Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)([O-])O.[Na+]>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.COCCOC>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccccn2)cc1
Yield: 88.3 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13; 132 mg, 0.3 mmol), 2-bromopyridine (40 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium (4 mg, 0.004 mmol), 1,2-dimethyoxyethane (1.5 ml) and a saturated aqueous solution of sodium hydrogen carbonate (1.5 ml) were stirred at 80-85° C. under an atmosphere of argon for 24 hours. The mixture was allowed to cool before being partitioned between ethyl acetate and water. The organics were separated, washed with brine, dried over magnesium sulfate, filtered and evaporated to yield the title compound (86 mg, 74%) which was used in the next reaction without further purification; Mass Spectrum: M+H+ 390.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][C:21]([O:23]C(C)C)=[O:22])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][C:21]([OH:23])=[O:22])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CC(=O)OC(C)C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CC(=O)O)c12
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a solution of isopropyl {4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}acetate (521 mg, 1.08 mmol) in methanol (4 mL) was added 8N aqueous sodium hydroxide (1 mL) at 0° C., and the mixture was stirred at the same temperature for 4 hours. Methanol was evaporated in vacuo, and the aqueous residue was adjusted to pH 4. Ethyl acetate was added to the mixture, followed by stirring at 0° C. for 1 hour. The resulting solid was collected by filtration and washed with water to give the title compound (330 mg, 0.749 mmol, 69%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:19][CH:18]=[CH:17][N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].Br[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.C(N(CC)C(C)C)(C)C>C(O)C>[C:10]1([C:9]2[C:8](=[O:16])[N:7]3[CH:17]=[CH:18][S:19][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:3])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1ccccc1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.092 mmol), 6-bromo-9H-purine (0.033 g, 0.16 mmol), and N,N-diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H16N7OS (M+H)+: m/z=390.1. Found: 390.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.08 (1H, s), 8.06 (1H, s), 7.97 (1H, d, J=4.8 Hz), 7.51 (1H, d, J=4.8 Hz), 7.44˜7.33 (6H, m), 5.15 (1H, m), 1.29 (3H, d, J=7.2 Hz) ppm.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:55]=[CH:56][CH:57]=[CH:58][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:42]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:55]=[CH:56][CH:57]=[CH:58][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: O=C(O[C@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(O[C@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 77 mg (0.09 mmol) of (R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 51) in 10 mL MeOH was combined with 50 mg 10% Pd/C and shaken for 3 h at RT and 50 psi hydrogen. The catalyst was suction filtered, the solvent was evaporated down i.vac., the residue was combined with acetonitrile and water and lyophilised.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[C:4]([NH2:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6]2.C(N(CC)C(C)C)(C)C.[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30](Cl)=[O:31]>ClCCl>[CH3:26][O:27][C:28]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[C:33]([S:41][CH3:42])[C:29]=1[C:30]([NH:16][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]1[CH2:9][CH2:8]2)=[O:31]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Reactant: CN1C2CCC1C(N)(c1ccccc1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCC2CCC1N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1RS,2RS,5SR)-8-methyl-2-phenyl-8-aza-bicyclo[3.2.1]oct-2-ylamine (intermediate A1) (670 mg, 3.1 mmol) in dichloromethane (10 ml) under nitrogen at room temperature, was added N,N-diisopropylethylamine (1.23 g, 1.61 ml, 9.29 mmol), followed drop-wise by a solution of 2-methoxy-6-(methylthio)-4-(trifluoromethyl)benzoyl chloride (intermediate B1) (970 mg, 3.41 mmol) in dichloromethane (7 ml). The reaction mixture was stirred at room temperature for 2 hours. The solution was washed once with a 2M sodium carbonate solution. The aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude yellow oil (2.04 g), which crystallized in the fridge, was suspended in diethyl ether. The white precipitate was filtered and rinsed with diethyl ether to provide 1.16 g (y: 80.6%) of the title compound as a white solid. MS (m/e): 465.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH:32]=[CH2:33])[CH:28]=[CH2:29]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:30]([CH2:31][CH:32]=[CH2:33])[CH2:27][CH:28]=[CH2:29])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=CCNCC=C
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1csc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A solution of 0.81 g (0.002 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 5 ml of tetrahydrofuran was treated with 3 ml (0.024 mol) of diallylamine and stirred at 50° for 8 hrs. All volatiles were removed in a water-jet vacuum and the residue was chromatographed over silica gel with methylene chloride/methanol 98:2 as the eluent. After recrystallization from diethyl ether there was obtained 0.52 g (55%) of (S)-8-chloro-1-(4-diallylaminomethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals; m.p. 186°-187° and [α]D20 =-67.5° (MeOH, c=1%).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=O)=O.O[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][S:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][O:5][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[CH:9][CH:10]=1)(=[O:17])=[O:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 66.1 %

Procedure:
30 g (0.102 mole) 4-(methylsulfonyloxy)phenethyl methanesulfonate was dissolved in acetonitrile and slowly added to a mixture of 31.1 g (0.255 mole) p-hydroxybenzaldehyde and 41.46 g (0.3 mole) potassium carbonate in acetonitrile and refluxed until the starting material was consumed. The salt was filtered off, the solvent evaporated in vacuo, dichloromethane was added and the organic phase was washed with water. After evaporation of the solvent, purification by chromatography on silica gel using dichloromethane as eluent gave 21.6 g (yield 66%) of 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25]O)[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]2[N:13]([CH2:25][Cl:34])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C1CCCN(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCN(CCl)c2c1cc(OCc1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.2 %

Procedure:
A solution of 83 (0.105 g, 0.24 mmol, 1 equiv) in CH2Cl2 (2 mL) was treated with CCl4 (0.225 mL, 2.33 mmol, 9.7 equiv) followed by Ph3P (0.212 g, 0.81 mmol, 3.3 equiv) and the mixture was stirred at 25° C. for 2.5 h. The crude reaction solution was passed through a plug of silica gel and concentrated. Radial chromatography (SiO2, 1 mm plate, 5% EtOAc-hexane) provided 86 as a pale yellow oil (0.048 g, 0.108 g theoretical, 44%): 1H NMR (250 MHz, CDCl3) major rotamer δ 8.44-8.36 (m, 1H), 8.15-7.12 (m, 1H), 7.62-7.33 (m, 7H), 6.64 (s, 1H), 5.31-5.15 (m, 2H), 4.46-4.41 (m, 1H), 4.17-4.08 (m, 1H), 3.92-3.81 (m, 1H), 3.74-3.63 (m, 1H), 2.78-2.69 (m, 1H), 2.41-2.35 (m, 1H), 2.17-2.05 (m, 1H), 1.72-1.67 (m, 2H), 1.30 (s, 9H); IR (film) νmax 2971, 2930, 2859, 1693, 1617, 1592 cm−1; FABHRMS (NBA-NaI) m/z 451.1933 (M+, C27H30CINO3 requires 451.1914).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:8]=[CH:7][CH:6]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([N:9]2[C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=[N:8]2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-n2nccc2CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nccc2CN)cc1
Reaction time: 8 h

Procedure:
To a solution of 5-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (0.344 g, 1.24 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added water (0.5 mL) and triphenylphosphine resin (0.5 g, 3 mol/g, 200-400 mesh, 1.2 equiv). The suspension was stirred overnight. Filtration and concentration afforded C-[2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-methylamine as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].[CH:8]1([SH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+].II>C(OCC)C.O>[CH:8]1([S:14][S:7][C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1occc1S
Reactant: SC1CCCCC1
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1occc1SSC1CCCCC1
Reaction time: 0.17 h

Procedure:
0.57 Grams (0.0050 moles) of 2-methyl-3-furanthiol and 1.16 grams (0.01 moles) of cyclohexylmercaptan are dissolved in 12 ml of diethyl ether. 0.8 Grams (0.0075 moles) of sodium carbonate dissolved in 8 ml water is added to the reaction mass. Over a period of 10 minutes, a solution of 1.9 grams (0.0075 moles) of iodine dissolved in 6 ml diethyl ether is added to the reaction mass with stirring until the iodine color remains. The reaction mass is then stirred over a period of 45 minutes.
Reaction SMILES: COC(=O)CC[S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7].C[O-].[Na+].C1C(=O)N([Cl:36])C(=O)C1>C1COCC1>[Cl:36][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)CCS(=O)(=O)c1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2ccc(S(=O)(=O)Cl)cc21
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl 6-[(3-methoxy-3-oxopropyl)sulfonyl]-1H-indole-1-carboxylate (400 mg, 1.13 mmol) in THF (5.5 mL) was added sodium methoxide (2.26 mL, 0.5 M, 1.13 mmol). The reaction mixture was stirred for 20 minutes, then the solvents were removed under reduced pressure and the residue was stripped down from heptanes to generate a white foam. This foam was suspended in DCM (5.5 mL) at 0° C. and then NCS (151 mg, 1.13 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was quenched by the addition of brine (4 mL) and the phases were separated using a phase separator. The aqueous layer washed with DCM. The combined organics were concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate to afford the title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([CH3:25])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccccc1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:23][S:24]([CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:26])=[O:25].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][S:24]([CH3:23])(=[O:25])=[O:26])[CH2:34][CH2:33]1)[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 69.6 %

Procedure:
1-Ethyl-2-fluoro-4-(ethyloxy)-5-nitrobenzene (Example 208, step A) (0.50 g, 2.3 mmol) was dissolved in DMSO (15 mL). K2CO3 (0.97 g, 7.0 mmol) and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, step B) (1.0 g, 4.7 mmol) were added and the reaction mixture was heated to 80° C. and allowed to stir over the weekend. The mixture was then heated to 120° C. for 4 h. The mixture was cooled to rt then poured into H2O and extracted with DCM. The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified on a 40 g ISCO column (EtOAc to 10% MeOH in EtOAc). The desired fractions were combined and the solvent removed in vacuo to give the title compound of Step A (0.63 g, 1.6 mmol, 66%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 6.56 (s, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.23-3.12 (m, 2H), 3.03 (s, 3H), 3.00-2.91 (m, 6H), 2.72-2.62 (m, 4H), 2.57 (q, J=7.5 Hz, 2H), 2.22 (s, 3H), 1.44 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H). MS (M+H, ES+) 386.
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[I:10].O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[I:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cncc(I)c1O
Product: N#Cc1cncc(I)c1Cl
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of 4-hydroxy-5-iodonicotinonitrile (57.5 g, 234 mmol) and POCl3 (200 mL) was heated at 100° C. for 2 hours, cooled to room temperature and evaporated to remove excess POCl3. The residue was cooled in an ice-water bath, adjusted to pH 8-9 with aqueous 10 N NaOH and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate and concentrated. The resulting solid residue was washed with a minimum amount of methanol and methylene chloride to give 46.5 g (75%) of 4-chloro-5-iodonicotinonitrile as a tan solid. Melting range: 120-122° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:10][C:11]=1[CH3:12])=[O:5])C.[OH-].[K+].Cl>C(OCCO)C.O>[CH3:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:23])[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]=1
Reactant: CCOC(=O)c1c(C)nc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCCO
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)O
Temperature: 150 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 5.21 g (16.1 mmol) of 4,6-dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 165 ml of 2-ethoxyethanol/H2O (9:1) was added 2.62 g=40.2 mmol of potassium hydroxide (86%); then, the reaction mixture was heated up to reflux in an oil bath of 150° C. After 4 hours, it was poured into crashed ice, acidified with HCl (25% in water) and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 4.29 g (90%) of the crude title compound as off-white solid. MS: 295.3 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:52])[CH2:33][C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)[CH3:30]>>[CH2:29]([O:31][C:32](=[O:52])[CH2:33][C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-methyl-3-(3-trifluoromethyl-phenyl)-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7](=[CH2:9])[CH3:8].[CH2:10]([O:17][C:18]([NH:20][C:21](=[O:27])[C@@H:22]([C@H:24]([CH3:26])[OH:25])[NH2:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH2:10]([O:17][C:18]([NH:20][C:21](=[O:27])[C@@H:22]([C@H:24]([CH3:26])[O:25][C:7]([CH3:9])([CH3:8])[CH3:6])[NH2:23])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](O)[C@@H](N)C(=O)NC(=O)OCc1ccccc1
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@H](OC(C)(C)C)[C@@H](N)C(=O)NC(=O)OCc1ccccc1
Reaction time: 96 h
Yield: 90.3 %

Procedure:
Concentrated H2SO4 (0.1 ml) and isobutylene (35 ml, 390 mmol) are added to a suspension of N-benzyloxycarbonyl-D-threonineamide (4.2 g, 16.6 mmol) in methylene chloride (35 ml) kept in a pressure resistant vessel cooled with dry ice/acetone. The reaction vessel is sealed and the temperature is allowed to raise up to the room value. After 4 days, excess isobutylene is evaporated off and the organic solution is washed with aqueous 5% Na2CO3 (3×30 ml), 5% citric acid (20 ml) and then with water up to pH 6. The organic phase is dried over MgSO4 and concentrated to dryness yielding the compound of the title as a clear oil (4.62 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[OH:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[CH:6]=[O:7])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(Cl)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-chloro-3-hydroxy-benzaldehyde* (0.354 g), 4-N,N-dimethylaminopyridine (0.028 g), tert-butyldimethylsilyl chloride (0.409 g) and triethylamine (0.473 ml) in DCM (15 ml) was stirred at room temperature under nitrogen for 19 h. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The combined organic extracts were concentrated under reduced pressure to give an oil which was purified using SPE (silica, eluting with cyclohexane followed by 10% to 30% ethyl acetate-cyclohexane) to give the title compound (0.42 g) as an oil. *Kelley, J; Linn, J; Selway, J. W. T., J. Med. Chem. (1989), 32(8), 1757–63.