrated, taken up in EtOAc, washed with brine, 10% aqueous sodium bisulfite, brine, dried (MgSO4), and concentrated to give 4.8 g (91%) of product as an off-white and solid m.p. 59°-63° C.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([F:23])[C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([F:23])[C:14]([CH:21]=[O:29])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C)c1F
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1C=O
Reaction time: 8 h

Procedure:
To a mixture of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-vinylbenzoate (7.97 g), acetone (93.0 mL), acetonitrile (93.0 mL) and water (93.0 mL) were added osmium oxide (fixed catalyst I) (2.89 g) and sodium periodate (24.3 g) at room temperature, and the mixture was stirred overnight at the same temperature. The insoluble substance was removed by filtration, and the filtrate was diluted with ethyl acetate. The solution was washed with saturated brine, the organic layer was and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.97 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: CS(O[C:6]1[C:23](=[O:24])[CH2:22][CH2:21][C@@:20]2([CH3:25])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:26])(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O.O>[N:27]([C:6]1[C:23](=[O:24])[CH2:22][CH2:21][C@@:20]2([CH3:25])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:26])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C(OS(C)(=O)=O)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 60 °C
Yield: 60.4 %

Procedure:
To a stirred solution of 1.0 g of 4-methanesulfonyloxyandrost-4-en-3,17-dione in 5 ml of dimethylformamide are added 220 mg of powdered sodium azide dissolved in 3 ml of water. The resulting mixture is heated at 60° C. for 1 hour, cooled, poured into 250 ml of cold water and extracted with ethyl acetate (4×50 ml). The combined extracts are washed with saturated NaCl aqueous solution, dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by flash column chromatography on neutral Al2O3. Elution with n-hexane:diethyl ether 1:1 gives 0.52 g of the title compound, m.p. 142°-143° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:18]=2)[CH:13]=[CH:14][CH:15]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:30][CH2:31]4)=[CH:22][CH:21]=3)[N:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1F
Reactant: CN(C)C(=O)CCl
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(CC(=O)N(C)C)CC5)cc4)nc23)c1F

Procedure:
2-(4-{4-[8-(2-Fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(2-fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.150 g, 0.359 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.055 mL, 0.539 mmol) in a manner analogous to Example 313 to give product (0.075 g, 42%). MP=237-240° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.82 (d, 1H), 7.60 (m, 3H), 7.25 (m, 3H), 7.10 (m, 3H), 3.90 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.85 (s, 3H), 2.35 (m, 1H), 2.10 (m, 2H), 1.65 (m, 4H). MS=503 (MH)+.
Reaction SMILES: COC1C=C(CNCCCNCCCCNCCCN)C=CC=1O.C(O[C:29]1([CH3:58])[CH2:34][CH:33]([CH:35]([CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])[CH3:36])[C:32]2C=[CH:44][C:45]([CH:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH3:48])=[CH:46][C:31]=2[O:30]1)(=O)C.[C:59](=[O:62])([O-])[O-].[K+].[K+]>CO>[C:40]([NH:39][CH2:38][CH2:37][CH:35]([CH:33]1[C:32]2[C:59]([OH:62])=[CH:44][C:45]([CH:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH3:48])=[CH:46][C:31]=2[O:30][CH:29]([CH3:58])[CH2:34]1)[CH3:36])(=[O:42])[CH3:41]
Reactant: CC(=O)NCCC(C)C1CC(C)(OC(C)=O)Oc2cc(C(C)CCCc3ccccc3)ccc21
Reactant: O=C([O-])[O-]
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [K+]
Solvent: CO
Product: CC(=O)NCCC(C)C1CC(C)Oc2cc(C(C)CCCc3ccccc3)cc(O)c21

Procedure:
A solution of 156 mg (0.335 mmole) dl-5-acetoxy-4-(4-acetylamino-2-butyl)-2-methyl-7-(5-phenyl-2-pentyl)-3,4-dihydro-2H-benzopyran and 46 mg (0.333 mmole) potassium carbonate in 40 ml of methanol is stirred at room temperature for two hours. After neutralization with acetic acid the mixture is evaporated in vacuo and the residue taken up in ethyl ether. The ether solution is washed successively with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of ether affords the title amide.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6](F)=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:4]=1[CH3:20])#[N:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:35])[C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:32]2[CH2:33][CH2:34][C@H:30]([N:29]([CH3:35])[CH3:28])[CH2:31]2)=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:4]=1[CH3:20])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: COC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 10 h
Yield: 86.6 %

Procedure:
Methyl 4-cyano-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-6-carboxylate (I-183) (100 mg, 0.37 mmol) was dissolved in dimethyl, then at room temperature, triethylamine (76 μl, 0.55 mmol) and (3S)-3-(dimethylamino)pyrrolidine (56 μl, 0.44 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 10 hours, then cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=92:8) to obtain the entitled compound (118 mg) as a roughly-purified product. This was washed with diisopropyl ether to obtain the entitled compound (109 mg, 81%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=O)[CH2:12][N:11]3[C:7](=[N:8][CH:9]=[N:10]3)[C:6]=2[CH:16]=1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:29][C:13]1[CH2:12][N:11]2[C:7](=[N:8][CH:9]=[N:10]2)[C:6]2[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cn2ncnc2-c2cc(F)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccc(N(C)C)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(c1)-c1ncnn1CC(Cl)=N2
Temperature: 65 °C
Reaction time: 20 h
Yield: 81.3 %

Procedure:
To a suspension of 9-fluoro-6H-1,3,3a,6-tetraaza-benzo[e]azulen-5-one (4.40 g, 20 mmol) in chloroform (250 mL) were added N,N-dimethyl-p-toluidine (12 mL) and phosphorus oxychloride (5.7 mL, 60 mmol), and the resulting mixture was stirred for 20 h at 65° C. Further N,N-dimethyl-p-toluidine (1.2 mL) and phosphorus oxychloride (0.6 mL, 6.3 mmol) were added, and stirring was continued for 1 h at 65° C. After cooling to ambient temperature the reaction mixture was poured onto aqueous sodium hydrogencarbonate (sat., 1 L), and the resulting mixture was stirred vigorously for 45 min. The layers were separated and the aqueous layers was extracted with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated. Purification by chromatography (SiO2, hexane:ethyl acetate=100:0 to 40:60) and recrystallisation from diisopropyl ether afforded 5-chloro-9-fluoro-4H-1,3,3a,6-tetraaza-benzo[e]azulene (3.85 g) as a brown solid which was dissolved in DMF (65 mL) and cooled to −55° C. 1-Chloro-3-isocyanomethyl-benzene (4.00 g, 26.4 mmol), and a solution of potassium tert-butylate (3.15 g, 27.3 mmol) in DMF (15 mL) were added at −50° C. to −55° C. The reaction mixture was stirred for 1 h at −40° C. to −50° C. before allowing to warm to ambient temperature. Acetic acid (1.1 mL) was added, and the mixture was poured onto aqueous sodium hydrogencarbonate (sat., 2 L) and extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium hydrogencarbonate (sat.) and dried over sodium sulfate. Purification by chromatography (SiO2, dichloromethane:ethanol=100:0 to 98.5:1.5) afforded the title compound (1.25 g, 18%) as a white crystalline solid. MS: m/e=352.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:29])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-(3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)propanoyl)pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=446.03 [M+H]+.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13](=[O:21])[CH2:14][N+:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:13]([C:14]1[N:15]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[C:23]([C:22]([O:26][CH2:27][CH3:28])=[O:25])[CH:24]=1)=[O:21]
Reactant: C=CC(=O)OCC
Reactant: COc1cc(C(=O)C[n+]2ccccc2)ccc1[N+](=O)[O-]
Agent: [Br-]
Product: CCOC(=O)c1cc(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2ccccc12

Procedure:
This compound is obtained according to the same method as the preceding example in Step B by 1,3-dipolar cycloaddition of 1-[2-(3-methoxy-4-nitrophenyl)-2-oxoethyl]pyridinium bromide (obtained in Step A of the preceding example) with ethyl acrylate. A yellow powder is obtained after purification by flash chromatography on a silica column, eluting with dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 90 °C
Yield: 81.5 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]propylamine (70 mg, 0.24 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (57 mg, 0.24 mmol) and DIPEA (84 μL, 0.48 mmol) in IPA (3 mL) was heated for 24 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-7% MeOH in DCM) to afford the title compound as a pale brown oil (96 mg, 82%). LCMS (Method J): RT=3.03 min, [M+H]+=491.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Br[C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH:18]([CH3:21])[C:19]#[N:20])=[CH:11]2.Cl>C(Cl)Cl.C1(C)C=C(C)C=C(C)C=1>[CH3:17][O:16][C:15]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:18]([CH3:21])[C:19]#[N:20])[CH:9]=[CH:8]2
Reactant: COc1ccc2cc(C(C)C#N)ccc2c1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc2cc(C(C)C#N)ccc2c1
Temperature: 0 °C
Yield: 71 %

Procedure:
10 Grams of anhydrous aluminum chloride are added portionwise and under stirring to a solution containing 14.5 g of 2-(5-bromo-6-methoxy-2-naphthyl)propionitrile dissolved in 60 ml of methylene chloride and 8.3 ml of mesitylene, while keeping the temperature at about 20° C. The reaction mixture is kept at this temperature under stirring for 1 hour and then is slowly poured into a mixture made of 60 g of crushed ice and of 20 ml of a 6N aqueous solution of hydrochloric acid. The layers are separated after 15 minutes of stirring and the aqueous layer is discarded. The organic layer is twice washed with 25 ml of a 6N aqueous solution of hydrochloric acid, then with 25 ml of water and is dried over anhydrous sodium sulfate. The organic solution is evaporated to dryness under vacuum and the residue is crystallized from tetrachloroethylene obtaining 7.5 g of product with a yield of 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[S:9])=[CH:4][CH:3]=1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:21])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[S:9])=[CH:22][CH:23]=1
Reactant: Oc1c(C(=S)NCc2ccc(Cl)cc2)cnc2ccc(I)cc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=S)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarbothioamide (0.20 g) from Preparation No. 43 and triphenylphosphine (0.15 g) in freshly distilled tetrahydrofuran (5 mL) is added MeOH (0.027 mL) followed by diethyl azodicarboxylate. After an initial exotherm, the reaction is stirred at room temperature for 3 h. To drive the reaction to completion, additional triphenylphosphine (0.030 g), methanol (0.010 mL), and diethyl azodicarboxylate (0.020 mL) are added. The reaction is stirred at room temperature overnight. The reaction is concentrated in vacuo. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 1% MeOH:CH2Cl2 (1 L)) affords N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide (0.065 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[CH2:26]1[NH:31][CH2:30][CH2:29][N:28]2[CH2:32][CH2:33][CH2:34][CH:27]12>>[CH2:26]1[N:31]([C:2]2[CH:7]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:5]=[C:4]([NH2:25])[N:3]=2)[CH2:30][CH2:29][N:28]2[CH2:32][CH2:33][CH2:34][CH:27]12
Reactant: C1CC2CNCCN2C1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCN3CCCC3C2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and octahydropyrrolo[1,2-a]pyrazine (Oakwood, Cat. No. 032034). LCMS (M+H)+: m/z=445.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1F
Product: O=C(Nc1ccccc1F)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 2-Fluoro-phenylamine to produce 4-Chloro-N-(2-fluoro-phenyl)-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.