Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)([O-])=O>C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=1
Reactant: COC(=O)Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1ccc(Oc2cccc(N)c2)cc1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Iron powder (5.03 g; 56 mmol), water (5 mL) and hydrochloric acid (0.1 mL; 36 mmol) are added consecutively to a solution of methyl 2-[4-(3-nitrophenoxy)phenyl]acetate (1.3 g; 4.5 mmol) in ethanol (20 mL). After stirring at 95° C. for four hours, the solid is filtered while still hot and the filtrate is stripped of solvent in vacuo to yield methyl 2-[4-(3-aminophenoxy)phenyl]acetate as an oil. Yield: 1.1 g (95%).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=O)=O.[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[C:36]([S:38][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:9]1)(=[O:39])[CH3:37]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (410 mg, 0.780 mmol) (obtained as described in Reference Example 52(7)) in dimethylformamide (21 ml) was added potassium thioacetate (534 mg, 4.68 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford 3-acetylthio-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (287 mg, yield 73%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH2:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:38][CH:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4-amino-N-methylpiperidine according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.41-1.84 (m, 10 H), 2.09 (s, 3 H), 2.54-3.03 (m, 4 H), 2.92 (s, 4 H), 3.63 (s, 1 H), 6.30 (s, 1 H), 6.94-6.98 (m, 2 H), 7.15 (d, J=8.8 Hz, 1 H), 7.37 (d, J=8.0 Hz, 1H), 7.43 (s, 1 H), 7.51-7.61 (m, 3 H), 7.80 (d, J=8.8 Hz, 1 H), 7.97 (d, J=8.4 Hz, 1 H), 8.20 (s, 1 H), 10.42 (s, 1 H).
Reaction SMILES: OC[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(CN2CCCCC2)cc1
Temperature: 57.5 °C
Yield: 98 %

Procedure:
To a stirred solution of 4-(hydroxymethyl)piperidine 38 (0.01 mol) and DIEA (0.02 mol) in anhydrous acetonitrile (20 ml) was added a solution of benzylbromide 39 (0.012 mol) in anhydrous acetonitrile (5 ml) at room temperature. The resulting mixture was heated at 55-60° C. for 12 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated on rotavapor and the residue was diluted with ethyl acetate (50 ml). The resulting ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate (Na2SO4) and evaporated the solvent. The residue was purified by silica gel column chromatography using a gradient of 0 to 100% ethyl acetate and hexane to get the title piperidine 40 in 98% yield (2.00 g) yield. 1H NMR (400 MHz, CDCl3): δ 1.26-1.33 (2H, m); 1.43-1.52 (1H, m); 1.70 (2H, broad d); 1.96 (2H, broad t); 2.90 (2H, broad d); 3.48 (2H, s); 3.49 (2H, s); 7.30 (5H, m). MS (ESI): m/z=206.20 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]1([CH3:43])[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[C@H:17]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[NH2:8][C:5]1[N:4]=[CH:3][C:2]([C:25]2[CH:24]=[CH:23][C:22]([N:18]3[C@@H:17]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:16]([CH3:15])([CH3:43])[O:20][C:19]3=[O:21])=[CH:27][CH:26]=2)=[CH:7][N:6]=1
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
Reactant: Nc1ncc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)nc3)cc2)[C@H]1c1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
5-Iodopyrimidin-2-amine (84 mg, 0.381 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.), sodium carbonate (2M, 254 μL, 0.509 mmol), (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (100 mg, 0.254 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium (II) (20.76 mg, 0.025 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) were combined in dioxane (848 μL) and stirred at 130° C. for 2 hours. LC-MS indicated complete conversion to the desired product. The reaction mixture was passed through a syringe filter, and the material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-3-(4-(2-aminopyrimidin-5-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 2H), 7.53 (s, 4H), 7.34-7.41 (m, 2H), 7.22-7.33 (m, 3H), 6.70 (s, 2H), 5.47 (s, 1H), 1.64 (s, 3H), 0.91 (s, 3H). m/z (ESI) 361.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].IC.[C:21](=O)([O-])[O-].[K+].[K+]>C(#N)C.C([O-])=O.[Na+]>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])=[CH:3][C:2]=1[O:1][CH3:21]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(O)c2)c1
Reactant: O=C([O-])[O-]
Agent: O=C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
Dissolve 5-(3-hydroxy-4-fluorophenylethynyl)-nicotinonitrile, (prepared essentially as described in EXAMPLE 77), (150 mg, 0.63 mmol) in anhydrous acetonitrile (5 mL) and sequentially add iodomethane (59 μL, 0.95 mmol) and potassium carbonate (174 mg, 1.26 mmol). Stir at room temperature for 12 h, dilute with an aqueous saturated solution of sodium carbanate and extract with dichloromethane. Sequentially wash the organic layer with water and an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes, to give the title compound (70 mg, 44%) as white solid.
Reaction SMILES: [NH2-].[Na+].[CH2:3]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH3:4].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28].Cl>C1C=CC=CC=1>[CH2:3]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[O:24][CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[CH3:4]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: CN(C)CCCl
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCN(C)C
Temperature: 25 °C

Procedure:
Stir a solution of 860 mg. of sodium amide in 15 ml. of benzene and add 3.0 g. of dl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17β-ol in 15 ml. of benzene. Heat for 2 hours at 70°-83°. Cool to room temperature and add 1.58 g. of N,N-dimethylamino-2-chloroethane hydrochloride and reflux for 16 hours. Pour over ice and acidify reaction mixture with 2 N hydrochloric acid. Extract with ether and basify the aqueous layer with 15% sodium hydroxide. Isolate material with ether. Evaporate the ether to obtain dl-13-ethyl-17β-(2-dimethylaminoethoxy)-3-methoxygona-1,3,5(10)-triene.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-methyl-1-naphthalenecarboxylic acid (268 mg, 1.44 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1) and recrystallized from ethyl acetate-hexane to give the title compound (487 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][C:9]=2[C:17]([NH:19][C:20]2[CH:36]=[CH:35][C:23]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)=[CH:22][CH:21]=2)=[O:18])=[CH:4][CH:3]=1.[C:37]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:37])[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][C:9]=2[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)=[CH:35][CH:36]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)c3nc(S(C)(=O)=O)[nH]c3-c3ccc(F)cc3)cc2)ccn1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)c3nc(S(C)(=O)=O)n(C)c3-c3ccc(F)cc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a chilled solution of 4-(4-(5-(4-fluorophenyl)-2-(methylsulfonyl)-1H-imidazole-4-carboxamido)phenoxy)-N-methylpicolinamide (200 mg, 0.39 mmol) and K2CO3 (119 mg, 0.86 mmol) in DMF (3.9 mL), was added methyl iodide (29 μL, 67 mg, 0.47 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC indicates completion of reaction with a single major product. Solvent was removed under reduced pressure and the crude material was dissolved in H2O (20 mL) and extracted with EtOAc (3×10 mL). The organic fractions were dried over Na2SO4 and concentrated. The crude material was purified by SiO2 chromatography (DCM/MeOH from 100% DCM to 94% DCM/6% MeOH, the desired product elutes in 97% DCM/3% MeOH) to yield a white solid (149 mg, 72% yield). 1HNMR (400 MHz, CDCl3): δ 8.88 (s, 1H), 8.33 (d, 1H, J=6.0 Hz), 7.97 (m, 1H), 7.66 (m, 3H), 7.50 (m, 1H), 7.43 (m, 2H), 7.22 (t, 2H, J=8.4 Hz), 7.03 (d, 2H, J=9.2 Hz), 3.79 (s, 3H), 3.50 (s, 3H), 2.98 (d, 3H, J=5.2 Hz). MS (ESI): m/z 524.0 [M+H]+
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6]
Reactant: [H][H]
Reactant: CCCCCCCCc1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Reaction time: 2 h

Procedure:
2-Nitro-2-(4-octylphenethyl)propane-1,3-diol (25 g), absolute ethanol (250 mL) and 10% Pd on carbon (5 g, 50% wet) are charged into a 500 mL steel hydrogenation flask under a N2 atmosphere and the flask is equipped with a para shaker hydrogen operator. The mixture is hydrogenated with a H2 pressure of 60 psi (415 kPa) at room temperature for 2 hours and filtered through a Celite bed and washed with ethylacetate (200 mL). The filtrate is concentrated under reduced pressure at 50° C. to give the title compound as a white solid. Yield: 16 g.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:11]=[CH:10][NH:9][C:8]2=[S:23].[CH3:24]I.Cl>O1CCCC1.O>[CH3:24][S:23][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:5]([O:4][CH3:3])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: COc1cc2c(=S)[nH]cnc2cc1OCc1ccccc1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(SC)ncnc2cc1OCc1ccccc1
Yield: 94.4 %

Procedure:
Sodium hydroxide (1.0 N, 200 ml) was added to a solution of 6-methoxy-7-benzyloxy-3,4-dihydroquinazolin-4-thione (30 g, 0.1 mol) in tetrahydrofuran (100 ml) and then methyl iodide (7.5 ml, 0.12 mol) was slowly added at ambient temperature over 30 minutes. The pH of the solution was then adjusted to 7 with hydrochloric acid (2.0 N), the reaction was diluted with water and the solid was recovered by suction filtration. Drying in vacuo yielded 4-(methylthio)-6-methoxy-7-benzyloxyquinazoline (29.5 g, 94% yield):
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11]N1C(=O)CCC1=O.O>ClCCl>[Br:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([NH2:10])=[O:9]
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: NC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzeneacetamide (3.0 g, 0.022 mol) was dissolved in dichloromethane (60 mL) and N-bromosuccinimide (4.0 g, 0.022 mol) was added. The reaction was stirred at room temperature under UV light for 24 hr. The mixture was poured into water and the layers were separated. The organic layer was washed with water (2×50 mL) then with brine (1×50 mL). The organic layer was dried (magnesium sulfate) then chromatographed on silica (40% ethyl acetate/hexanes) to give 2-Bromo-2-phenylacetamide, compound h Rf 0.37, 40% ethyl acetate/hexanes; MS m/z 216 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pt](=O)=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCN2C=CN=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CCO
Product: O=S1(=O)CCN2CCNC(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 33 %

Procedure:
A mixture of 9-(4-phenoxyphenyl)-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (96.0 mg), and platinum(IV) oxide (15.0 mg) in EtOH (5 mL) was stirred at room temperature for 2.5 hr under H2. The mixture was added with NH silica gel, concentrated, purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc), then recrystallized from EtOAc-IPE to give the title compound (32.0 mg) as white powder.
Reaction SMILES: C(O[C:4]([CH:6]1[CH:10]([NH2:11])[N:9]([CH:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:8]=[CH:7]1)=[O:5])C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26](Cl)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:4](=[O:5])[C:6]3[CH:7]=[N:8][N:9]([CH:12]4[CH2:13][CH2:14][S:15][CH2:16][CH2:17]4)[C:10]=3[N:11]=[C:26]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=[CH:23][CH:24]=1
Reactant: Fc1ccccc1C(Cl)=Nc1ccc(Br)cc1
Reactant: CCOC(=O)C1C=NN(C2CCSCC2)C1N
Product: O=c1c2cnn(C3CCSCC3)c2nc(-c2ccccc2F)n1-c1ccc(Br)cc1

Procedure:
5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one is prepared from 5-amino-1-(tetrahydro-thiopyran-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester and N-(4-bromo-phenyl)-2-fluoro-benzimidoyl chloride by following the procedure described in example 2. The crude is purified by preparative LC/MS to provide the titled compound 5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid. HPLC-MS calculated for C22H18BrFN4OS (M+H+): 485.0. Found: 485.0.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:15]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccs1
Product: Cc1noc(NS(=O)(=O)c2cccs2)c1Br
Yield: 34 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-thiophenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-thiophenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 125°-127° C., yield 34%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19](COCC[Si](C)(C)C)[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12>Cl.O1CCOCC1>[NH:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:16]1[S:17][C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[S:33])=[CH:3][C:2]=2[F:1])[CH:15]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ncc[nH]4)sc23)c(F)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
A solution of 112 (21 mg, 0.033 mmol) in 4N HCl in dioxane (3.5 mL) was allowed to stir at 55° C. for 1 h. The mixture was then cooled and solvent was removed under reduced pressure. The resultant gum was triturated with ether several times to form a solid material that was dried under high vacuum to afford the product 113 as a beige solid (5 mg, 28% yield). 1H NMR (400 MHz,DMSO-d6) δ ppm 12.50 (1H, s), 11.84 (1H, s), 8.66 (1H, d, J=5.67 Hz), 8.39 (1H, s), 8.06 (1H, d, J=12.72 Hz), 7.68 (2H, s), 7.59-7.58 (2H, m), 7.36-7.30 (5H, m), 6.86 (1H, d, J=5.48 Hz), 3.83 (2H, s). MS (m/z) 504.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([OH:21])=O)=[CH:11][C:12]=3[C:13]3(OCCC[O:14]3)[C:5]2=[N:4][CH2:3]1.[O:24]([CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([N:33]4[CH2:34][CH2:35][CH2:36][C@H:32]4[CH2:31][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:21])=[CH:11][C:12]=3[C:13](=[O:14])[C:5]2=[N:4][CH2:3]1
Reactant: CC1(C)CN=C2N(C1)c1ccc(C(=O)O)cc1C21OCCCO1
Reactant: c1ccc(OC[C@@H]2CCCN2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN=C2C(=O)c3cc(C(=O)N4CCC[C@H]4COc4ccccc4)ccc3N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carboxylic acid (0.090 g, 0.284 mmol) in CH2Cl2 (7 mL) was added (2S)-2-(phenoxymethyl)pyrrolidine (0.75 g, 0.427 mmol), DCC (0.082 g, 0.039 mmol), HOBT (0.038 g, 0.281 mmol) and Et3N (0.045 mL, 0.277 mmol) and the solution stirred overnight at rt. The reaction was filtered through 1 cm of silica gel washing with EtOAc. The filtrate was dried over Na2SO4, filtered, concentrated and purified on silica gel eluting with acetone/hexane (30/70). The resulting white foam was dissolved in CH2Cl2 (1.5 mL) and methanesulfonic acid (1 mL) was added and the solution was stirred at rt overnight. The reaction was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (35/65) to give the title compound as a yellow foam (0.021 g, 20%). NMR (400 Mz, DMSO-d6): consistent. MS (ES+) m/z 418.3 [M+H].
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.CCCCC.[CH3:23][S:24]SC>O1CCCC1>[CH3:23][S:24][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: CSSC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CSc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A mixture of potassium hydride in mineral oil (35 wt. %, 3.04 g, 26.52 mmol) in tetrahydrofuran (53 mL) was cooled to 0° C. then was treated with a solution of 6-bromo-1H-indole (5.20 g, 26.52 mmol) in tetrahydrofuran (53 mL). The reaction was stirred at 0° C. for 30 min. At this time, the reaction was cooled to −78° C. and was treated with a 1.7M solution of tert-butyllithium in pentane (31.2 mL, 53.04 mmol). The reaction mixture was stirred at −78° C. for 20 min. At this time, the reaction was added to a solution of methyl disulfide (4.78 mL, 53.04 mmol) in tetrahydrofuran (15 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 18 h. The reaction was then quenched by the addition of a saturated aqueous ammonium chloride solution (300 mL) and was extracted with ethyl acetate (1×500 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×300 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded 6-methylsulfanyl-1H-indole (2.3 g, 53%) as an off-white solid: mp 88-90° C.; EI-HRMS m/e calcd for C9H9NS (M+) 163.0456, found 163.0457.