Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:26][C:25]([C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:14][C:13]=2[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1=Cc2cc(OCc3ccccc3)ccc2OC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5-Benzyloxy-2-hydroxybenzaldehyde (2.01 g, 8.80 mmol) is dissolved in 30 ml of DMF and treated successively with potassium carbonate (1.22 g, 8.80 mmol) and tert-butyl acrylate (1.22 g, 13.2 mmol). The mixture is heated at 100° C. for 1 hour. The temperature is gradually raised to 135° C. over a period of 2 hours, and held at 135° C. for 1 hour. The resultant dark mixture is cooled and evaporated to remove most of DMF. The residue is partitioned between ether and water, and the aqueous phase is discarded. The organic layer is dried (MgSO4), evaporated and purified by silica gel chromatography (6% ethyl acetate/hexane) to give tert-butyl 6-benzyloxy-2H-1-benzopyran-3-carboxylate as a yellow crystalline solid, m.p. 64°-67° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16]1([CH2:22][C:23](=O)[C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:22]([C:23]1[C:24](=[O:25])[N:8]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: Cc1cccc(Nc2ncccc2N)c1
Solvent: CCO
Product: Cc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Yield: 53.8 %

Procedure:
A mixture of 3-amino-2-[(m-tolyl)amino]pyridine (299 mg) and phenylpyruvic acid (246 mg) in ethanol (5 ml) was refluxed for 2 hours. The mixture was cooled and the precipitates were collected and washed with ethanol to give 2-benzyl-3-oxo-4-(m-tolyl)-3,4-dihydropyrido[2,3-b]-pyrazine (264 mg).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:13]=1.[ClH:19]>C(#N)C>[Cl:19][C:9]1[S:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:13]=1
Reactant: Cl
Reactant: CCOC(=O)c1cnc(N)s1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)s1
Yield: 97 %

Procedure:
To a solution of tert-butyl nitrite (9.3 g, 90 mmol) and cupric chloride (9.7 g, 72 mmol) in 150 mL of acetonitrile at 65° C. was added portionwise ethyl 2-aminothiazole-5-carboxylate (10.3 g, 60 mmol) (prepared by the method of Dann, O. Chem Ber 76 419 (1943)) resulting in vigorous gas evolution. After the addition was complete, the solution was stirred until gas evolution ceased (30 minutes). The solution was cooled and poured into 250 mL of cold 20% v/v aqueous HCl. The aqueous solution was extracted 3 times with 200 mL of EtOAc. The organics were combined, washed once with 100 mL of 20% aqueous HCl and 2 times with 100 mL saturated brine and dried over magnesium sulfate. Concentration in vacuo gave 11.1 g (97% yield) of a brown oil which required no purification.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[O:13][CH:12]([CH2:15][NH2:16])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>O1CCCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:16][CH2:15][CH:12]1[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:14]=2[O:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC1Cc2cccc(C3CCCC3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(C3CCCC3)c2O1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
To a suspension of (7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.4 g, 9.46 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was added diisopropylethylamine (2.14 g, 16.58 mmol) followed by benzyl chloroformate (2.08 g, 12.19 mmol) and the reaction mixture was allowed to stir for 15 min. The reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 2.52 g (76%) of (±)-benzyl(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a yellow oil. Rf=0.21 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C22H25NO3 C, 75.19; H, 7.17; N, 3.99. Found C, 74.74; H, 7.02; N, 3.85. Chiral HPLC separation of (±)-benzyl(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=9.678 min, Chiralcel OJ, ethanol:hexane 1:1); Fraction 2 (Rt=12.824 min, Chiralcel OJ, ethanol:hexane 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH3:13])=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([Cl:24])=[N:10][C:9]=2[CH3:13])=[N:6][CH:7]=1
Reactant: Cc1ncoc1-c1ccc(Br)cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
A solution of Example 57A (7.32 g, 30.6 mmol) in THF (150 mL) was cooled to −78° C., and treated carefully with LiHMDS (1 M in THF, 37 mL, 37 mmol). The mixture was stirred at −78° C. for 20 minutes, then was treated all at once with hexachloroethane (14.5 g, 61.2 mmol). The flask was removed from the cold bath, and the reaction mixture was stirred overnight at room temperature. After this time, the mixture was diluted with Et2O and washed with saturated NH4Cl solution and water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (100% hexane, then 0% to 20% EtOAc/hexane) to afford 7.44 g (89%) of the title compound as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J=2.4, 1H), 7.87 (dd, J=8.4, 2.4, 1H), 7.48 (dd, J=8.7, 0.7, 1H), 2.57 (s, 3H). MS (DCI+) m/z 273/275 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([C:15]#[C:16][CH2:17]O)([OH:14])[C@@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([SnH:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]2([O:14][CH2:17][C:16]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:15]2)[C@@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Agent: [Pd]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)C1=C[C@@]2(CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)OC1
Yield: 66.7 %

Procedure:
Crude (2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol (Description 18; 45 g) was dissolved in toluene (750 ml) and degassed with nitrogen. Tetrakis(triphenylphosphine) palladium (0) (2.30 g, 2.0 mmol) in toluene (600 ml) was added and the mixture was degassed. Tributyltin hydride (35.78 ml, 38.71 g, 133 mmol) was added dropwise over 15 minutes, with stirring and cooling (internal temperature below 25° C.). The mixture was stirred at room temperature for 1 hour, then the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (600 ml) and triphenylphosphine (34.88 g, 133 mmol) was added. A solution of diethyl azodicarboxylate (20.94 ml, 23.16 g, 133 mmol) in tetrahydrofuran (150 ml) was added dropwise with stirring and cooling and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, acetonitrile (600 ml) was added and the mixture was extracted with hexane (8×150 ml). The hexane fractions were combined and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/ethyl acetate (100:0 increasing to 99:1) to give the title compound as a yellow oil (53.64 g, 67% from (2s,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine). 1H NMR (CDCl3) δ 7.38-7.40 (2H, m), 7.15-7.25 (3H, m), 5.96 (1H, t, J 2.3 Hz), 4.93 (1H, s), 4.63 (1H, dd, J 2.23, 12.9 Hz), 4.22 (1H, dd, J 2.23, 12.9 Hz), 4.09-4.14 (1H, m), 3.09-3.17 (1H, m), 1.95-1.99 (1H, m), 1.83-1.86 (1H, m), 1.72-1.76 (2H, m), 1.40-1.51 (6H, m), 1.38 (9H, s), 1.25-1.32 (6H, m), and 0.86-0.99 (15H, m).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C:15]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>C(Cl)Cl>[CH3:8][S:9]([O:13][CH2:14][C:15]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:16]=1[O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:20]([C:21]#[N:22])[CH:19]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc(Oc2cc(C(F)(F)F)ccc2CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C(F)(F)F)cc1Oc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.33 ml) followed by methanesulphonyl chloride (0.185 ml) were added to a solution of the product from step (ii) (0.7 g) in DCM (20 ml) at −20° C. The mixture was stirred at 0° C. for 1 h, then diluted with dichloromethane, washed with water, dried and evaporated under reduced pressure, yield 0.97 g.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[O:47][CH3:48]>>[CH3:48][O:47][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCCc3ccccc3)cc2)C(O)C1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCOCCc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate as a yellow solid; MS: 642 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.CN(C)C1C=CC=CC=1.[CH3:18][O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:23](=[O:24])[CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:26])=[N:3][CH:4]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1cnc(Br)cn1
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Yield: 70 %

Procedure:
The 2-amino-5-bromopyrazine (commercially available, 0.687 g, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL). Then N,N-dimethylaniline (500 μL, 1.0 eq.) and methyl-4-chloro-4-oxo-butanoate (535 μL, 1.1 eq.) was successively added. The mixture was refluxed for 12 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer were dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate A2 (70%). 1H NMR (400 MHz, DMSO-d6) δ 11.02 (bs, 1H), 9.12 (s, 1H), 8.62 (s, 1H), 3.60 (s, 3H), 2.74 (t, 2H), 2.62 (t, 2H) ppm. LC-MS (Method A): RT 1.28, 290 (M+H+)
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1>>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:31])=[CH:25][CH:24]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: Cc1ccc(N=C=S)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(C)cc4)CC3)nc21

Procedure:
Pipemidic acid (89 mg, 0.293 mmol) and p-tolyl isothiocyanate (40 mg, 0.268 mmol) were used. Purification on silica yielded compound 27 in Table 1, below (82 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.67 (s, 1H), 7.40 (s, 1H), 7.17 (d, J=7.60 Hz, 2H), 7.09 (d, J=7.44 Hz, 2H), 4.33 (q, J=6.40 Hz, 2H), 4.23-3.91 (m, 8H), 2.34 (s, 3H), 1.49 (t, J=7.03 Hz, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:27])(=O)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([O:14][CH3:27])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)OC(C)(C)C)CC1O
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CC1N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
A suspension of 6 (52 g, 0.16 mol) in tetrahydrofuran (THF, 150 mL) was stirred at room temperature for about 30 min and cooled to −10 to −15° C. A solution of potassium hexamethyldisilylamide (KHMDS, 40% solution in THF, 144 mL, 0.256 mol) was slowly added while controlling the temperature between −5 and −15° C. After 15 min, dimethyl sulfate (18.7 mL, 1.20 mol) was added dropwise to the reaction mixture while maintaining a temperature between −10 and 0° C., and the resulting reaction mixture was then stirred at this temperature for about 30 min. The reaction mixture was quenched by the addition of water (100 mL), followed by acetic acid (50 mL). The product was extracted with methyl tert-butyl ether (2×150 mL). The combined organic layer was washed with water (100 mL), brine (50 mL) and dried over anhydrous Na2SO4. Evaporation under reduced pressure gave compound 7 as an oil (54 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].B.C1COCC1>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5][OH:6]
Reactant: Nc1cc(C(=O)O)ccc1F
Agent: B
Solvent: C1CCOC1
Product: Nc1cc(CO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
3-Amino-4-fluorobenzoic acid (15 g, 97 mmol) in THF at 0° C. was treated with 1.0 M BH3•THF (50 mL) with stirring overnight at room temperature. An additional 130 mL 1.0 M BH3•THF was added with stirring for 10 hours. The reaction mixture was quenched by the addition of methanol, stirred 3 hours at room temperature, solvent evaporated, and the product partitioned between aqueous sodium bicarbonate/methylene chloride. The organic layer was dried (sodium sulfate), filtered, and the solvent evaporated. The crude product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[Br:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1Br
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3ccccc3Br)c2cn1
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 33.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (198 mg, 1.03 mmol) (described in a previous experimental) and 2-bromoaniline (1.00 mL, 9.18 mmol) is stirred under N2 at 180° C. for 2.5 h, and the resulting product is chromatographed on alumina (1% EtOH/CHCl3) to give 7-amino-4-(2-bromoanilino)pyrido[4,3-d]pyrimidine (108 mg, 33%) as a pale yellow solid, 1H NMR (DMSO) δ 9.91 (1H, brs), 9.27 (1H, s), 8.20 (1H, s), 7.73 (1H, d, J=7.9 Hz), 7.50 (1H, m), 7.44 (1H, t, J=6.9 Hz), 7.25 (1H, m), 6.59 (2H, brs), 6.42 (1H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N:31]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][CH:39]=2)[C:34]([S:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:33][CH:32]=1>C(O)(C)(C)C>[N:31]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][CH:39]=2)[C:34]([S:41][C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)=[N:4][N:3]=3)=[CH:44][CH:43]=2)=[CH:33][CH:32]=1
Reactant: Nc1ccc(Sc2ccnc3cccnc23)cc1
Reactant: Clc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)(C)O
Product: Clc1ccc(-c2nnc(Nc3ccc(Sc4ccnc5cccnc45)cc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-Chloro-4-(4-chlorophenyl)phthalazine (30 mg, 109 μmol), p-toluenesulfonic acid monohydrate (10 mg, 55 μmol) and 4-(1,5-naphthyridin-4-ylthio)benzenamine (33 mg, 131 μmol) were combined in t-butanol in a sealed tube and the reaction mixture was stirred at 100° C. for 2 h. The mixture was concentrated in vacuo and the crude material was purified by silica gel chromatography (0 to 100% 90/10/1 CH2Cl2/MeOH/NH4OH) in CH2Cl2. The material was further purified by silica gel chromatography (0 to 100% EtOAc/hexane) to afford N-(4-(1,5-naphthyridin-4-ylthio)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine. MS [M+H]=492; Calc'd 491.99 for C28H18ClN5S.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH3:6].O.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16]>CN(C)C=O>[CH3:6][O:5][CH2:4][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)c1ccccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1C(C)=O
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
In N,N-dimethylformamide (25 mL) was dissolved 3.39 g (24.9 mmol) of commercially available 1-(2-hydroxyphenyl)-ethanone, 1.52 g (38.0 mmol) of 60% sodium hydride was added to the solution in an ice bath, and the resulting mixture was stirred in an ice bath for 20 minutes. To the mixture was gradually added dropwise 3.00 mL (39.5 mmol) of chloro(methoxy)methane, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 4.33 g (24.1 mmol, Yield: 96.8%) of 1-[2-(methoxymethoxy)phenyl]ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O>O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:21][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1nc(OC)nc(C2C(=O)Nc3c(F)cccc32)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1nc(OC)nc(-c2c(OS(=O)(=O)c3ccc(C)cc3)[nH]c3c(F)cccc23)n1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 23.3 %

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-1,3-dihydro-2H-indol-2-one (1.15 g), 4-methylbenzenesulfonyl chloride (1.06 g) and sodium carbonate (0.41 g) are introduced as initial charge in 5.5 ml of water and 11 ml of acetone and, with stirring, heated to 80° C. in a preheated oil bath. After 45 minutes, the hot solution is filtered, and the solid is washed with 20 ml of water/acetone (1:1) and methanol and dried in vacuo. This gives 0.76 g of product in an HPLC purity of 97% (42% of theory). Structure elucidation by NMR verifies that it is the O-sulfonylated product. A further 0.41 g of product in an HPLC purity of 89% can be isolated from the filtrate (21% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COC(=O)CCCCCCC(=O)c1cc(C)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)CCCCCCC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
Methyl 8-(2-hydroxy-5-methyl-phenyl)-8-oxo-octanoate (271 mg), 4-chloro-6,7-dimethoxyquinoline (220 mg), and 4-dimethylaminopyridine (237 mg) were suspended in o-dichlorobenzene (20 ml) to prepare a suspension which was then stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (16 mg, yield 3.5%).