Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]1([C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15]1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[N:22]=2)[CH:7]=1
Reactant: Nc1cccc(C2CC2)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Temperature: 140 °C
Yield: 33.4 %

Procedure:
A pressure tube charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol), 6-cyclopropylpyridin-2-amine (273 mg, 2.04 mmol), and acetonitrile (8 mL) was heated at 140° C. for 20 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (silica, 50 μm, 80 g, Analogix, 0 to 10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxylate (145 mg, 34%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.64 (br. s., 1H) 9.39 (s, 1H) 7.63 (t, J=7.83 Hz, 1H) 6.94 (d, J=7.58 Hz, 1H) 6.78 (d, J=8.08 Hz, 1H) 4.12 (s, 3H) 1.99-2.10 (m, 1H) 1.06-1.12 (m, 4H). LCMS (EI/CI) m/z: 319 [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[N:2]1.[N:12]1([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=3)[N:23]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O)(=O)C>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:15]2[CH2:14][CH2:13][N:12]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]([F:28])([F:29])[F:30])=[N:25][N:26]=4)[N:23]=3)[CH2:17][CH2:16]2)=[N:2]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Solvent: CC(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4n[nH]c5ccccc45)CC3)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
1H-Indazole-3-carboxaldehyde (75 mg, 0.51 mmol) and (polystyrylmethyl)trimethylammonium cyanoborohydride (125 mg, 0.51 mmol) were added to a solution of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.37 mmol) in DCM (2 mL)/acetic acid (0.2 mL). The mixture was stirred at ambient temperature for 18 hours. The resin was filtered off and the filtrate was evaporated. The crude product was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-(1H-indazol-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (89 mg, 60%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+].CN(C)C=O>O>[CH2:18]([N:9]1[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[C:3]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=2[OH:1])[CH2:11][CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C(=O)C2CCNCC2)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)c(O)c1
Reaction time: 15 h
Yield: 57.4 %

Procedure:
A mixture of 14.50 g of 4-(2-hydroxy-4-methoxybenzoyl)piperidine, 6.40 ml of benzyl bromide, 10.20 g of sodium bicarbonate and 74.0 ml of dimethylformamide was stirred at 60° for 15 hrs. The reaction mixture was poured into 250 ml of water and a precipitate formed. The precipitate was collected, washed with water and recrystallized from ethanol to yield 10.0 g (57.4%) of product, mp, 123°-125°.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([NH2:27])[CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([NH:27][C:34](=[O:36])[CH3:35])[CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: Nc1cc(C(=O)NC2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C(=O)NC2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamide (35 mg, 0.09 mmol) in methylene chloride (1 mL) was added pyridine (11 μL, 0.14 mmol) and acetic anhydride (11 μL, 0.10 mmol) at 0° C. and stirred for 30 min, then allowed to warm to room temperature for 1 h. The reaction mixture was quenched with saturated solution of sodium bicarbonate and concentrated under reduced pressure. The crude was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-acetylamino-2-phenylbenzoxazole-4-carboxamide (13 mg, 44%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.58 (d, J=7.4 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H), 8.20 (d, J=6.8 Hz, 1H), 8.13 (s, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.55-7.50 (m, 4H), 4.35-4.27 (m, 1H), 3.57-3.48 (m, 1H), 3.16-3.03 (m, 2H), 2.97-2.82 (m, 2H), 2.27 (s, 3H), 2.17-2.05 (m, 2H), 1.85-1.60 (m, 3H); MS (ESI+) m/z 405 (M+H); HPLC>99% (AUC), tR=23.81 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH2:26])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH:26][CH:37]([CH3:38])[CH2:36][CH2:35][C:32]4[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4N)cc3)cc2)CC1
Reactant: CC(=O)CCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
1-[4′-(5-Amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.125 g, 0.346 mmol) and 4-(4-chloro-phenyl)-butan-2-one (0.095 g, 0.52 mmol) were dissolved in MeOH (5 mL). Acetic acid (0.030 mL, 0.52 mmol) was added along with a few molecular sieves and the reaction stirred at 30° C. overnight. Sodium cyanoborohydride (0.033 g, 0.52 mmol) was then added and the reaction was heated to 60° C. for 4 hours. An additional 0.5 equivalents of sodium cyanoborohydride was added and the reaction continued heating for 1 hour. All solvent was removed and the residue was submitted to EtOAc/H2O workup. The residue was purified twice on silica gel (0-100% EtOAc in hexanes followed by 0-10% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:12]1[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13]1
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2F)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(ccn2Cc2ccccc2F)c1O

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 344 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>>[N:1]1([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 65, but using indole and methyl 4-(bromomethyl)benzoate as starting material, the title compound was obtained as a solid.
Reaction SMILES: Cl[S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[NH3:21]>>[NH2:21][S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Product: NS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 0.88 NH3 (50 ml) was added benzyl 4-(chlorosulfonyl)piperidine-1-carboxylate (4 g) and the reaction stirred for 72 h at RT. The reaction was then extracted with DCM (3×150 ml). Organics were recovered, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a clear oil. Yield 3.3 g
Reaction SMILES: [CH:1]1([P:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH:33][S:34](O)(=[O:36])=[O:35].[OH-].[Na+:39]>CO>[CH:24]1([P:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([S:34]([O-:36])(=[O:35])=[O:33])[C:15]=2[O:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1.[Na+:39]
Reactant: O=S(=O)(O)O
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped with a Teflon-coated magnetic stir bar and rubber septum was added 2-dicyclohexylphosphino-2′6′dimethoxybiphenyl (5.13 g, 12.5 mmol) and CH2Cl2 (5 mL). The solution was cooled to 0° C. using an ice/water bath and then concentrated H2SO4 (32.5 mL, 625 mmol) was added dropwise. The solution slowly turned yellow in color. The solution was heated to 40° C. in a preheated oil bath and was allowed stir for 24 h. At this time it was cooled to 0° C. using an ice/water bath and crushed ice (˜50 g) was added. The solution turned cloudy and white in color. An aqueous solution of NaOH (6.0 M, ˜200 mL) was then added dropwise to the cooled solution until it became neutral (pH ˜7.0 as judged by pH paper). The aqueous solution was extracted with CH2Cl2 (3×300 mL) and concentrated under reduced pressure to give a light yellow solid. The crude material was then dissolved in a minimum amount of cold methanol (˜20 mL), filtered and concentrated (this cycle was repeated) to give sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (2) as a light yellow solid (6.35 g, 99%). Mp=165° C. (turned red, dec.) 1H NMR (400 MHz, CD3OD) δ: 7.88 (d, 1H, J=8.8 Hz), 7.60 (m, 1H), 7.36 (m, 2H), 7.22 (m, 1H), 6.76 (d, 1H, J=8.8 Hz) 3.70 (s, 3H), 3.39 (s, 3H), 1.14-2.01 (m, 22H). 13C NMR (125 MHz, CD3OD) δ: 161.3, 157.1, 143.3, 142.9, 137.9, 137.8, 133.7, 133.6, 133.3, 133.2, 131.9, 130.0, 129.3, 128.0, 127.9, 127.8, 105.9, 61.6, 56.1, 50.0, 37.0, 36.9, 34.8, 34.6, 31.7, 31.6, 31.5, 31.2, 31.0, 30.8, 30.7, 28.9, 28.8, 28.7, 28.4, 28.34, 28.31, 28.2, 27.8, 27.7. 31P NMR (162 MHz, CD3OD) δ: −8.02. IR (neat, cm−1): 3453, 2925, 2849, 1577, 1462, 1448, 1400, 1229, 1191, 1099, 1053, 736. Anal. Calcd for C26H34NaO5PS: C, 60.92; H, 6.69. Found: C, 60.40; H, 6.85. 1H NMR (d4-MeOH/D2O) is shown in FIG. 7. 31P NMR (d4-MeOH) is shown in FIG. 7.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CO.O>[C:13]([O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:17])=[O:4])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)CCCCC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
Lithium hydroxide (0.53 g, 22 mmol) was added to a solution of hexanedioic acid tert-butyl ester methyl ester (4.8 g, 22 mmol) in 3:1 methanol-water (80 mL), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was evaporated under vacuum. The residue was partitioned between water (60 mL) and methylene chloride (75 mL), and the aqueous phase was washed with methylene chloride (3×75 mL) and evaporated, providing 4.0 g of hexanedioic acid mono-tert-butyl ester, lithium salt; 1H NMR (D2O) δ 1.45 (s, 9H), 1.54-1.58 (m, 4H), 2.15-2.20 (m, 2H), 2.25-2.34 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4]O.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>N1C=CC=CC=1>[CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1

Procedure:
Ex-36a) As depicted in Scheme 10, 2-Trimethylsilylethanol is treated with tosyl chloride in pyridine to give 2-trimethylsilyl-1-tosylethane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]([C:22](=[O:25])[CH2:23]Cl)[CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:5]2.Cl.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:12][CH2:13][NH:14][CH2:23][C:22]1=[O:25])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1Cc2ccc(Br)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CNCCN1C1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Step B (0.17 g, 0.39 mmol) in 10 mL of DCM was added 5 mL of HCl/Et2O and the mixture was stirred at RT for 2 hours and then concentrated. The residue was dissolved in 20 mL of EtOH and added K2CO3 (163 mg, 1.18 mmol), and then the mixture was refluxed for 4 hours. The reaction mixture was filtered and concentrated and the residue was used directly for next step.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:20]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:20]=2)=[N:13][CH:14]=1
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(OCc3ccccc3)cn2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)cn2)c1=O
Reaction time: 1 h
Yield: 77.1 %

Procedure:
5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (1.8 g, 4.8 mmol) was dissolved in DCM (30 ml) and BBr3 (1.0 M in DCM, 6.0 ml, 6.0 mmol) was added, causing solid to form. The reaction stirred at room temperature (flask in water bath) under nitrogen. After 1 hour, more BBr3 (1 M in DCM, 6.0 ml, 6.0 mmol) was added, and stirring was continued. When LCMS analysis indicated the product had formed, the reaction was quenched with saturated sodium bicarbonate (50 ml) and the flask put in a water bath and stirred. After about 30 minutes, the layers were separated, using MeOH to help dissolve the solid material suspended in the organic layer. The aqueous phase was extracted exhaustively with 5:1 DCM/MeOH and 4:1 DCM/MeOH). Some water remained in organic phase, so these layers were separated. This aqueous phase was extracted with 10:1 DCM/MeOH (3×75 ml). All of the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and washed with hexanes, 1:1 hexanes/Et2O, and Et2O, Solid dissolved in 1N NaOH and this basic, aqueous phase was washed with DCM to remove impurities. The pH of the aqueous phase was lowered to 7 with concentrated HCl and 10% HCl. This aqueous phase was extracted exhaustively with 10:1 and then 5:1 DCM/MeOH. The organic extracts were combined and concentrated. These were combined with residual solid obtained after neutralizing aqueous phase. The material was concentrated and put on high vac overnight to afford the desired product 5-(5-hydroxypyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (1.1 g, 3.7 mmol, 77% yield). MS (ESI pos. ion) m/z: 295 (MH+). Calc'd exact mass for C16H14N4O2: 294.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[O:11]1[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12]1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH:13]([OH:11])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCCCC1CO1
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(O)CSc1ccc(Cl)cc1

Procedure:
To 28.9 g (0.2 mole) the p-chlorothiophenol and 8.0 g (0.2 mole) of sodium hydroxide in 100 ml of water is added 22.0 g (0.22 mole) of 1,2-epoxyhexane over 10 minutes. When addition is completed, the mixture is heated to reflux for 16 hours. The mixture is cooled, combined with 300 ml of water and the organic phase is separated.
Reaction SMILES: C(=O)=O.C([Sn](CCCC)(OCCCC)[O:9][Sn:10]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])CCC.[CH2:33](O)[CH2:34][CH2:35][CH3:36]>>[CH2:20]([Sn:10]([CH2:16][CH2:17][CH2:18][CH3:19])([O:9][CH2:33][CH2:34][CH2:35][CH3:36])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCCCC
Reactant: CCCCO
Agent: O=C=O
Product: CCCCO[Sn](CCCC)(CCCC)OCCCC
Reaction time: 0.22 h
Yield: 37.5 %

Procedure:
From the gas supply line 29, 1-butanol (manufactured by Wako Pure Chemical Industries Ltd., Japan, industrial product) was fed at 566 g/Hr and carbon dioxide was fed at 3 NL/Hr. All of the 1-butanol was vaporized by the heat exchanger 30 and fed to the reactor lower portion 33. A feed pump was used to start supplying the starting material 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane prepared in the same manner as in Example 12 from supply line 26 at 280 g/Hr and the reaction solution 1-butanol (manufactured by Wako Pure Chemical Industries Ltd., Japan, industrial product) from supply line 27 at 1,330 g/Hr. The holding time in the reactor was 13 minutes. The liquid temperature inside the reactor was 140° C., and the pressure of the back pressure valve 37 was adjusted to 0.096 MPa-G. Continuous supply was continued in this state for 10 hours, after which the system reached a steady state. Low boiling point components flowed from the reactor upper portion 32 and through the low boiling point component recovery line for liquefaction at the condenser 35, and were thereby recovered from the liquid-phase recovery line 39 at 1,006 g/Hr. Furthermore, from the reactor lower portion 33 a dibutyltin alkoxide-containing component was recovered at 1,170 g/Hr from the extraction line 40. Analysis of the liquid recovered from the generated product extraction line 40 showed that, using dibutyltin oxide as a reference, the liquid contained a dibutyltin alkoxide consisting of a yield of about 37.5% dibutyl-di(butyloxy)tin and 62.4% of 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane. Tributyltin butoxide had a yield of 0.022%. Meanwhile, the liquid recovered from the liquid-phase recovery line 39 was transparent and contained 2,200 ppm of moisture. The dehydration rate in the column reactor was 0.39 mol/Hr, which was greater than the value 0.0015 mol/Hr calculated from expression (16).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:29])([F:28])[C:11]1[CH:12]=[C:13]([C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][CH2:21][C:22]3=[O:27])[CH:14]=[CH:15][CH:16]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>C1COCC1>[O:27]=[C:22]1[C:23]2[C:18](=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:28])([F:29])[F:9])[CH:12]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:20][CH:21]1[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1CCCc2c1cccc2-c1cccc(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCc3c(cccc3-c3cccc(C(F)(F)F)c3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 0.8 mL, 1.6 mmol) was added to a solution of 5-(3-(trifluoromethyl)phenyl)-3,4-dihydronaphthalen-1(2H)-one (435 mg, 1.5 mmol) in THF (5 mL) at −78° C. After 1 h at −78° C., a solution of methyl 4-(bromomethyl)benzoate (378 mg, 1.65 mmol) in THF (2.5 mL) was added via cannula. The reaction mixture was allowed to warm to room temperature naturally. After stirring at room temperature overnight, the reaction was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→40% EtOAc/hexanes, gradient) to afford 55 mg (8%) of methyl 4-((1-oxo-5-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)benzoate.
Reaction SMILES: O1CCOCC1.[C:7]([C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]#[N:15])#[N:8].C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>>[CH3:23][N:24]([CH3:28])[C:25]([N:10]1[C:9]([C:7]#[N:8])=[C:13]([C:14]#[N:15])[N:12]=[CH:11]1)=[O:26]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1nc[nH]c1C#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1cnc(C#N)c1C#N
Temperature: 25 °C

Procedure:
To 50 ml of dry 1,4-dioxane 6.0 g (0.05 mole) of 4,5-dicyanoimidazole, 5.0 g (0.05 mole) of triethylamine and 6.0 g (0.055 mole) of dimethylcarbamoyl chloride are added in succession at room temperature. This mixture is stirred and refluxed for 3 days, cooled to room temperature and evaporated to dryness. The residue is stirred in 50 ml of ethyl acetate and 50 ml water. The organic layer is separated, washed, dried and evaporated to give 8 g. (85%) of white product.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH:32]([C:37](O)=[O:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][CH:32]1[C:37](=[O:38])[NH:22][CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[CH:13][N:12]([S:2]([C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=3)(=[O:3])=[O:4])[C:16]2=[N:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CN(C(=O)OC(C)(C)C)CCC4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (29.6 g, 87.0 mmol, Step F), 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (21.2 g, 87.0 mmol, Step G) and HATU (33.2 g, 87.0 mmol) in DCM (400 mL) was added DIEA (46.0 mL, 263 mmol). After stirring for about 18 h at ambient temperature, the reaction mixture was washed with aqueous saturated NaHCO3 (400 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (330 g column) eluting with a gradient of 50-100% EtOAc in heptane to give tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 95%) as a tan foam: LC/MS (Table 2, Method a) Rt=2.38 min; MS m/z: 528 (M+H)+.