Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:21][O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 70 h
Yield: 99.8 %

Procedure:
Estrone (1, 100.0 g, 370 mmol) was dissolved in MeOH (1.5 L), followed by the addition of K2CO3 (300.0 g, 2.17 mol). MeI (310 mL, 4.98 mol) was added and the mixture stirred at room temperature for 70 h. The reaction mixture was concentrated in vacuo to remove some of the MeOH and was then poured into ice water forming a precipitate. The solid was collected and dried by partitioning into CH2Cl2. The organic layer was dried over MgSO4, and the solvent was removed in vacuo to yield compound 2 (105.0 g) as white crystals in quantitative yield. 1H NMR (250 MHz, CDCl3); δ 0.91 (s, 3, C-18 H), 3.78 (s, 3, MeO), 6.65 (s, 1, C-4 H), 6.72 (d, 1, J=8.57 Hz, C-2 H), 7.21 (d, 1, J=8.57 Hz, C-1 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]([O:17]CC)=[O:16])=[CH:4][NH:5][C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[CH:4][NH:5][C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)c[nH]c1C(=O)c1ccccc1
Yield: 88.4 %

Procedure:
Ethyl 4-methyl-5-benzoylpyrrole-3-carboxylate (0.8 g.) was combined with 20 ml. of methanol and 15 ml. of 1N sodium hydroxide and boiled in an open flask for 1.5 hours on a steam bath. The aqueous residue was cooled, extracted with 10 ml. of ether, and acidified with conc. hydrochloric acid to yield crystalline 4-methyl-5-benzoylpyrrole-3-carboxylic acid (630 mg., m.p. 241°-243° C., m/e 229).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12](O)[CH2:13][CH2:14][CH3:15].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCCCOC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a mixture of 3-phenylpropionic acid (15.0 g) and 1-butanol (8.15 g) in pyridine (30 ml) pTSA (0.100 g) is added. When the solution is homogeneous, DCC (24.8 g) is added, and the solution is stirred at room temperature for 24 h. After addition of acetic acid (10 ml) the reaction mixture is worked up as in Example 1. A 96% yield of butyl 3-phenylpropionate is obtained, b. p. 112°-3° C. (1 mm Hg) [lit. (12), 91° C. (0.3 mm Hg)].
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].[OH-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>O.C(O)CC>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:9]1[C:10]2[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=2[N:7]=[CH:8]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: Cn1c(=O)c2c(ncn2CCCCCCBr)n(C)c1=O

Procedure:
1,3-dimethylxanthine is dissolved in a mixture of 250 ml of water and 750 ml of n-propanol by adding an equimolar quantity of sodium hydroxide and heating. An equivalent amount of 1,6-dibromohexane is quickly added to the solution and the mixture is boiled under reflux for 1 hour. After evaporation of the n-propanol, 7-(6-bromohexyl)-1,3-dimethylxanthine is isolated.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2=[N:44][CH:45]=[N:46][C:47](Cl)=[C:42]2[CH:41]=[N:40]1>C1COCC1>[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2[N:44]=[CH:45][N:46]=[C:47]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])[C:42]=2[CH:41]=[N:40]1
Reactant: Clc1cccc(Br)c1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Br)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.875 g, 21.87 mmol) was added to (S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ2) (3.0 g, 7.29 mmol) in anhydrous THF (35 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then a solution of 1-(2-bromo-6-chlorophenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BO2) (2.507 g, 7.29 mmol) in anhydrous THF (20 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 10minutes and then allowed to warm to ambient temperature for 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:18])([CH3:17])[CH2:4][C@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][NH:7][CH3:8].C([O-])([O-])=O.[K+].[K+].[C:25]([O:34]N1C(=O)CCC1=O)([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=O>CC(C)=O.O>[CH3:1][O:2][C:3]([CH3:18])([CH3:17])[CH2:4][C@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:6][N:7]([CH3:8])[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])=[O:34]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CNC[C@H](CC(C)(C)OC)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(C)(C)C[C@@H](CN(C)C(=O)OCC[Si](C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a solution of the above (S)-tert-butyl 4-methoxy-4-methyl-1-(methylamino)pentan-2-ylcarbamate (˜2.99 mmol) in acetone (9 mL) and water (3 mL), there was added K2CO3 (1.24 g, 9.0 mmol), followed by Teoc-OSu (0.85 g, 3.29 mmol). The resulting mixture was stirred at rt until no starting material remained (˜1 h). Acetone was removed under vacuum, and the aqueous residue was extracted with CH2Cl2 (4×5 mL). The combined organic layers were concentrated, and crude residue was purified with flash column chromatography to give (S)-tert-butyl 4-methoxy-4-methyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)pentan-2-ylcarbamate (0.18 g, 15%, 3 steps) as a clear oil. 1H NMR (400 MHz, CDCl3): 4.82, 4.92 (br, 1 H), 4.16 (m, 2 H), 3.88 (m, 1 H), 3.44 (m, 1 H), 3.24 (m, 1 H), 3.16 (s, 3 H), 2.88, 2.90 (s, 3 H), 1.44 (s, 9 H), 1.18, 1.20 (s, 6 H), 0.98 (m, 2 H), 0.02 (s, 9 H); MS m/z 405 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.[BH4-].[Na+].CO>ClCCl>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH2:25][OH:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nn(-c2ncccc2CO)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde (180 g, 377 mmol) in anhydrous dichloromethane (1.5 L) at 0° C. is sequentially added sodium borohydride (7.2 g, 188.5 mmol) and anhydrous methanol (0.5 L) and the contents are allowed to reach room temperature while stirring 30 min. LC/MS analysis of the reaction mixture reveals completion. Volatiles are removed under reduced pressure and the residue obtained is partitioned between dichloromethane (2 L) and water (300 mL). The layers are separated and the organic layer is sequentially washed with 1 N aqueous solution of sodium hydroxide (300 mL), water (3×300 mL), brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue is purified on silica gel using 50-55% ethyl acetate in hexane containing 1% triethylamine to afford [2-[4-[(2-Chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol as a solid (167 g, 92% yield). MS (m/z): 481 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=1.[C:24](Cl)(=[O:26])[CH3:25]>C(OCC)(=O)C>[C:24]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methoxycarbonylbenzoyl)indole (Example 133) and acetyl chloride. m.p.: 190-193° C. (ethyl acetate)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:5][CH:4]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(C)N
Reactant: COc1ccc(CCCCBr)cc1
Product: COc1ccc(CCCCNC(C)C)cc1
Temperature: 100 °C

Procedure:
A solution of (50 ml) isopropylamine and 4-(4-methoxyphenyl)butyl bromide (13.7 g) in a glass lined vessel was heated under nitrogen (initial pressure, 500 psi) for 12 hours at 100° C. The solvent was removed in vacuo and water (200 ml) was added to the residue. The solution was acidified with concentrated hydrochloric acid and the solution was extracted with ether. The extract was dried over potassium carbonate and the solvent was removed in vacuo. The residue, 4-(4-methoxyphenyl)-N-(1-methylethyl)butylamine, weighed 9.3 g (75%). The identity and purity (94.8%) of the product was determined by mass spectrum and gas chromatography.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([C@@H:36]([OH:38])[CH3:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:38][C@@H:36]([CH3:37])[C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:23])[CH2:34][OH:35]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@H](O)[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (102 mg, 0.23 mmol), (2R,3S)-2-aminobutane-1,3-diol (34 mg, 0.32 mmol), and HATU (97 mg, 0.25 mmol). Then added acetonitrile (6 mL) followed by N,N-diisopropylethylamine (0.25 mL, 1.43 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-100% EtOAc) to afford 100 mg (82%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2S)-2-hydroxy-1-hydroxymethyl-propyl)-amide as a white solid. MS: [M+Na]+=551.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[Na+]>>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNCCCC
Reactant: Cc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCN(CCCC)c1ccccc1C
Yield: 36 %

Procedure:
According to the general procedure B, 2-bromotoluene (171 mg, 1.00 mmol) reacted with N,N-di-n-butylamine (129 mg, 1.00 mmol) using 1 mol % of catalyst and sodium tert-butoxide (115 mg, 1.20 mmol) at 60° C. to give the title compound (79 mg, 37%) as an oil: 1H-NMR (300 MHz, CDCl3): δ 7.20-7.08 (m, 3H), 6.98 (app.t, 1H), 2.94 (t, 4H), 1.41 (m, 4H), 1.27 (m, 4H), 0.88 (t, 6H). GC/MS (EI): m/z 219 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[NH:54][CH:53]=2)[CH2:48][CH2:47]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([NH:43][CH2:44][CH2:45][N:46]2[CH2:47][CH2:48][CH:49]([C:52]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[NH:54][CH:53]=3)[CH2:50][CH2:51]2)=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: COCCOCOc1ccc(/C=C/C(=O)O)cc1OC
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of 3-[3-methoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(E)-propenoic acid (1.75 g) and triethylamine (1.81 ml) in dry N,N-dimethylformamide (10 ml) was added slowly diphenyl phosphinic chloride (1.47 g) at -10° to -15° C. under an inert atmosphere. After being stirred for 30 minutes, a solution of 1-(2-aminoethyl)-4-(3-indolyl)piperidine (1.5 g) in dry N,N-dimethylformamide (10 ml) was added slowly to the reaction mixture at -10° C. After being stirred for 1 hour at ambient temperature, the reaction mixture was poured into ice-water (200 ml) and extracted with chloroform (100 ml). The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silicagel (47 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the object compound were combined and concentrated under reduced pressure to give syrup of 1-[2-[3-[3-methoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(E)-propenoylamino]ethyl]-4-(3-indolyl)piperidine (2.8 g).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH:13]=1)=[O:10])([CH3:4])[CH3:5])#[N:2]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])nc1
Yield: 62.4 %

Procedure:
A solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methylphenyl)benzamide (8.35 g, 28.4 mmol), 5-bromo-2-nitropyridine (5.24 g, 25.8 mmol) and cesium carbonate (16.8 g, 51.6 mmol) in N,N-dimethylformamide (70 mL) was stirred at 60° C. for 4 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL, 2×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=90/10→60/40), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (6.70 g, 63%) as a yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:26])([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:14]([F:17])([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:13]([F:12])([F:26])[C:14]([F:15])([F:16])[F:17])=[CH:25][CH:24]=1)=[O:9]
Reactant: Nc1ccc(OC(F)(F)C(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.3 using 5-bromo-6-chloro-nicotinic acid and 4-(perfluoroethoxy)aniline to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.73 min, UPLC-MS (Condition 3) tR=1.30 min, m/z=443.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]([CH3:32])[NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=5)[CH:23]=4)[CH:28]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ncccc1-c1ccc2c(c1)CCNC2C
Product: COc1ncccc1-c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]([O:18][C:19](OC2C=CC=CC=2)=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:34].C(O)(=O)C>O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]2[NH:34][C:19](=[O:20])[O:18][C:8]=2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Yield: 70.9 %

Procedure:
Ethyl 6-(4-chlorobenzoyl)-6-phenoxycarbonyloxyhexanoate (32.3 g), ammonium acetate(29.7 g) and acetic acid(150 ml) was stirred for 1 hour under reflux. Water was added to the reaction mixture to give ethyl 5-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]pentanoate(17.7 g, 71%). This was recrystallized from acetone-isopropyl ether to give colorless needls. mp 143-144° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][CH:19]([C:24]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])C(OC)=O)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(O)(=O)C.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][CH2:19][C:24]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(CC(C(=O)OC)C(=O)c3ncccc3C)co2)cc1OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OCC
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A 0.8 g quantity or methyl 2-[2-(3,4-diethoxyphenyl)oxazol-4-ylmethyl]-3-(3-methylpyridin-2-yl)-3-oxopropionate obtained in Example 180 was added to a mixture of 5 ml acetic acid and 1.5 ml of concentrated hydrochloric acid, and the resulting mixture was stirred at 110° C. for 4 hours. After cooling the obtained solution to room temperature, 30 ml of ethyl acetate and 30 ml of saturated sodium hydrogen carbonate solution were gradually added thereto with stirring, and stirring was further continued. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=3:1), and further recrystallized from ethyl acetate/n-hexane to give 0.28 g of white powdery 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[N:13]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[N:14]=[CH:15][C:16]=1[CH:17]1[CH2:19][CH2:18]1)=O)C>C1COCC1>[CH:17]1([C:16]2[CH:15]=[N:14][N:13]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[C:12]=2[CH2:10][OH:9])[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1c(C2CC2)cnn1-c1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(C2CC2)cnn1-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a 0° C. mixture of LAH powder in THF (20 mL) is added a solution of 4-cyclopropyl-2-(2,6-dichloro-phenyl)-2H-Pyrazole-3-carboxylic acid ethyl ester (2.4 mmol, 0.8 g) in THF (10 mL). The reaction is stirred for 2 h at 0° C. The reaction is quenched with a sequence of water (0.26 mL), 5N NaOH (0.26 mL) and water (0.78 mL). The reaction mixture is stirred for 1 h at 0° C. The reaction is filtered and the filtrate is adsorbed onto silica gel and purified using a gradient of 30-50% EtOAc/Hexanes to yield the title compound (0.36 g, 53%). LC-ES/MS m/e 283.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[N:23]=1.O>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1)[O:19][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)[N:23]=1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)n2)cc1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
16 mg (0.39 mmol) of 95% sodium hydride were added at 0° C. to a solution of 86 mg (0.37 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 100 mg (0.37 mmol) 2-chloromethyl-6-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at r.t overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was dried at 40° C. to give 145 mg (84%) of the title compound as white powder.