Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (3.6 g, 14 mmol) and 10% Pd/C moistered with water (0.8 g) was mixed in MeOH (75 mL) and stirred under H2 (1 atm) for 4 h. The mixture was filtered through Celite and concentrated to give the title compound (3.6 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]3[C@@H:18]([C:26]([NH:28][NH2:29])=[O:27])[O:17]2)=[C:4]([F:32])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:29][NH:28][C:26]([C@@H:18]1[C@H:19]2[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][C:5]2[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=2[F:32])[O:17]1)=[O:27])(=[O:44])[CH3:43]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(Cl)cc4F)ncnc31)O[C@@H]2C(=O)NN
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 0 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
To a stirred solution of (3aR,4S,6R,6aR)-6-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole4-carbohydrazide (50 mg) in N,N′-dimethylformamide (2 ml) at 0° C. was added diisopropylethylamine (28 μl) and acetyl chloride (9 mg). The reaction mixture was stirred at 0 ° C. for 5 h. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with brine (20 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by automated preparative HPLC (gradient profile 5-95% (ii) over 18.5 min) to give the title compound (25 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](OCC)=O.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][C@@H:19]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:35]2[C:34](=[O:40])[CH2:33][C@@:32]2([CH3:41])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[C:29](=[O:31])[CH3:30])[CH2:20]1.[H-].[Na+].Cl>CS(C)=O.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:30][C:29](=[O:31])[C@@H:28]1[C@:32]2([CH3:41])[C@H:25]([C@H:24]3[C@H:35]([C:34](=[O:40])[CH2:33]2)[C@:36]2([CH3:39])[C@H:21]([CH2:20][C@H:19]([O:18][CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][O:12]4)[CH2:38][CH2:37]2)[CH2:22][CH2:23]3)[CH2:26][CH2:27]1
Reactant: CCOC(=O)c1ccccn1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: C[C@]12CC[C@@H](OC3CCCCO3)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCc4ccccn4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 0.5 h

Procedure:
Ethyl picolinate (1.0 ml.) was added to a mixture of 3α-(tetrahydropyran-2ξ-yloxy)-5α-pregnane-11,20-dione (840 mg) and sodium hydride (130 mg.) in dry dimethyl sulphoxide (15 ml.). The mixture was stirred, under N2, for 1/2 hr., then treated with methanol and poured into 2N-hydrochloric acid. The precipitate was collected, washed and dried to give 21-picolinyl-3α-(tetrahydropyran-2ξ-yloxy)-5α-pregnane-11,20-dione (695 mg.).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH3:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1>>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[Cl:1].[CH3:5][S:6]([C:16]1[CH:15]=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=1[CH3:10])(=[O:8])=[O:7]
Reactant: [Cl-]
Reactant: Cc1ccc(C)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Al+3]
Product: Cc1ccc(C)c(Cl)c1
Product: Cc1ccc(C)c(S(C)(=O)=O)c1
Yield: 70 %
Yield: 1 %

Procedure:
The use of sulfonyl fluorides, instead of sulfonyl chlorides, is essential to the process of the present invention. While not wishing to be bound by theoretical considerations, it appears that when alkyl sulfonyl chlorides react with aromatic hydrocarbons in the presence of aluminum chloride, the major reaction which occurs is chlorination, not sulfonylation, of the aromatic compound. For example, the reaction of p-xylene with methanesulfonyl chloride in the presence of aluminum chloride gave a 70% yield of 2,5-dimethylchlorobenzene and less than 1% yield of 2,5-dimethylphenyl methyl sulfone, as shown below: ##STR3## The corresponding chlorination reaction was found to occur with toluene, xylenes, and mesitylene, often to the virtual exclusion of sulfonylation. This undesired chlorination reaction accounts for the low yields previously reported in attempted alkyl sulfonyl chloride Friedel-Crafts reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.C([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])C>C(#N)C>[NH2:9][C:3]([C@@H:32]1[CH2:30][CH2:29][N:28]([C:16]2[CH:17]=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:14]([CH3:21])[C:15]=2[F:20])[CH2:31]1)([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Solvent: CC#N
Product: Cc1c(F)c(N2CC[C@@H](C(C)(C)N)C2)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Yield: 244.2 %

Procedure:
A solution of 0.92 g (2.62 mmol) of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.90 g (3.9 mmol) of (3R)-(1,-methyl-1'-t-butoxycarbonylaminoethyl)pyrrolidine (9a), 0.80 g (7.9 mmol) of triethylamine, and 50 mL of acetonitrile was heated at reflux for 18 hours. The solution was cooled to room temperature and concentrated in vacuo to an orange solid. The residue was chromatographed on E. Merck silica gel (230-400 mesh), eluting with 90:10 CHCl3:MeOH to give 1.47 g of (R) 7-[3-(1-t-butoxycarbonylamino-1-methylethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid; NMR (CDCl3) δ8.47 (s, 1 H), 7.44 (m, 1 H), 7.15 (m, 2 H), 5.64 (d, J=7 HZ, 1 H), 4.47 (bs, 1 H), 3.50- 3.20 (m, 4 H), 2.85 (d, J=3.5 HZ, 3 H), 1.91 (m, 1 H), 1.74 (m, 2 H), 1.42 (s, 9 H), 1.29 (d, J=11 HZ, 6 H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](B(O)O)[CH:20]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[F:14][C:15]1[CH:20]=[C:19]([C:5]2[CH:4]=[N:3][C:2]([NH:24][C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)[CH:18]=[N:17][CH:16]=1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3cncc(F)c3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=352.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-fluoro-5-pyridineboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([CH3:21])[NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][N:34]=[C:35]=[O:36]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:20][C:35]([NH:34][CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:36])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C=NCc1ccco1
Solvent: ClCCl
Product: C[C@H](NC(=O)NCc1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.7 %

Procedure:
(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (100 mg, 0.28 mmol), as described in Example 1, is dissolved in 1.77 mL dichloromethane and furylmethylisocyanate (34.1 mg, 0.28 mmol) is dropwise added. After stirring for 45 min at r.t. the solvent is removed and the residue purified by chromatography (silicagel, eluents: hexane/ethylacetate). 116.2 mg (86.7%) of the title compound are obtained.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.[ClH:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][C:31](=O)[CH3:32])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C(O)C>C(OCC)(=O)C>[OH2:7].[ClH:14].[OH:7][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:1]=1)[NH:10][CH:9]=[C:8]2[CH2:11][CH2:12][NH:13][CH:31]([CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][C:26]([NH:25][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=1)=[O:34]
Reactant: COc1ccc(NC(=O)CCCCC(C)=O)cc1OC
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(NC(=O)CCCCC(C)NCCc2c[nH]c3ccc(O)cc23)cc1OC
Product: O

Procedure:
The compound was prepared as in Example 2B except using 178 mg of serotonin hydrochloride and using N-(3,4-dimethoxyphenyl)-6-oxo-heptanamide (225 mg), running the reaction 21 hours at ca. 25° C. The compound as the free amine had an Rf of 0.5 in 10:90 ethanol:ethyl acetate. The title compound was obtained as a tan solid (247 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>[Pd]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Product: CCOC(=O)C=Cc1ccc(Cl)cc1
Yield: 72 %

Procedure:
The procedure described in Example 26 is repeated, but using 4.79 g (25 mmols) of 4-bromochlorobenzene and 2.99 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 8 hours at 130° C., 3.79 g (18.0 mmols) of ethyl 4-chlorocinnamate are obtained, corresponding to a yield of 72% of theory (conversion figure 7200; Pd content 0.01 mol %).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29].O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)#[N:29]
Reactant: NN
Reactant: N#Cc1ccccc1CCC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Yield: 97 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(2-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (991 mg, 2.51 mmol, prepared in Synthetic Example 11) in DMF (25 ml) was added hydrazine monohydrate (80%, 371 μl, 9.26 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-[2-(2-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (953 mg, 97%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.CC[N:36]([CH:40]([CH3:42])C)[CH:37]([CH3:39])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:36]6[CH2:37][CH2:39][CH2:42][CH2:40]6)=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)=[O:33])[CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
To a solution of acid 225 (70 mg, 0.151 mmol), DIPEA (0.105 mL, 0.603 mmol) and pyrrolidine (0.025 mL, 0.301 mmol) in DMF (4 mL) was added HATU reagent (143 mg, 0.377 mmol). The mixture was stirred for 16 h at RT then partitioned between ethyl acetate and water. The organic phase was collected, washed with water, 1M NaOH, and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge), then using chromatotron (eluent MeOH/DCM, 5-10%) followed by trituration with a mixture Et2O/MeOH/Acetone to give title compound 226 (15 mg, 0.029 mmol, 19% yield) 1H NMR (400 MHz, DMSO-d6) δ (ppm): OH from carboxylic acid is missing, 9.66 (bs, 1H), 8.98 (dd, J=1.9, 0.9 Hz, 114), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.1, 1.9 Hz, 1H), 8.17 (dd, J=8.1, 0.9 Hz, 1H), 7.77 (dd, J=13.7, 2.5 Hz, 1H), 7.45 (bs, 1H), 7.37 (t, J=9.1 Hz, 1H), 7.26 (dd, J=8.9, 1.5 Hz, 1H), 6.62 (d, J=5.3, 0.8 Hz, 1H), 2.60-2.52 (m, 1H), 0.69-0.56 (m, 2H), 0.50-0.37 (m, 2H). MS (m/z): 465.3 (M+H)
Reaction SMILES: ClC1C=CC(C([C:8]2[CH:20]=[CH:19][C:11]([O:12][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=O)=CC=1.OO.[CH2:25]([Cl:27])Cl.[CH:28]([OH:30])=[O:29]>O>[Cl:27][C:25]1[CH:19]=[CH:20][C:8]([C:28]([O:30][C:8]2[CH:9]=[CH:10][C:11]([O:12][C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=2)=[O:29])=[CH:9][CH:10]=1
Reactant: O=CO
Reactant: COC(=O)[C@@H](C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: ClCCl
Agent: OO
Solvent: O
Product: COC(=O)[C@@H](C)Oc1ccc(OC(=O)c2ccc(Cl)cc2)cc1
Reaction time: 13 h
Yield: 69 %

Procedure:
A mixture of 15.9 g (50 mmol) of methyl (R)-2-(4-(4-chlorobenzoyl)phenoxy)propionate, 25 g (220 mmol) of a 30% strength solution of hydrogen peroxide in water and 200 ml of formic acid was stirred at 35°-40° C. for 13 hours. The mixture was then stirred into a mixture of 0.5 l of methylene chloride and 2 l of water. The organic phase was separated off, dried over sodium sulfate and concentrated under reduced pressure. Yield: 69% (94-95% enantiomeric excess).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[OH-:21].[Na+].O>CS(C)=O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2](=[O:21])[NH:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Reaction time: 3 h
Yield: 68 %

Procedure:
2-Chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine* (60 g, 0.20 mol) was added to a mixture of NaOH (100 g, 2.50 mol), water (100 mL) and DMSO (100 g) at 100° C. After being stirred for 3 h, the mixture was allowed to cool and partitioned between toluene (100 g) and water (200 mL). Water (300 mL), crushed ice (200 g), EtOAc (600 g) and sodium chloride (100 g) were added to the aqueous layer. The layers were separated and the aqueous layer was extracted with an additional portion of EtOAc (600 g). The combined organic layers were concentrated in vacuo to furnish 38 g (68%) of the title product. 1H and 13C NMR data support the stated structure. HPLC purity: 100%. HRMS m/z calcd for C13H20N4O3 (M)+ 280.1535, found 280.1530. *Prepared according to the procedure described in WO 00/76984, Example 52, Step 1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C-:16]#[N:17].[Na+]>C(O)C>[C:16]([CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: CCOC(=O)C=Cc1ccccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=Cc1ccccc1CC#N

Procedure:
Reagent XV is prepared from ethyl o-bromomethylcinnamate by the following series of reactions. (1) The starting ester is heated with a solution of sodium cyanide in ethanol to yield ethyl o-cyanomethylcinnamate. (2) This ester is hydrogenated over a Pt or Pd catalyst to afford ethyl o-cyanomethylhydrocinnamate. (3) This ester is reduced with sodium bis(2-methoxyethoxy)aluminum hydride in benzene to yield [2-(3-hydroxypropyl)phenyl]acetonitrile. (4) The nitrile is hydrolyzed by being heated with aqueous-ethanolic sodium hydroxide solution, and the acid is esterified (ethanol and mineral acid catalyst) to give ethyl [2-(3-hydroxypropyl)phenyl]acetate. (5) This hydroxy-ester is treated with phosphorus tribromide in ether to afford reagent XV.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[C:12]([NH2:26])[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[C:31](Cl)(=[O:33])[CH3:32].[O:35]1CCO[CH2:37][CH2:36]1>O>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)=[C:12]([N:26]([C:36](=[O:35])[CH3:37])[C:31](=[O:33])[CH3:32])[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: Nc1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1-c1cccc(C(F)(F)F)c1
Reactant: C1COCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N(C(C)=O)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1-c1cccc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 4 g (0.01 mol) of 2,4-di-[3-trifluoromethylphenyl]-5-amino-2H-pyridazin-3-one in 50 ml of dioxane, 0.62 g (0.02 mol) of NaH (80% dispersion) is added and the mixture is warmed to 40° C. for 30 minutes. It is then cooled, 1.6 g (0.02 mol) of acetyl chloride dissolved in 30 ml of dioxane are added dropwise at 15°-20° C. and the mixture is then stirred at room temperature for 16 h. The reaction mixture is diluted with 300 ml of water and extracted twice with 150 ml of methylene chloride. The organic phase is washed with bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel 60 using methylene chloride and yields 2.3 g (47% of theory) of 2,4-di-[3-trifluoromethylphenyl]-5-diacetylamino-2H-pyridazin-3-one of melting point 174° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23]CO2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].F[C:29](F)(F)[C:30](O)=[O:31].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.O1CCC(CN)CC1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][O:31][CH2:30][CH2:29]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Agent: NCC1CCOCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 15 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: C(N(CC)CC[CH2:6][N:7]1[C:15]2[C:10](=[C:11](Cl)C=C[CH:14]=2)C(N)=N1)C.[NH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=2)[NH:23][N:22]=1.Br.Br[CH2:33]CCN(CC)CC.NC1C2C(=CC=CC=2Cl)NN=1>>[CH3:33][N:7]([CH3:6])[CH:15]([CH3:14])[CH2:10][CH2:11][N:23]1[C:24]2[C:29](=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]([NH2:20])=[N:22]1
Reactant: Nc1n[nH]c2ccc(Cl)cc12
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: Nc1n[nH]c2cccc(Cl)c12
Product: CC(CCn1nc(N)c2cc(Cl)ccc21)N(C)C

Procedure:
The same procedures for preparing 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole as described in Example 89 were repeated except that 1-(1-methyl-3-bromopropyl)-dimethylamine hydrobromide and 3-amino-5-chloroindazole were employed instead of the 3-bromopropyldiethylamine hydrobromide and the 3-amino-4-chloroindazole, respectively. As a result, 1-(3-dimethylaminobutyl)-3-amino-5-chloroindazole was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH2:10])[CH2:7][CH2:8][CH3:9]>ClCCl.C(Cl)(Cl)Cl>[CH2:6]([NH:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Methanesulfonyl chloride (6.76 ml., 87.3 mmole, 1.0 eq.) was dissolved in distilled dichloromethane (44 ml., 0.5M). The solution was cooled in an ice bath and treated dropwise with n-butylamine (17.3 ml., 175 mmole, 2.0 eq.). After the addition was complete, the clear solution was stirred overnight at room temperature. The mixture was diluted with chloroform (200 ml.), dried, washed with 0.5N HCl (2×200 ml.) and saturated NaCl solution (200 ml.), dried (MgSO4) and freed of solvent in vacuo leaving an oil. This was purified by distillation to give N-butylmethanesulfonamide (11.4 g., 86%,. b.p. 106°-110°/0.5 mm) which solidified on standing.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CC(N(C)C)=O.[Br:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][C:46]=1[F:52].C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:49][C:48]3[CH:50]=[CH:51][C:45]([Br:44])=[C:46]([F:52])[CH:47]=3)=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Br)c(F)c1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2ccc(Br)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A solution of (R)-4-(5-carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.47 mmol, Preparation 33), EDC (130 mg, 0.70 mmol), and HOAt (95 mg, 0.70 mmol) dissolved in DMA (4.3 mL, 47 mmol) was stirred at RT for 30 min and then 4-bromo-3-fluoroaniline (89 mg, 0.47 mmol) was added, followed by N,N-diisopropylethylamine (0.2 mL, 1.2 mmol). The reaction mixture was stirred at RT overnight and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted: 0-40% EtOAc:hexanes) to provide the title compound as a light yellow oil (100 mg, 40% yield). (m/z): [M+H]+ calcd for C22H26BrFN4O3 493.12 found 493.2.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].[CH2:36]([CH2:38][NH2:39])[OH:37]>>[OH:37][CH2:36][CH2:38][NH:39][C:3](=[O:4])[C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:31])([F:33])[F:32])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[CH3:1]
Reactant: CC(C)(C(=O)O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Reactant: NCCO
Product: CC(C)(C(=O)NCCO)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 453, 2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionic acid was reacted with ethanolamine to give 324. MS (ESI+) 548.1. 1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 8.30-8.25 (m, 2H), 8.07 (s, 1H), 7.52 (dd, J=8.3, 1.5, 1H), 7.41 (d, J=1.5, 1H), 7.20 (t, J=5.4, 1H), 5.86 (q, J=8.7, 2H), 4.59 (t, J=5.4, 1H), 4.40 (t, J=4.8, 2H), 3.47 (t, J=4.9, 2H), 3.36 (q, J=6.0, 2H), 3.12 (q, J=6.0, 2H), 1.75 (s, 6H)