Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[C:24]([F:39])=[C:25]([C:30]3[C:31]([C:37]#[N:38])=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:26]([F:29])=[CH:27][CH:28]=2)O1>>[OH:14][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:27]3[C:26]([F:29])=[C:25]([C:30]4[C:31]([C:37]#[N:38])=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C:24]([F:39])=[CH:23][CH:28]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2F)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,2′,6′-trifluorobiphenyl-2-carbonitrile as described in Example 65 to give 3′-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]-4,2′,6′-trifluorobiphenyl-2-carbonitrile as an off-white solid: δH (400 MHz, d6-DMSO) 1.51 (6H, s), 7.42 (1H, d, J 7), 7.54-7.58 (1H, m), 7.80-7.85 (1H, m), 7.89-7.96 (3H, m), 8.14 (1H, dd, J 9 and 2), 8.78 (1H, dd, J 7 and 3).
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[C:7]([CH3:8])=[N:6][N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cc1nn(C)c(=O)cc1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(C)c(=O)cc1Cl
Temperature: 85 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 5-hydroxy-2,6-dimethylpyridazin-3(2H)-one (736 mg, 5.25 mmol) and POCl3 (4.5 mL) was stirred at 85° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was quenched with saturated aqueous Na2CO3. The resulting mixture was stirred for 2 hours and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 587 mg (70%) of the desired product that was used directly without further purification.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1)[CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32]
Reactant: COCCOCCBr
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 76 %

Procedure:
3 g (8.66 mmol) of 1,4,7-tris-(carboxymethyl)-1,4,7, 10-tetraazacyclododecane is stirred in 50 ml of dimethylformamide for 10 hours with 1.83 g (10 mmol) of 1-bromo-3,6-dioxa-heptane, 100 mg of sodium iodide and 4 g of potassium carbonate at 90° C. It is concentrated by evaporation in a vacuum and the residue is spread between 100 ml of water and 50 ml of diethyl ether. The aqueous phase is adjusted to pH 2 with 5 N hydrochloric acid and evaporated to dryness. The residue is refluxed with 200 ml of methanol, the undissolved material is filtered out, evaporated to dryness in a vacuum, the residue is dissolved in 50 ml of water, adjusted to pH 2 with 5 N hydrochloric acid and the solution is put on a column with 200 ml of cation exchanger IRC 50. It is eluted first with 0.5 l of water, which is discarded. Then, it is eluted with 0.5 l of 0.5 N ammonia solution. It is evaporated almost to dryness in a vacuum, mixed with 100 ml of water and enough cation exchanger IRC 50 is added with stirring to reach pH 3.5. The solution is then filtered and freeze-dried. 2.95 g of the title compound with a water content of 3.5% is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:25])[CH3:24]>CS(C)=O>[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([CH3:20])=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:25])[CH3:24]
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccccc1
Reactant: CC(=O)O[C@H](C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C)n2Cc2ccccc2)n(C)c1=O
Temperature: 75 °C

Procedure:
7-Benzyl-3,8-dimethylxanthine (500 mg, 1.85 mmol) was added to a suspension of sodium hydride (50.5 mg) in anhydrous DMSO (20 ml) and stirred for 30 min. (R)-5-acetoxy-1-chlorohexane (357 mg) (prepared according to Kline et al. U.S. Pat. No. 5,629,423 (1997)) was added and the mixture was heated at 70-80° C. for 12 h. After cooling to room temperature, the reaction was quenched by the addition of water (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with water (2×50 ml), with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (silica gel) eluting with ethyl acetate. Yield=638 mg.
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]([S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)(=[O:35])=[O:34])[CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[OH:8][NH:9][C:10]([C:12]1[CH:17]=[N:16][C:15]([N:18]2[CH2:19][CH:20]3[CH:22]([CH:21]3[N:24]([S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)(=[O:35])=[O:34])[CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])[CH2:23]2)=[N:14][CH:13]=1)=[O:11]
Reactant: CC(C)COC(C)ONC(=O)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2=O)S(=O)(=O)c2ccc3ccccc3c2)nc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2=O)S(=O)(=O)c2ccc3ccccc3c2)nc1
Reaction time: 8 h
Yield: 11 %

Procedure:
To N-(1-isobutoxyethoxy) 2-(6-{(naphthalene-2-sulfonyl)-[2-(2-oxopyrrolidin-1-yl)ethyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide was added TFA:DCM:MeOH (3.5 ml, 1:2:2 mixture). The solution was stirred overnight, and then concentrated in vacuo. The product was purified by reverse phase HPLC to yield the title compound as a white solid (18 mg, 11%). LCMS Purity >98%, m/z 537 [M+H]+, 1H NMR (300 MHz, d6-DMSO) 1.83-1.95 (3H, m), 2.17 (2H, t, J=8.2 Hz), 2.22-2.26 (2H, m), 3.36-3.45 (6H, m), 3.52-3.59 (2H, m), 3.79 (2H, t, J=11.8 Hz), 7.66-7.76 (2H, m), 7.83 (1H, dd, J=1.8, 8.7 Hz), 8.04-8.09 (1H, m), 8.18 (1H, d, J=8.8 Hz), 8.22-8.27 (1H, m), 8.53-8.56 (1H, m), 8.63 (2H, s), 8.99 (1H, br s), 11.03 (1H, br s).
Reaction SMILES: [O:1]([C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>C(O)C.[C].[Pd]>[O:1]([C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Yield: 92.1 %

Procedure:
Ethyl 3-[(2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylpyrrolidin-2-yl]acrylate (10 g, 26.8 mmol) was subjected to catalytic hydrogenation in ethanol (200 ml) by means of 10% palladium carbon (500 mg) at 60° C. for 3 hours. The reaction solution was left to cool, and the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel™ C-300, 300 ml, ethyl acetate-hexane 1:10) to obtain ethyl 3-[(2R,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylpyrrolidin-2-yl]propionate (9.91 g, yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)[NH2:6].Cl[C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:27][O:26][CH2:25]2)[CH:20]=[C:19]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:17]2[N:22]=[C:21]([NH:23][CH:24]3[CH2:27][O:26][CH2:25]3)[CH:20]=[C:19]([CH2:28][O:29][CH2:30][C:31]([F:33])([F:34])[F:32])[N:18]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: FC(F)(F)COCc1cc(NC2COC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(NC3COC3)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C
Yield: 51 %

Procedure:
A mixture of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (78 mg, 0.38 mmol), 2-chloro-N-(oxetan-3-yl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (57 mg, 0.19 mmol), cesium carbonate (125 mg, 0.38 mmol), palladium(II) acetate (6.45 mg, 0.03 mmol) and 2-(dicyclohexylphosphino)biphenyl (10.07 mg, 0.03 mmol) in dioxane (1 mL) was heated at 120° C. by microwave irradiation under nitrogen atmosphere for 90 minutes. The mixture was filtered through diatomeous earth and the filter pad was washed with methanol. The eluate was concentrated in vacuum and purified by preparative chromatography yielding the title compound as a solid 45 mg (51%).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=2)[CH:14]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: COC(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
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: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Temperature: 90 °C
Yield: 94.8 %

Procedure:
A mixture of 2-bromo-3,5-dichloropyridine (2.72 g, 12 mmol), 4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.78 g, 6 mmol)), 2N Na2CO3 (9.0 mL, 18 mmol), Pd(PPh3)4 (0.35 g, 0.3 mmol) in toluene/ethanol (30 mL/6 mL) was sealed and heated at 90° C. for 12 hrs. The mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine and was dried over MgSO4. After filtration and concentration, purification by silica gel chromatography eluting with ethyl acetate/hexane (5/95) gave 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid methyl ester (1.8 g). MS (M+H)+: 315.6, tR=8.505 min (method 2)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.[SH:18][CH2:19][CH2:20][OH:21].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.CCOCC>[OH:21][CH2:20][CH2:19][S:18][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(SCCO)cc2)cc1C
Reaction time: 6 h

Procedure:
12.2 g (0.05 mol) of 4'-chloro-3,4-dimethylbenzophenone and 4.3 g (0.055 mol) of 2-mercaptoethanol in 50 ml of dimethylacetamide are warmed to 95° under nitrogen. 13.8 g (0.1 mol) of calcined K2CO3 are then added. The suspension is kept at 90°-100° C. for 6 hours. 100 ml of water are poured over the resulting reaction mixture and the product is taken up in ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The resulting crystals are recrystallised from methanol and dried in vacuo at 60° C. Yield: 10.1 g (71%). Melting point 92-93° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[Br:11]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>CN(C)C=O.O>[Br:11][CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1c(Cl)cncc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: Clc1cncc(Cl)c1CBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
A cold (0° C.) solution of 4-hydroxymethyl-3,5-dichloropyridine (3.0 g) and N-bromosuccinimide (6.1 g) in dry dimethylformamide (100 mL) is treated with triphenylphosphine (8.9 g), portionwise, during 5 minutes. The resulting red solution is stirred at 0° C. for 45 minutes, and then treated with methanol (5 mL), followed by water (300 mL). The mixture is extracted with diethyl ether (4×200 mL), the combined organic washings dried over sodium sulfate, and the solvent removed under reduced pressure. The resulting residue is chromatographed on silica gel, eluting with a mixture of diethyl ether and pentane (1:2 v/v), to give 4-bromomethyl-3,5-dichloropyridine (3 g), in the form of an off-white solid, m.p. 40°-44° C.
Reaction SMILES: CCN(CC)CC.[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[S:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]=1)=[O:20].[Cl:30][CH2:31][C:32](Cl)=[O:33].C([O-])(O)=O.[Na+]>ClCCl>[Cl:29][C:27]1[S:26][C:24]2[NH:25][C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][C:32](=[O:33])[CH2:31][Cl:30])=[O:20])=[CH:22][C:23]=2[CH:28]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Et3N (3 mL, 21.6 mmol) was added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 21, 3.11 g, 6.98 mmol) in anhydrous dichloromethane (55 mL) and stirred at ambient temperature for 5 miuntes. The suspension was cooled to −78° C. and chloroacetylchloride (611 μL, 7.68 mmol) was added and the reaction was warmed to 0° C. and stirred at this temperature for 3 hours. NaHCO3 (50 mL) was added, the phases were separated and the aqueous phase was extracted with THF (2×50 mL). The combined organic fractions were washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was triturated (THF:isohexane, 1:5), collected by filtration, washed with hexane (20 mL) and dried to give the title compound (1.92 mg, 68%) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C1COCC1>[CH2:22]([O:21][CH:20]([O:24][CH2:25][CH3:26])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH3:23]
Reactant: CCOC(CBr)OCC
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(COc1ccc(C(=O)OC)cc1)OCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture containing 10 g of methyl 4-hydroxybenzoate and 22.71 g of K2CO3 in 100 ml of THF is heated at 100° C. for 5 min and cooled to room temperature, 15.54 g of 2-bromo-1,1-diethoxyethane are added and the mixture is stirred for 2 hours at room temperature and then for 32 hours at 100° C., and is allowed to return to room temperature. The inorganic material is filtered off and then rinsed with DMF. The filtrate is evaporated and then taken up in DCM, washed with water (3 times) and then with saturated NaCl solution, dried over MgSO4 and evaporated. 16.68 g of the expected compound (greater than the theoretical mass) are obtained.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1>CN(C)C(=O)C>[CH:25]1([CH:28]=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:27][CH2:26]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=CC1CC1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=CC1CC1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
The product of Example 268D (0.15 g, 0.41 mmol) was reacted with cyclopropanecarbaldehyde (1.0 g, 14 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 120° C. for 90 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.104 g, 60%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14](Br)[CH:15]=1.[C:18]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:21][O:20][C:18](=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([C:14]2[CH:13]=[N:12][C:11]([NH2:17])=[C:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:15]=2)[CH:27]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2s1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Temperature: 90 °C

Procedure:
A mixture of 3-benzothiazol-2-yl-5-bromopyridin-2-ylamine (BB7) (1.37 g, 4.5 mmol), 3-(carbomethoxy)phenylboronic acid (0.85 g, 4.7 mmol), Pd(PPh3)4 (5 mol %), and Cs2CO3 (3.5 g, 10.8 mmol) in dioxane/H2O (4:1, 30 mL) were heated under nitrogen at 90° C. for 5 h. Solvents were removed in vacuo, water (10 mL) was added to the residue, and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material thus obtained was purified by column chromatography on silica gel using mixtures of EtOAc/Hexanes to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=7.28 (brs, 2H), 7.41 (t, J=6.9 Hz, 1H), 7.51 (t, J=6.9 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.77 (d, J=6.3 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.01-8.05 (m, 2H), 8.18 (d, J=2.1 Hz, 1H), 8.26 (t, J=1.8 Hz, 1H), 8.47 (d, J=2.1 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:22]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)=[O:23])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g) was dissolved in 20 ml toluene. 50% aqueous sodium hydroxide (1.25 g) was added followed by 2-thiophenecarbonylchloride (0.76 g). The mixture was stirred at room temperature for 14 hours. The solid product, N'-t-butyl-N-benzoyl-N'-(2thiophenecarbonyl)hydrazine, was removed by filtration and washed with water. m.p. >200° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][CH:15]=2)=[O:18])=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 21 h
Yield: 64.3 %

Procedure:
To commercially available nitromethane (5 ml) were added commercially available anisole (541 mg), commercially available 4-t-butylbenzoyl chloride (983 mg) and commercially available scandium(III) trifluoromethanesulfonate (492 mg), and the admixture was stirred at 60° C. for 21 hours. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/acetone to obtain 862 mg of the title compound (yield: 64%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]=O)=[CH:7][CH:8]=2)[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][N:14]3[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]3)=[CH:7][CH:8]=2)[NH:3]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the compound (19.8 g) obtained in Step 1-4 and tert-butyl piperidin-4-ylcarbamate (24.8 g) in CHCl3 (450 mL) was stirred at 70° C. for 1.5 hours and allowed to cool to room temperature. Thereafter, NaBH(OAc)3 (35.9 g) was added to the mixture under ice cooling and the mixture was stirred at room temperature for 12 hours. A saturated aqueous NaHCO3 solution was added to the reaction mixture and then a water layer and an organic layer were separated. The water layer was extracted three times with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60 N, mobile phase: MeOH/CHCl3=33/66 to 100/0; v/v) to obtain tert-butyl {1-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl]piperidin-4-yl}carbamate (37.8 g, a colorless solid).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[CH:7]([CH2:18][O:19][CH3:20])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9]>C(#N)C>[C:1]([O:4][CH:7]([CH2:18][O:19][CH3:20])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: COCC(Br)C(=O)Nc1ccc(C)cn1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC(OC(C)=O)C(=O)Nc1ccc(C)cn1
Yield: 88.9 %

Procedure:
Potassium acetate (2.01 g, 20.50 mmol) was added to a stirred solution of 2-bromo-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (Step 1) (1.40 g, 5.13 mmol) in ACN (20 mL). The reaction mixture was refluxed for 5 hrs. The reaction mixture was filtered and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:2/1) to give the title compound as a colourless solid (1.15 g), 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H), 8.11 (m, 2H), 7.52 (dd, 1H), 5.44 (dd, 1H), 3.89 (dd, 1H), 3.78 (dd, 1H), 3.39 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H).