Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:26]([C:23]1[CH:24]=[CH:25][C:19]2[CH:18]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[S:21][C:20]=2[CH:22]=1)=[O:27]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)N(C)C)cc2s1
Yield: 75.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carboxylic acid (175 mg, 0.387 mmol), DMAP (142 mg, 1.16 mmol), EDC (111 mg, 0.580 mmol), and dimethylamine hydrochloride (47 mg, 0.580 mmol) are reacted analogous to Example 3 to afford the title compound (140 mg, 76%).
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:41])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:41])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:39])[F:40])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid (2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl)-amide (122 mg, 0.21 mmol) in dry THF (2.0 mL) was treated at 0° C. with TBAF (0.41 mL of a 1M solution in THF, 0.41 mmol). The reaction mixture was stirred at 0° C. for 45 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as a white solid. TLC:rf (19:1 CH2Cl2-MeOH)=0.26. LC-MS-conditions 02: tR=1.01 min; [M+H]+=479.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc(C)n1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(Oc2cc(C)nc(C)c2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 53.4 %

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,6-dimethyl-4-pyridinyloxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.62 g, 0.9 mmol) was reacted with trimethylsilyl acetylene (0.89 g, 9 mmol), CuI (5 mg), triethylamine (2.74 g, 27 mmol), and dichlorobis(triphenylphosphine) palladium (0) (50.7 mg, 0.07 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,6-dimethyl-4-pyridinyloxy)-5-ethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a pale yellow solid (Yield 0.28 g, 53%)
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[N:3][N:2]=1>CO.[Pd]>[NH:16]1[CH2:15][CH2:14][CH:13]([C:1]2[N:5]3[C:6]4[CH:12]=[CH:11][NH:10][C:7]=4[N:8]=[CH:9][C:4]3=[N:3][N:2]=2)[CH2:18][CH2:17]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Agent: [Pd]
Solvent: CO
Product: c1cc2c(ncc3nnc(C4CCNCC4)n32)[nH]1
Yield: 82.5 %

Procedure:
Benzyl 4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate (0.34 g, 0.90 mmol) and 10% Pd on carbon (0.10 g, 0.09 mmol) in MeOH (30 mL) were shaken under hydrogen at about 60 psi for about 5 h. The H2 source was removed, and the reaction was filtered through Celite® and concentrated under reduced pressure to give 1-(piperidin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a yellow solid (0.18 g, 77%): LC/MS (Table 2, Method a) Rt=0.70 min; MS m/z: 243 (M+H)+.
Reaction SMILES: C([N:3](CC)[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8](C(=O)C2C=CC=CC=2)=[CH:7][CH:6]=1)C.C(N1C2CCC1CC(=O)C2)CC1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:4]([NH2:3])(=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=C1CC2CCC(C1)N2CCc1ccccc1
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1

Procedure:
A suspension of 52 g (0.8 mole) of zinc powder and 800 mL of THF was cooled in an ice bath 44 mL (0.4 mole) of TiCl4 was added dropwise with stirring. The ice bath was removed and the reaction refluxed for 2 h. A solution of 26.45 g (0.094 mole) of N,N-diethyl-4-benzoylbenzamide and 23.9 g (0.094 mole) of 8-phenethyl-8-azabicyclo[3.2.1]octan-3-one, in 100 mL of THF was added dropwise and the reaction was refluxed 4 h. After cooling, the reaction mixture was poured into a beaker containing excess K2CO3 and ice. The mixture was extracted with ether, washed with brine, dried (K2CO3) and concentrated. There was obtained 47 g (˜0.1 mol) of crude (±)-N,N-diethyl-4-[(8-phenethyl-8-azabicyclo[3:2:1]oct-3-ylidene)phenylmethyl]benzamide as an oil. A sample of the oil and 38.33 g (0.1 mole) of (+)-ditoluoyl-D-tartaric acid were combined in 600 mL of acetonitrile. The solid was collected and recrystallized twice from acetonitrile. The solid was collected and partitioned between dilute sodium hydroxide and CH2Cl2. The organic solution was dried (K2CO3) and concentrated. The residue was converted to a hydrochloride salt (Et2O/HCl). It was recrystallized from 2-PrOH to give 5.6 g of white solid. Et2O, filtered, and precipitated after the addition of ethereal HCl; mp 210-211° C. MS m/z (MH+) 479. 1H NMR 300 MHz (CDCl3) δ 12.6 (s, 1H), 7.2-7.45 (m, 14H), 3.85 (S, 2H), 3.5-3.1 (m, 10H), 2.6 (d, 1H), 2.5 (d, 2H), 2.05 (m, 2H), 1.2 (br. s, 3H), 1.1 (br. s, 3H). [α]D25=−3.7°.
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:24])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:25].[NH2:26][O:27][CH2:28][CH2:29][OH:30]>CO.C(Cl)Cl>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:24])[N:6]([CH3:25])[N:5]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Solvent: CO
Solvent: ClCCl
Product: C/C(=N\OCCO)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 58.8 %

Procedure:
A solution of 1-(3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (62 mg, 0.136 mmol) and 2-(aminooxy)ethanol (intermediate S) (77 mg, 0.681 mmol) in 3 mL of MeOH and 2 mL of DCM was stirred at rt for 2 days. Solvent was evaporated to give a residue, which was purified by chromatography (DCM:MeOH 10:1) and recrystallized from MeOH to give the title compound as a white solid (32 mg, 59%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1H), 8.04 (d, 1H), 7.62 (t, 2H), 7.48 (d, 1H), 4.44 (s, 2H), 4.24 (t, 2H), 4.00 (s, 3H), 3.68 (m, 2H), 2.29 (s, 3H). LCMS (method E): [MH]+=401.1, tR=5.591 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:16]=[C:15]([Si:12]([CH3:14])([CH3:13])[CH3:11])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1cc(-c2ccc(Br)cc2)no1
Reaction time: 22 h

Procedure:
The product from Example 42A (0.124 g, 0.621 mmol) and trimethylsilylacetylene (0.35 mL, 2.5 mmol) were combined in tetrahydrofuran (2.2 mL), treated bleach (2.2 mL), and stirred for 22 hours. The mixture was diluted with ethyl acetate (7 mL), washed with brine (5 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (7% ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:18]([CH:16]2[CH:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[O:35])=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound 4-chloro-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-chloro-3-(trifluoromethyl)benzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a white foam. MS m/e: 616.3 [M]+.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(C)c1F
Yield: 74.9 %

Procedure:
Prepared according to Method A step A from 2-fluoro-3-methylbenzoic acid (5.0 g, 32.5 mmol), N,O-dimethylhydroxylamine hydrochloride (8.4 g, 87 mmol), oxalyl chloride (2.83 mL, 32.5 mmol) and 8 mL of pyridine to give the title compound (4.8 g) as an oil. Used as is in the next prep
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:37]
Reactant: CCOC(=O)CCCCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Product: CCOC(=O)CCCCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Yield: 93.3 %

Procedure:
Using the procedure of example 122, rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (example 121), was alkylated with ethyl 6-bromohexanoate giving the title compound as a pale-yellow oil, in 93.3% yield.
Reaction SMILES: [F:1][C:2]1([F:12])[CH2:7][CH2:6][CH:5]([C:8](NC)=[O:9])[CH2:4][CH2:3]1.[CH3:13][Mg+].[Br-].O>C1COCC1>[F:1][C:2]1([F:12])[CH2:7][CH2:6][CH:5]([C:8](=[O:9])[CH3:13])[CH2:4][CH2:3]1
Reactant: C[Mg+]
Reactant: CNC(=O)C1CCC(F)(F)CC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C1CCC(F)(F)CC1
Temperature: -78 °C
Reaction time: 5 h
Yield: 63.8 %

Procedure:
To a solution of 4,4-difluoro-N-methyl cyclohexanecarboxamide (3 g, 14.5 mmol) in THF (20 mL) were added CH3MgBr (5.19 g, 43.5 mmol) in −78° C. The mixture was stirred at −78° C. for 5 hr. Water (10 mL) was added and the mixture was concentrated and extracted by CH2Cl2 (40 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanone (1.5 g, crude) for next step.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[N:21]=[C:20]([Br:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:23])=[CH:8][CH:7]=1>N1C=CC=CC=1>[Br:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:23])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:7][CH:8]=2)[N:21]=1
Reactant: Nc1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 12 h
Yield: 65 %

Procedure:
Acetyl chloride (0.15 g, 1.90 mmol) was added at room temperature to a stirred solution of 2-(4-amino-phenyl)-4-bromo-2H-phthalazin-1-one (0.30 g, 0.95 mmol) in pyridine (3 ml). Stirring was continued for 12 h before the solvent was evaporated in vacuum. The resulting raw product was dissolved in H2O and the title compound was collected by filtration (0.22 g, 65% yield). 1H-NMR: (400 MHz, D6-DMSO) 10.16 (1H, s), 8.37 (1H, d), 8.08 (1H, t), 8.00–8.03 (2H, m), 7.72 (2H, d), 7.52 (2H, d), 2.05 (3H, s); MS (ESI+)=358.15 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.O.[CH2:18]([OH:20])[CH3:19]>>[CH2:18]([O:20][CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:19]
Reactant: CCO
Reactant: ClCc1c2ccccc2cc2ccccc12
Solvent: O
Product: CCOCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 9-chloromethylanthracene (5.2 g, 23 mmole) obtained in Synthesis Example 2-(1) in ethanol (700 ml) was reacted with stirring for 10 hours at room temperature, poured into H2O (700 ml), and extracted with methylene chloride (500 ml×1). The resulting organic layer was dried over anhydrous MgSO4 and evaporated. The residual crude solid (4.25 g) was recrystallized from 50% THF/H2O to give 4.02 g of 9-ethoxymethylanthracene as orange yellow crystals, mp. 74-75° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6].N[NH:9][C:10]([NH2:12])=[S:11].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][C:5]1[S:11][C:10]([NH2:12])=[N:9][N:6]=1
Reactant: NNC(N)=S
Reactant: CN(C)CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C)CCc1nnc(N)s1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
A solution of 2.00 ml (17.7 mmol) of 3-(dimethylamino)propanenitrile and 1.70 g (18.6 mmol) of thiosemicarbazide in trifluoroacetic acid (5 ml) was heated at 80° C. for 6 hr. The reaction solution was cooled to room temperature and was then diluted with water. The diluted solution was rendered weakly basic by the addition of a 10% aqueous potassium carbonate solution. The solution was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was washed with diethyl ether-ethyl acetate to give 1.00 g (yield 33%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:16]O>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: O=C(O)c1cncc(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc(Cl)c1

Procedure:
5-Chloronicotinic acid (200 mg, 1.269 mmol) was refluxed overnight in the presence of concentrated sulfuric acid (8.20 mg, 0.063 mmol) in methanol (8 mL) at 70° C. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the compound was purified by column chromatography affording the title compound (120 mg). 1H NMR (400 MHz, CDCl3): δ 9.07 (d, 1H, J=1.6 Hz), 8.72 (d, 1H, J=2.0 Hz), 8.26 (m, 1H), 3.95 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1>>[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)=[CH:33][N:32]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: COc1ncc(-c2nc(N3CCOCC3)c3nc(CN4CCN(S(C)(=O)=O)CC4)n(C)c3n2)cn1

Procedure:
4-(2-Chloro-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 2-methoxypyrimidin-5-ylboronic acid via General Procedure A and purified via reverse phase HPLC to give 5.5 mg 136 as a white solid. MS (Q1) 504.3 (M)+.
Reaction SMILES: N[C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[H+].[B-](F)(F)(F)[F:16].N([O-])=O.[Na+]>O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[F:16])[CH:6]=[O:7]
Reactant: F[B-](F)(F)F
Reactant: COc1cc(C=O)cc(OC)c1N
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COc1cc(C=O)cc(OC)c1F

Procedure:
A solution of 1.4 g. of 4-amino-3,5-dimethoxybenzaldehyde in 20 ml. of 50% hydrogen tetrafluoroborate was diazotized at 0° C. with a solution of 0.59 g. of sodium nitrite in about 2 ml. of water. After irradiation with a low pressure mercury lamp (Hanau NK 6620) for 6 hours at room temperature, the solution was extracted with ether, the ether extracts dried over magnesium sulfate and concentrated. After recrystallization from heptane, the residue produced 3,5-dimethoxy-4-fluoro-benzaldehyde of melting point 97°-98° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:20][C:21](=[O:32])[C:22]2[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=2[N:24]=1)[CH2:10][CH3:11]>CN(C)C=O>[Br:1][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:9][CH2:10][CH3:11])=[C:14]([C:19]2[NH:20][C:21](=[O:32])[C:22]3[N:27]([CH3:28])[N:26]=[C:25]([CH2:29][CH2:30][CH3:31])[C:23]=3[N:24]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 83.6 %

Procedure:
N-Bromosuccinimide (2,6g, 0.016 mol) in dimethylformamide (40 ml) was added dropwise to a stirred solution of 5-(2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Preparation 10, 4.0 g, 0.010 mol) in dimethylformamide (40 ml) at room temperature. After 7 hours the solvent was removed by evaporation under vacuum, the residue suspended in saturated aqueous sodium carbonate solution, and the resulting solution extracted with ethyl acetate (3×50 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum. Trituration of the residue with ether, followed by crystallisation from ethyl acetate-hexane, gave the title compound as white crystals (3.39 g, 68%), m.p. 117°-118° C. Found: C,53.15; H,5.03; N,13,78. C18H21BrN4O2 requires C,53,34; N,5.22; N,13.82%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:25]=4[F:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1

Procedure:
4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure C by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-fluoro-4-(methylsulfonyl)aniline (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.90-2.00 (m, 4H), 2.95-3.05 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.03-4.09 (m, 2H), 4.90-4.93 (m, 1H), 7.79-7.81 (m, 1H), 7.88-7.91 (m, 1H), 8.21-8.24 (m, 1H), 8.40-8.42 (m, 2H), 10.36 (s, 1H). Mass spectrum MH+=491.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:17]([C:28](O)=[O:29])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH:49]=2)=[C:36]([CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[CH:37]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:11]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:17]([C:28]([N:47]2[CH2:46][CH:45]=[C:44]([C:35]3[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][C:36]=3[CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[CH2:49][CH2:48]2)=[O:29])[CH2:16]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: COC(=O)C(C)c1cc(Cl)ccc1C1=CCNCC1
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)c1cc(Cl)ccc1C1=CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 18 h

Procedure:
N,N-diisopropylethylamine (1.00 mL, 5.76 mmol) was added to a stirred suspension of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (1-7) (0.614 g, 1.92 mmol), methyl 2-[5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]propanoate (2-3) (0.605 g, 1.92 mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.876 g, 2.30 mmol) and 1-hydroxy-7-azabenzotriazole (0.314 g, 2.30 mmol) in N,N-dimethylformamide (3.8 mL) at ambient temperature. After approximately 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-15% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) provided 2-4 as a pale yellow oil; (m/z (ES) 545 (MH+).