Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[F:37][C:38]1[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42](B(O)O)[CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1COCC1.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>[F:37][C:38]1[CH:43]=[CH:42][C:41]([O:47][CH3:48])=[C:40]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:39]=1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: COc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
The product from Example 15B (165 mg, 0.3 mmol), 5-fluoro-2-methoxyphenylboronic acid (68 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) in THF (10 ml) were treated with 3M aqueous sodium carbonate (0.4 mL) and heated at reflux for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water, acidified with 1N hydrochloric acid and extracted with diethyl ether. The organic layers were combined, dried with magnesium sulfate, filtered and the filtrate concentrated. The residue was purified by a Prep Nova Pak (HRC18) column using 0.1% trifluoroacetic acid:acetonitrile (10:90 to 95:5) as eluant to provide the title compound (50 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([CH:11]=O)[N:10]=[C:4]2[N:3]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[C:21]([CH2:11][C:9]3[N:10]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]4[N:8]=3)=[C:20]([OH:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Reactant: Cc1ccn2nc(C=O)nc2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)ccn4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(224) where 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 3H), 1.30-1.80 (brm, 8H), 2.00-2.40 (brm, 3H), 2.50 (q, J=10.74 Hz 2H), 2.68 (s, 1H), 2.70(s, 2H); 2.92 (m, 2H), 3.69 (m, 3H), 6.64 (d, J=3.56 Hz, 1H), 6.66 (d, J=3.56 Hz, 1H), 7.00 (m, 2H), 8.55 (d, J=6.97 Hz, 1H). Anal. Calcd. For C27H32O4N4: C, 68.05; H, 6.77; N, 11.76. Found: C, 68.24; H, 6.80; N, 11.77.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:25])[CH2:4][CH2:3]1.[BH4-].[Na+]>C1COCC1.C(O)C.O>[OH:25][CH:5]1[CH2:4][CH2:3][C:2]([CH3:1])([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Reaction time: 6 h

Procedure:
To a cold solution (0° C.) of 980 mg (2.8 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl) ethynyl]benzoate (Compound 1) in 5 ml of THF and 10 ml of ethanol was added 78 mg (2 mmol) of sodium borohydride. The mixture was stirred for 6 hours, diluted with water (10 ml) and extracted with Et2O (4×40 ml). The combined organic layers were washed with 10% HCl (5 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:4]=1[NH2:5].Br[C:20]1[N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:23]([CH3:29])=[N:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:20]2[N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:23]([CH3:29])=[N:22][CH:21]=2)[CH:7]=[CH:6][C:4]=1[NH2:5]
Reactant: COCCn1c(Br)cnc1C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Product: COCCn1c(-c2ccc(N)c(OC)c2)cnc1C

Procedure:
The title compound was prepared according to the method described for Preparation 158 using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 5-bromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole (Preparation 209).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Product: Cc1cc(OCCCCSc2ccc(Cl)cc2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 4-chloro-thiophenol.
Reaction SMILES: [O:1]1[C:12]2[C:4](=[CH:5][C:6]3[S:10][CH:9]=[N:8][C:7]=3[CH:11]=2)[O:3][CH2:2]1.Br[C:14]1[CH:15]=[CH:16][C:17]([NH:20][CH3:21])=[N:18][CH:19]=1.COC1N=CC(C2SC3C=CC=CC=3N=2)=CN=1>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[O:1]1[C:12]2[C:4](=[CH:5][C:6]3[S:10][C:9]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][CH3:21])=[N:18][CH:19]=4)=[N:8][C:7]=3[CH:11]=2)[O:3][CH2:2]1
Reactant: c1nc2cc3c(cc2s1)OCO3
Reactant: CNc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: COc1ncc(-c2nc3ccccc3s2)cn1
Product: CNc1ccc(-c2nc3cc4c(cc3s2)OCO4)cn1
Temperature: 170 °C
Yield: 35.7 %

Procedure:
To [1,3]Dioxolo[4,5-f][1,3]benzothiazole (98 mg, 0.55 mmol) and 5-bromo-N-methylpyridin-2-amine (112 mg, 0.60 mmol) were subjected to the procedure used for the preparation of 2-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole, with the following exceptions: 5 mol % bis(tri-t-butylphosphine) palladium (0) was used and the reaction was heated under argon at 170° C. in a microwave oven for 30 min. The crude material was purified by flash chromatography (Heptane/EtOAc 1:1) to give the title compound (56 mg) as a yellow solid. 1H NMR δ 8.62 (d, 1H) 7.94 (dd, 1H) 7.61 (s, 1H) 7.47 (s, 1H) 7.19 (q, 1H) 6.57 (d, 1H) 6.13 (s, 2H) 2.85 (d, 3H); MS m/z (M+H) 286.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1.[Ce].[Cl-].[BH4-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Nc1cnc(C2=CC(=O)CCC2)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Ce]
Solvent: CCO
Solvent: O
Product: Nc1cnc(C2=CC(O)CCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 3-(5-aminopyrazin-2-yl)cyclohex-2-enone (150 mg, 0.793 mmol) in ethanol (2643 μL) was added cerium (Ill) chloride (293 mg, 1.189 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h until all the materials were dissolved. The reaction mixture was then cooled to 0° C. and sodium borohydride (45.0 mg, 1.189 mmol) was added in portions. The reaction mixture was stirred upon warming up to room temperature for 2 h. The reaction mixture was cooled to 0° C. and 2 mL of water was slowly added until the bubbles clearly showed up and then disappeared, Continued to stir for 30 min. Then, sodium sulfate was added and stirred for 30 min. Filtered and dried under high vacuum to provide 149 mg of desired product. LCMS (m/z): 192.1 (MH+), 0.46 min.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([CH3:28])=[N:30][CH:31]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)cn1

Procedure:
The title compound, white solid (30 mg, 27%), MS (ISP) m/z=450.3 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 6-methyl-nicotinic acid.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][OH:22])[CH2:26][CH2:27]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: OCCN1CCNCC1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(CCO)CC4)cc3nc21
Yield: 52.7 %

Procedure:
7-Fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 1 but starting from 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 6.8 g of 1-(2-hydroxyethyl)-piperazine in 16 cm3 of pyridine. After concentrating the reaction mixture to dryness under reduced pressure, the residue is taken up in 50 cm3 of water. The mixture is brought to pH 6.9 by adding 0.4 cm3 of acetic acid. The precipitate obtained is drained, washed with twice 10 cm3 of water and recrystallized twice from 10 cm3 of dimethylformamide. 1.1 g of 7-fluoro-8-[4-(2-hydroxyethyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 275°-276° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (220 mg, 0.81 mmol) [prepared according to the procedure of Example 188], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (281 mg, 0.84 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (472 mg, 1.0 mmol) in Chloroform (8 mL). DIEA (710 μL, 4.07 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (281 mg, 0.51 mmol, 63%): LC-MS (ES) m/z=553 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[C:13]1([CH:9]2[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCOC(c3ccccc3)C2)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: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCOC(c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 69.6 %

Procedure:
106 mg of 4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 91 mg of 2-(Trifluoromethyl)phenyl boronic acid, 18 mg of tetrakis(triphenylphosphine)palladium(0), 1.1 mL of 2M sodium carbonate solution, 2.9 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting in a 10 to 40% ethyl acetate/hexanes gradient. The product fractions were pooled and concentrated to afford 88.3 mg of product. ES MS (+) m/z 398
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[H-].[Na+].C(Cl)Cl.CCOC(C)=O>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(Cl)nc(N3CCOCC3)n2)CC1
Yield: 81.3 %

Procedure:
A mixture of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine (0.47 g, 2 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (0.40 g, 2 mmol), and a small excess of NaH (58 mg, 2.4 mmol) in THF (20 mL) was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc. Chromatography on silica eluting with CH2Cl2/EtOAc (9:1) gave 0.65 g (81% yield) of tert-butyl 4-(4-chloro-6-morpholino-1,3,5-triazin-2-yloxy)piperidine-1-carboxylate as a white solid: mp (i-Pr2O) 150-152° C.; 1H NMR (CDCl3) δ 5.18 (tt, J=7.7, 3.8 Hz, 1H), 3.87 (m, 2H), 3.83 (m, 2H), 3.78-3.71 (m, 6H), 3.30 (ddd, J=13.5, 8.3, 3.8 Hz, 2H), 1.95 (m, 2H), 1.78 (m, 2H), 1.46 (s, 9H); Anal. Calcd. for C17H26ClN5O4: C, 51.06; H, 6.55; N, 17.51. Found: C, 51.21; H, 6.28; N, 17.4%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:15].[CH3:16][N:17](C)C=O>[C-]#N.[Zn+2].[C-]#N.[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:16]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:15])#[N:17]
Reactant: CCOC(=O)C(C)c1ccc(I)c(C)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)C(C)c1ccc(C#N)c(C)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stirred solution of ethyl 2-(4-iodo-3-methylphenyl)propanoate (1.22 g, 5.34 mmol) in anhydrous dimethylformamide were added zinc cyanide (645 mg, 5.50 mmol) and tetrakis(triphenylphosphine) palladium (617 mg, 0.53 mmol). The reaction mixture was refluxed for overnight then cooled to room temperature. The mixture was filtered using celite pad and the filtrate was evaporated. The residue was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to get the crude. The crude was purified by column chromatography. Ethyl 2-(4-cyano-3-methylphenyl)propanoate (1.05 g) was obtained as 90% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:16]1([C:2]2[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=2[O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH2:18][CH2:17]1
Reactant: OB(O)C1CC1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d, 1.5 g, 5.5 mmol), cyclopropylboronic acid (CAN 411235-57-9, 0.57 g, 7 mmol), palladium diacetate (CAN 3375-31-3, 62 mg, 0.28 mmol), tricyclohexylphosphine (CAN 2622-14-2, 154 mg, 0.1 mmol) and potassium phosphate (4.1 g, 19 mmol) in toluene/water (20/1v/v, 30 mL) was heated to 100° C. overnight. After that the mixture was evaporated to dryness, dissolved in 30 mL of water, extracted with ethyl acetate (30 mL) and the organic layer was dropped. The water layer was adjusted to pH=3 and extracted with ethyl acetate (2×30 mL), this organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate then evaporated to dryness. The residue was purified by column chromatography (silica gel, 10 g, eluting with 15% ethyl acetate in petroleum ether) to obtain the title compound (0.96 g, 75%) as white solid; MS (LC/MS): 234.1 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=[CH:20]2)=[O:11].C(O)=O.C(N(CC)CC)C.C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24]([C:23]([NH2:26])=[CH:22][CH:21]=[CH:20]2)=[CH:25][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c([N+](=O)[O-])cccc3nc2-1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(N)cccc3nc2-1
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
9-nitro camptothecin (3.4 g) was dissolved in distilled DMF (100 ml). Palladium acetate (0.08 g), formic acid (0.95 ml), and triethylamine (3.5 ml) were added. The solution was heated to 80° C., and the heating was continued for 1 hour. DMF (200 ml) and charcoal were added to the reaction mixture, and the stirring was continued for 0.5 hours at 80° C. The mixture was filtered hot through a celite filter aid, and the filtrate was concentrated to small volume. The precipitated orange solid was collected by filtration to yield 2.5 g of 9-amino camptothecin.
Reaction SMILES: [CH2:1]([N:10]1[C:15]([CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[C:14]([CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[NH:12][C:11]1=[O:29])[CH:2]=[CH:3][C:4]1C=CC=CC=1.C1(C#CCN2C(CC3C=C(C)C=C(C)C=3)=C(C(C)C)C(=O)NC2=O)C=CC=CC=1>>[CH2:1]([N:10]1[C:15]([CH2:16][C:17]2[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=2)=[C:14]([CH:25]([CH3:26])[CH3:27])[C:13](=[O:28])[NH:12][C:11]1=[O:29])[CH:2]=[CH:3][CH3:4]
Reactant: Cc1cc(C)cc(Cc2c(C(C)C)c(=O)[nH]c(=O)n2CC=Cc2ccccc2)c1
Agent: Cc1cc(C)cc(Cc2c(C(C)C)c(=O)[nH]c(=O)n2CC#Cc2ccccc2)c1
Product: CC=CCn1c(Cc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O

Procedure:
1-cinnamyl-5-isopropyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione; 1-(3-phenyl-2-propynyl)-5-isopropyl-6-(3,5-dimethylbenzyl)-2,4-pyrimidinedione;
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:42][CH:43]=1
Reactant: Clc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2ccc(Cl)cc2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((4-chlorophenyl)ethynyl)pyridazine (Intermediate 34) except that the solvent used for the hydrogenation was tetrahydrofuran and the final compound was recrystallised from a mixture of ethyl acetate and heptane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Br[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=1)=[O:23]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:21][C:22](=[O:23])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: CSc1ccc(NC(=O)CBr)cc1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(CC(=O)Nc2ccc(SC)cc2)c1=O
Yield: 90 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 2-bromo-4′-(methylthio)acetanilide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 90.0%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=O)[CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:7]=1.Cl.[NH2:30][OH:31]>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)/[C:16](=[N:30]/[OH:31])/[CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:7]=1
Reactant: COC1(c2cc(F)cc(S(=O)(=O)c3ccc4c(c3)CCC4=O)c2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(S(=O)(=O)c3ccc4c(c3)CC/C4=N\O)c2)CCOCC1
Yield: 49 %

Procedure:
Using an analogous procedure to that described in Example 50, 5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylsulphonyl]indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylsulphonyl]indan-1-one oxime in 49% yield, m.p. 225°-226° C.;