Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][OH:17].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH:5]1[C:16](=[O:17])[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)COCCCC=CCCC=CCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)COC1CCC=CCCC=CCCC1=O
Reaction time: 1 h
Yield: 86.6 %

Procedure:
The method employed was identical to that described in example 1(c), but using as starting products 4.82 g of 12-(2,2-dimethylpropoxy)-4,8-dodecadien-1-ol, 7.8 g of PCC and 50 ml of dichloromethane. The stirring was carried out for 1 h. 4.11 g of 12-(2,2-dimethylpropoxy)-4,8-cyclododecadien-1-one were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH3:10][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[CH3:10][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:9]=2)=[CH:14][CH:13]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: CNc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1ccc(-c2nc3ccccc3n2C)cc1
Temperature: 80 °C

Procedure:
10.14 mL (86.5 mmol) N-Methyl-o-phenylenediamine and 13.08 g (86.5 mmol) 4-(methylamino)benzoic acid are stirred in 70.0 g polyphosphoric acid at 200° C. for 3 hours. The mixture is cooled to 80° C., poured into water and stirred over night at RT. The mixture is alkalinized with sodium hydroxide solution. The precipitate is filtered off and washed with water. The product is dried in vacuo at 50° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.O>CN1C(=O)CCC1>[Cl:11][C:10]1[C:3]2[C:2]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:22]3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cl)c2c(Cl)ncnc21
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(c2ncnc3c2c(Cl)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4,5-dichloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine D40 (400 mg) and N-4-piperidinylbenzamide (300 mg, 1.46 mmol) were dissolved in NMP (4 ml), then N,N-diisopropylethylamine (315 mg, 2.44 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours then poured into water extracted with EtOAc (2×100 ml). Organic layer was washed with water (4×30 ml), brine (50 ml), dried with MgSO4, filtered and solvent removed. Yellow solid obtained was purified by flash chromatography on silica gel eluting with pet eth/ethyl acetate 3/1 to give the desired product D41 in 260 mg as a yellow solid. LCMS [MH+] 496.0@1.54 min (5 min run)
Reaction SMILES: [I-:1].[C:2]([CH2:5][C:6]1[CH:7]=[C:8]([S+:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([OH:4])=[O:3].Br[CH:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I-:1].[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([S+:14]2[C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=3)=[CH:7][C:6]=1[CH2:5][C:2](=[O:4])[O:3][CH:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33]
Reactant: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)O
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-(3-(carboxymethyl)-4-methoxyphenyl)-dibenzothiophenium iodide (50 g, 105 mmol), 3-bromodihydrofuran-2(3H)-one (17.3 g, 105 mmol), and cesium carbonate (68.3 g, 210 mmol) are dissolved in DMF (400 mL) and stirred at 25° C. for 4 h. The reaction mixture is quenched with water (1 L), extracted with DCM (2×400 mL), the combined organic layers washed with water (4×500 mL), concentrated to a viscous oil and precipitated from MTBE (2 L) to afford the title compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=O)[C:17]([N:19]2[CH2:22][CH:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:20]2)=O)=[CH:8]1>O1CCCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH:21]2[CH2:20][N:19]([CH2:17][CH2:16][C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:7][CH:8]=3)[CH2:22]2)=[CH:29][CH:28]=1
Reactant: O=C(C(=O)N1CC(Oc2ccc(F)cc2)C1)c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(OC2CN(CCc3c[nH]c4ccccc34)C2)cc1

Procedure:
By following the manipulative procedure described in Example 2(d), 0.7 g of lithium aluminum hydride in 30 ml. of tetrahydrofuran and 1.5 g of 1-(indol-3-ylglyoxyloyl)-3-(p-fluorophenoxy)azetidine in 30 ml. of tetrahydrofuran are reacted to produce a white solid. The solid is recrystallized twice from an ethanol and water mixture to give colorless needles of 3-{2-[3-(p-fluorophenoxy)azetidinyl]ethyl}indole, m.p. 111°-113°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]2[NH:38][CH:37]=[N:36][N:35]=2)[CH2:29][CH2:28]1>>[O:18]=[C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:21]([CH2:22][CH2:23][CH2:24][CH3:25])[N:35]2[N:36]=[CH:37][N:38]=[C:34]2[N:33]1[CH:30]1[CH2:29][CH2:28][O:27][CH2:32][CH2:31]1
Reactant: c1nnc(NC2CCOCC2)[nH]1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (1.3 g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.52 g, 62%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:38])[C@@H:16]([NH:21][C:22](=[O:37])/[CH:23]=[CH:24]/[C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[N:32]2[CH:36]=[N:35][N:34]=[N:33]2)[CH2:17][C:18](O)=[O:19])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.O.[OH-].[Li+].Cl.[CH2:43]1[CH2:47]OCC1>O>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[C:25](/[CH:24]=[CH:23]/[C:22]([NH:21][C@@H:16]([CH2:17][C:18]([N:21]2[CH2:43][CH2:47][N:14]([CH3:11])[CH2:15][CH2:16]2)=[O:19])[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:5])=[O:7])=[CH:9][CH:10]=2)=[O:38])=[O:37])[CH:30]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@H](CC(=O)O)NC(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(C(=O)C[C@H](NC(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)C(=O)Nc2ccc(C(=O)O)cc2)CC1
Reaction time: 1 h

Procedure:
(S,E)-4-(4-(tert-butoxycarbonyl)phenylamino)-3-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-4-oxobutanoic acid: To a solution of 17A (1.8 g, 3.24 mmol) in THF (16 mL) was added lithium hydroxide monohydrate (0.30 g, 7.14 mmol) in H2O (16 mL). After 1 h, the reaction mixture was acidified to pH 5-6 with 1.0M HCl and extracted with EtOAc (3×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford the desired product as an off-white solid. LCMS m/z 541 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.C(#N)C.N=C=N.ON1C2N=CC=CC=2N=N1.[NH2:36][C:37]1[N:38]=[C:39]([CH:42]2[CH2:47][CH2:46][N:45]([C:48](=[O:60])[CH2:49][N:50]3[C:54]([CH3:55])=[CH:53][C:52]([C:56]([F:59])([F:58])[F:57])=[N:51]3)[CH2:44][CH2:43]2)[S:40][CH:41]=1>C(OCC)(=O)C>[CH3:55][C:54]1[N:50]([CH2:49][C:48]([N:45]2[CH2:44][CH2:43][CH:42]([C:39]3[S:40][CH:41]=[C:37]([NH:36][C:10]([C:3]4[C:2]([OH:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=4)=[O:12])[N:38]=3)[CH2:47][CH2:46]2)=[O:60])[N:51]=[C:52]([C:56]([F:59])([F:57])[F:58])[CH:53]=1
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Agent: N=C=N
Agent: On1nnc2cccnc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccnc(C(=O)Nc2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-hydroxy-4-methoxy-pyridine-2-carboxylic acid acid (70 mg, 0.34 mmol) in 4 ml of acetonitrile triethylamine (0.13 mL, 0.96 mmol), 1-ethyl-3-dimethylaminopropyl)carbodiimide (77 mg, 0.41 mmol) and 1-hydroxy-7-azabenzotriazole (53 mg, 0.38 mmol) were added at RT. After stirring 15 min at RT, 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (120 mg, 0.32 mmol) was added to the reaction mixture. After stirring 16 h at RT, the reaction mixture was diluted with 20 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 1 M hydrochloric acid and brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2) to give 3-hydroxy-4-methoxy-pyridine-2-carboxylic acid (2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-amide (Compound No. 1.g.025) as a beige solid. 1H-NMR (400 MHz, CDCl3): δ=1.64-1.77 (m, 2H), 2.05-2.16 (m, 2H), 2.27 (s, 3H), 2.81-2.89 (m, 1H), 3.12-3.28 (m, 2H), 3.92 (s, 3H), 3.94-3.99 (m, 1H), 4.44-4.51 (m, 1H), 4.93 (d, 2H), 6.27 (s, 1H), 6.89 (d, 1H), 7.59 (s, 1H), 8.00 (d, 1H). MS: m/z=525 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].C(OCC)(=O)C>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Yield: 82.2 %

Procedure:
Methyl 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.32 mmol) and sodium hydroxide (0.2 g, 5 mmol) was dissolved in methanol/water (10 mL/2 mL) and the reaction mixture was allowed to reflux for 1.5 h. Thin layer chromatography (petroleum ether:ethyl acetate=3:1, Rf=0.1) showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified with 1 M hydrochloric acid solution to pH=6. The precipitated off-white solid was collected by filtration and dissolved in 50 ml of acetone, dried over sodium sulfate. Filtered and concentrated, the residue was recrystallization from dichloromethane/hexane to afford 78 mg of 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, Yield: 82.1%, MS (ES+APCI) M+1=297.1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]4[CH:45]=[CH:44][C:34]([CH2:35][P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:33][C:32]=4[O:46][CH3:47])[N:21]=3)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:55][S:56]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:23]=[C:22]([NH:30][C:31]4[CH:45]=[CH:44][C:34]([CH2:35][P:36]([O:37][CH2:38][CH3:39])([O:40][CH2:41][CH3:42])=[O:43])=[CH:33][C:32]=4[O:46][CH3:47])[N:21]=3)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:4][CH2:3]1)(=[O:58])=[O:57]
Reactant: CS(=O)(=O)Cl
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of diethyl (4-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.45 g, 0.66 m mol) in DCM (1.68 mL), cooled to 0° C., was slowly added triethylamine (0.185 mL, 1.33 mol) followed by methanesulfonyl chloride (0.13 mL, 1.66 mmol) and 4-dimethylaminopyridine (0.81 mg, 6.60 pmol). The mixture was stirred at rt overnight. After 16 hrs, a precipitate formed. The organic layer was re-dissolved in DCM and washed with water (2×), dried over sodium sulfated, filtered and concentrated in vacuo to a solid. The crude product was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded, 3×12 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0→4% 7N NH3 (MeOH) in DCM] to afford 220 mg (44%) of the desired product. 1H NMR (400 MHz, MeOD) δ 8.48 (br. s., 1H), 8.33 (s, 1H), 7.82 (d, J=8.08 Hz, 1H), 7.40 (d, J=8.59 Hz, 1H), 7.06 (d, J=2.02 Hz, 1H), 6.96 (d, J=7.58 Hz, 1H), 4.74-4.80 (m, 1H), 4.51 (s, 2H), 4.09 (quin, J=7.20 Hz, 4H), 3.89 (s, 3H), 3.34 (s, 1H), 3.29 (br. s., 2H), 3.18 (s, 3H), 3.10 (s, 3H), 2.64 (br. s., 1H), 2.29 (d, J=11.37 Hz, 2H), 1.69-2.00 (m, 6H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 756.19/757.23 (100/90) [MH+]. HPLC: tR=1.53 min (Micromass TOF: polar—3 min).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methyl ester (865 mg, 2.43 mmol) in tetrahydrofuran (6 mL) was treated with a 0.8M aqueous lithium hydroxide solution (4.6 mL, 3.65 mmol). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with water (25 mL) and then treated with a 1N aqueous hydrochloric acid solution (10 mL). The resulting aqueous layer was then extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ¼ hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (723 mg, 87%) as a white foam. Analytical data indicated the presence of a small impurity; however, the 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid was used without further purification in subsequent reactions.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:29])=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(F)=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:46]=2)C=CC=1)C1C=CC=CC=1>O=P(Cl)(Cl)Cl>[NH2:46][C:20]1[C:19]2[N:18]([C:17]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:29])[CH:23]=[CH:22][N:21]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl)C1CCC1
Reactant: Fc1c(OCc2ccccc2)cccc1-c1nc(C2CCC2)n2ccnc(Cl)c12
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: 55 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
1-(3-Benzyloxy-2-fluorophenyl)-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine: Cyclobutanecarboxylic acid [(3-benzyloxy-2-fluoro-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-amide (0.850 g, 2 mmole) was dissolved in POCl3 (6 mL) and heated at 55° C. overnight. The excess POCl3 was removed in vacuo. The residue was cooled to 0° C. and charged with a saturated solution of NH3 in 2-propanol (6 mL). The mixture was left overnight at room temperature. The separated solid was then filtered and washed with methylene chloride. The filtrate was evaporated to dryness and purified by silica-gel column chromatography using hexane:ethyl acetate (60:40) as the eluant to afford the title compound (615 mg, 75%). FAB-MS: m/z 408.3 (M+H)+.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:16][CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[S:21][CH:22]=1.Cl.[CH2:33]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1.C(Cl)Cl>[Cl:16][CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:43][CH2:42][C:41]3[CH:44]=[CH:45][C:38]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=3)=[O:29])=[CH:30][CH:31]=2)[S:21][CH:22]=1
Reactant: CCCCCc1ccc(CN)cc1
Reactant: O=C(O)c1ccc(-c2nc(CCl)cs2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCc1ccc(CNC(=O)c2ccc(-c3nc(CCl)cs3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
N-methylmorpholine (1.7 mL, 15.3 mmol) and isobutyl chloroformate (1.0 mL, 7.65 mmol) were added to a solution of 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoic acid (1.85 g, 7.29 mmol) in anhydrous THF (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then (4-pentylbenzyl)amine hydrochloride (1.64 g, 7.65 mmol) was added neat. The reaction mixture was stirred for 15 min at 0° C., then 2 hours at RT. The reaction mixture was diluted with DCM (100 mL) and washed with 1M aqueous HCl (50 mL), then saturated aqueous NaHCO3 (50 mL). The aqueous layers were extracted with DCM (100 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give a brown solid. Recrystallization from a mixture MeOH/water gave 2.30 g (75%) of the title compound as beige solid. HPLC, Rt: 5.2 min (purity: 98.0%). 1H NMR (CDCl3) δ: 8.01 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.37 (s, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.47 (m, 1H), 4.76 (s, 2H), 4.63 (d, J=5.5 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.63 (m, 2H), 1.34 (m, 4H), 0.90 (t, J=6.8 Hz, 3H).
Reaction SMILES: C(OC(C1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH:14](N)[C:15]2=[O:18])=[CH:10][CH:9]=1)=O)(C)(C)C.[H-].[Na+].IC.C(OCC)(=O)C.CCCCCC.[CH3:36][N:37]([CH:39]=O)[CH3:38]>>[CH3:38][N:37]([CH3:36])[C:39]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)C(=O)C(N)CC2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CI
Product: CN(C)c1ccc2c(c1)C(=O)CCC2

Procedure:
7-Dimethylaminotetralone was prepared by treating 7-tert-butoxycarbonyl amino-1-tetralone (2.0 g, 7.6 mmol) with sodium hydride (337 mg of a 60% dispersion in oil) and iodomethane (0.48 ml, 7.6 mmol) in DMF (15 ml) at 100° for 3 h. The solvent was removed under reduced pressure to give an oil which was subjected to column chromatography (silica gel, 30% ethyl acetate/hexane) to give the desired product as a buff solid (137 mg) m.p. 107°. MS (ES+) 190 (MH+. 100%).
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]1COC[CH2:12]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(I)C>CS(C)=O.O>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:11][CH3:12])[C:8]#[N:9]
Reactant: CC(C#N)c1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCI
Solvent: CS(C)=O
Product: CCC(C)(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-phenylpropionitrile (5 g, 38 mmol) in 50 mL of DMSO was added 42 mL of 1 M THF solution of sodium bis(trimethylsilyl)amide (NaHMDS). After 15 minutes, the reaction was cooled to 0° C. and 4.6 mL of ethyl iodide was added. The reaction was then stirred for 30 minutes. As TLC showed the reaction was complete, the reaction mixture was poured into water and extracted with diethyl ether. The organics were combined, washed four times with water, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give 6.1 g of 2-methyl-2-phenylbutyronitrile as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C=O)C>[N:17]1([C:2]2[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc(N2CCNCC2)nc1
Temperature: 80 °C
Yield: 17.4 %

Procedure:
A mixture of 6-chloro-N-(thiazol-2-yl)pyridine-3-sulfonamide (8.2 g, 30 mmol) and piperazine (12.5 g, 145 mmol) in DMF (150 mL) was heated to 80° C. overnight under a nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and purified by column chromatography over silica gel with dichloromethane/20% 3.5 M NH3 in methanol. The product containing fractions were dissolved in a minimal amount of water and methanol and purified by reversed phase column chromatography (ISCO) with a gradient of water and methanol. After about half of the solution was purified, crystals had formed in the liquid. This material was collected by filtration washed with methanol to yield additional material. In total 1.7 g (17%) of 6-(Piperazin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide was obtained. 1H-NMR (300 MHz, DMSO-d6): δ 8.41 (d, J=2.3 Hz, 1H), 7.76 (dd, J=2.3, 9.0 Hz, 1H), 7.02 (d, J=4.1 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 6.55 (d, J=4.1 Hz, 1H), 3.62-3.58 (m, 4H), 2.94-2.90 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:15][CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]C(C)([O-])C.[K+].CI.O>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH2:15][CH3:16])([CH3:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: CCC1CN(Cc2ccccc2)CCC1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CCC1(C)CN(Cc2ccccc2)CCC1=O
Reaction time: 0.25 h

Procedure:
1-Benzyl-3-ethylpiperidin-4-one (2 g, 9.2 mmole) was added to the stirred suspension of potassium tert.-butoxide (1.5 g, 13.3 mmole) in tetrahydrofuran (25 ml) at 0° C. The reaction mixture was stirred for 15 min, methyl iodide (2 g, 14.1 mmole) was added over a period of 10 min at 0° C. and stirring continued for 1 hr. The resulting mixture was stirred for 16 hr at ambient temperature, water (25 ml) was added and extracted with ethyl acetate (100 ml). Ethyl acetate layer on concentrated furnished 1-benzyl-3-ethyl-3-methylpiperid-4-one as oil, which was used as such in the next step. Yield 1.5 g (71%), C15H2NO, m/z 232 (M+1).