Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@@H:5]([CH2:26][CH:27]=C)[C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][C:9]1=[O:25])=[O:7].[O:34]=O.N#N.S(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@H:5]([C:6](=[O:7])[N:8]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][C:9]1=[O:25])[CH2:26][CH:27]=[O:34]
Reactant: O=O
Reactant: C=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: N#N
Solvent: ClCCl
Solvent: CSC
Product: O=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Dissolve (4S,5R)-3-((R)-2-(2-chloro-6-fluorobenzyl)pent-4-enoyl)-4,5-diphenyloxazolidin-2-one (1.05 g, 2.27 mmol) in CH2Cl2 (200 mL). Cool the solution to −78° C. Bubble O2 into the solution until the solution turns blue. Then bubble N2 for 5 minutes and add Me2S (0.706 g, 11.3 mmol). Stir the mixture for one hour and then remove the solvent. Purify the residue by chromatography (Silica gel) to afford (S)-3-(2-Chloro-6-fluorobenzyl)-4-oxo-4-((4S ,5R)-2-oxo-4,5-diphenyloxazolidin-3-yl)butanal (0.384 g, 36%). 1H NMR (CDCl3) δ 7.18 (m, 2H), 7.12 (m, 6H), 6.98 (m, 3H), 6.82 (m, 2H), 6.00 (d, 1H), 5.69 (d, 1H), 4.72 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.92 (m, 1H), 2.61 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:35]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[C:36]=[O:37].CCN(CC)CC>C(Cl)Cl>[CH2:38]([NH:35][C:36](=[O:37])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)NCc5ccccc5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (150 mg, 0.33 mmol) and 1-(isocyanatomethyl)benzene (162 μL, 1.32 mmol) in CH2Cl2 (2 mL) was added Et3N (1.38 mL, 9.9 mmol). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The residue was triturated using MeOH and drops of CH2Cl2 to afford tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (100 mg, 52%)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.[H-].[Na+].CI.[C:38](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:38][O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: O=C([O-])O
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@@H]1CCCC[C@H]1n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 73 mg, 0.17 mmol) was dissolved in degassed N,N-dimethylformamide (3 mL), cooled to 0° C. and treated with sodium hydride (10 mg, 0.25 mmol, 1.5 equiv). After stirring for 15 minutes, the mixture was warmed to ambient temperature, stirred for 15 minutes and cooled to 0° C. The mixture was treated with methyl iodide (0.026 mL, 0.41 mmol, 2.5 equiv) and stirred at 0° C. for 1 hour. The mixture was treated with sodium bicarbonate (1.5 mL, aqueous saturated) and then poured into sodium bicarbonate (25 mL, aqueous saturated). The aqueous layer was extracted with ethyl acetate (2×100 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.40-8.37 (1H, m), 7.89 (1H, d, J=2.4 Hz), 7.72-7.68 (3H, m), 7.46-7.42 (2H, m), 7.40-736 (1H, m), 7.28 (2H, d, J=8.9 Hz), 6.46 (1H, m), 5.44 (2H, s), 4.39 (1H, td, J=10.2, 5.5 Hz), 3.83-3.77 (1H, m), 3.22 (3H, s), 2.27-2.23 (1H, m), 2.04-1.93 (2H, m), 1.86-1.77 (2H, m), 1.48-1.34 (4H, m) ppm; high resolution mass spectrometry (ES+) m/z 454.2250 [(M+H)+; calculated for C27H28N5O2: 454.2238].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:20]([C:22]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH2:21]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:14]([F:17])([F:16])[C:13]([NH:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:3]=[C:2](/[CH:21]=[CH:20]/[C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:7]=[C:6]([F:8])[CH:5]=1)[OH:19])=[O:18]
Reactant: O=C(NCCC(O)c1cc(F)cc(Br)c1)C(F)(F)F
Reactant: C=CC1(O)CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NCCC(O)c1cc(F)cc(/C=C/C2(O)CCCCC2)c1)C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of N-(3-(3-bromo-5-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (0.58 g, 1.57 mmol), 1-vinylcyclohexanol (0.3 g, 2.38 mmol) and palladium acetate (0.03 g, 0.12 mmol) in tetrabutyl ammonium acetate (1.0 g) and DMF (1 ml) was heated at 90° C. for 1 h. After cooled to room temperature, the reaction mixture was partitioned between water (40 ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried over Na2SO4. Purification by chromatography (40 to 60% EtOAc-hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-fluoro-5-(2-(1-hydroxycyclohexyl)vinyl)phenyl)-3-hydroxypropyl)acetamide as a colorless oil. Yield (0.25 g, 54%): H NMR (400 MHz, DMSO-d6) δ 9.32 (t, J=5.6 Hz, 1H), 6.94-7.18 (m, 3H), 6.41-6.53 (m, 2H), 5.42 (d, J=4.4 Hz, 1H), 4.54-4.60 (m, 1H), 3.18-3.26 (m, 2H), 1.72-1.86 (m, 2H), 1.38-1.66 (m, 10H).
Reaction SMILES: FC1C=CC2C(C3CCN([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[C:18]4=[O:25])CC3)=NOC=2C=1.[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1>>[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[C:18]4=[O:25])[CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1
Reactant: CC(C)N1CCN(CCN2CCC(c3noc4cc(F)ccc34)CC2)C1=O
Reactant: Fc1ccc2c(N3CCNCC3)noc2c1
Product: CC(C)N1CCN(CCN2CCN(c3noc4cc(F)ccc34)CC2)C1=O

Procedure:
This product is prepared in the same manner as the compound of Example 1 but using 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperazine instead of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine in Step 1. The title compound so obtained melts at 125°-127° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:22]1([NH:26][CH:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=4[N:11]=3)=[CH:6][CH:5]=2)[CH3:2])[CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Reactant: NC1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NC1CCC1)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of EXAMPLE 1A (0.07 g, 0.3 mmol) and cyclobutylamine (0.34 mL, 4.8 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (0.016 g, 0.3 mmol) and acetic acid (0.2 mL). The mixture was stirred at ambient temperature for 48 hours then concentrated. The residue was purified by chromatography on a silica gel column with 0-10% methanol/dichloromethane/0.1% ammonium hydroxide to provide the title compound. 1H NMR (DMSO-d6) δ 9.34 (s, 1H), 8.19 (d, J=7.7 Hz, 2H), 7.86 (d, J=7.7 Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.57 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.7 Hz, 1H), 3.97 (s, 1H), 3.16 (d, J=5.2 Hz, 4H), 2.09 (s, 1H), 1.88 (s, 2H), 1.75 (s, 1H), 1.60 (s, 1H), 1.52 (s, 1H), 1.36 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O=S(Cl)Cl.[CH3:16]O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:16])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccccc1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2-hydroxyphenyl)acetic acid (11 g, 72.3 mmol) in 100 mL of MeOH was added SOCl2 (17.2 g, 144.7 mmol) at 0° C. The mixture was stirred at 50° C. overnight. The reaction was concentrated. The residue was purified column chromatography to give methyl (2-hydroxyphenyl)acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([OH:22])=O)=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.Cl.[F:26][CH:27]1[CH2:30][NH:29][CH2:28]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20]([N:29]3[CH2:30][CH:27]([F:26])[CH2:28]3)=[O:22])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: FC1CNC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), 3-fluoroazetidine hydrochloride (152 mg, 1.37 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (398 μl, 2.28 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at room temperature under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution; the precipitated solid is collected by filtration, washed with water and dried affording N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamide (158 mg, 89.8%) as a white solid. Mp.: 243-4° C. MS: m/z=387.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][C:6]2=[C:7]([C:12]([OH:14])=O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:30](=[N:33]O)([NH2:32])[CH3:31]>O1CCOCC1>[CH3:17][C:2]1([CH3:1])[CH2:15][C:6]2=[C:7]([C:12]3[O:14][N:33]=[C:30]([CH3:31])[N:32]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1
Reactant: CC(N)=NO
Reactant: CSc1sc(C(=O)O)c2c1C(=O)CC(C)(C)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CSc1sc(-c2nc(C)no2)c2c1C(=O)CC(C)(C)C2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a solution of 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboxylic acid (1.0 g, 3.7 mmol) in dioxan (90 mL) was added carbonyldiimidazole (0.6 g, 3.7 mmol) and the mixture stirred at 20° C. for 30 min. Acetamide oxime (0.41 g, 5.5 mmol) was added and the mixture was heated at 100° C. for 48 h. The solution was evaporated to dryness and the residue was purified by chromatographed on silica gel, eluting with ethyl acetate:hexane (2:3) to yield the title compound as a pale yellow solid (0.1 g, 9%). mp 177-180° C. Found: C, 54.90; H, 5.05; N, 8.71%. C14H16N2O2S2 requires: C, 54.52; H, 5.23; N, 9.08%. 1HNMR (250 MHz, CDCl3) δ 1.11 (6H, s), 2.45-2.47 (5H, m), 2.65 (3H, s), 3.11 (2H, s). MS (ES+) 309 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([Cl:21])=[O:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of m-phenoxyphenylacetic acid (110) (1.14 g, 5.0 mmol) in 15 mL of dichloromethane was added 1.27 g (0.87 mL) of oxalyl chloride. The resulting solution was allowed to stir at room temperature for 24 hr. Solvent was evaporated to give an oil (1.233 g, 97%), which was used in next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([NH2:12])=[O:11].C(O)=O>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: O=Cc1ccc(O)cc1
Solvent: O=CO
Solvent: O
Product: O=CNCc1ccc(O)cc1
Temperature: 189 °C
Yield: 77.4 %

Procedure:
4-hydroxybenzaldehyde (1.22 g or 10 mmol), formamide (22.72 g or 20.03 mL) and formic acid (2.43 g or 2 mL) were placed into a 50 mL round bottom flask equipped with a thermometer, a reflux condenser, a magnetic stirrer and a heating mantle. The reaction mixture was heated to 189° C. The heating was immediately turned off; the reaction flask was quickly raised from the heating mantle and allowed to cool to room temperature. The TLC conducted on the cold reaction mixture confirmed that the reaction was complete. The reaction mixture was diluted with 50 ml of water and extracted with ethyl acetate. The extract was dried with sodium sulfate and the solvent was evaporated to produce 1.17 g (77.1%) of 4-hydroxybenzylformamide (IV).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.[F:20][C:21]([F:33])([F:32])[O:22]C1C=CC=CC=1C(Cl)=O.COC(=O)CN.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[F:20][C:21]([F:33])([F:32])[O:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: O=C(O)c1nc(-c2ccccc2Cl)oc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Agent: COC(=O)CN
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)c1nc(-c2ccccc2OC(F)(F)F)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid above. 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid was prepared from 2-trifluoromethoxy-benzoyl chloride, amino-acetic acid methyl ester and trifluoroacetic anhydride. LCMS calcd for C12H5F6NO4 (m/e) 341, obsd 342 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:61])[CH2:59][CH3:60])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:61][CH:58]([C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][CH:56]=2)[CH2:59][CH3:60])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.209 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g), 1-(4-chlorophenyl)propan-1-amine (0.085 g) and DIPEA (0.262 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.138 g, 66.8
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:10]#[CH:11]>C(NCC)C.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CCN1CCCCC1
Reactant: Cc1ccccc1I
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: Cc1ccccc1C#CCN1CCCCC1
Yield: 62.3 %

Procedure:
A mixture of 2-iodotoluene (6.54 g), N-(2-propynyl)piperidine (3.69 g), dichlorobis(triphenylphosphino)palladium(II) (0.05 g) and copper(I) iodide (0.1 g) in dry diethylamine (50 ml) was heated under reflux for 5 hours. The solvent was removed under reduced pressure and the residue was taken up in diethyl ether and washed with water. The organic phase was dried over magnesium sulfate and concentrated completely under reduced pressure. Distillation of the residue under reduced pressure gave 3.98 g of an oil of boiling point 96–98° C./0.08 mm Hg.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.CS(O[CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:12]=1
Reactant: Brc1cn[nH]c1
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(n2cc(Br)cn2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (1.96 g, 6 mmol) and 4-bromopyrazole (321 mg, 2.2 mmol) were added to a solution of ethyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.50 g, 2 mmol) in DMF (10 mL). The mixture was stirred at 80° C. for 16 hours. Upon cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give ethyl 4-(4-bromo-1H-pyrazol-1-yl)cyclohexanecarboxylate. MS ESI calc'd. for C12H18BrN2O2 [M+H]+ 301 and 303. found 301 and 303. 1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 7.44 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 2.46-2.38 (m, 1H), 2.26-2.18 (m, 4H), 2.06-1.98 (m, 2H), 1.86-1.78 (m, 3H), 1.36 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].[Cl:14][C:15]1[C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[N:19][CH:18]=[CH:17][N:16]=1>>[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[O:4][CH2:3][CH2:2][NH:1][CH2:24][CH:23]([OH:25])[CH2:22][O:21][C:20]1[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][N:19]=1)(=[O:8])[NH2:9]
Reactant: NCCOc1ccccc1C(N)=O
Reactant: Clc1nccnc1OCC1CO1
Product: NC(=O)c1ccccc1OCCNCC(O)COc1nccnc1Cl

Procedure:
Analogously to the process described in Example 23, 9.0 g of 2-(2-aminoethoxy)-benzamide and 9.3 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine give 1-[2-(2-carbamoylphenyloxy)-ethyl-amino]-3-(2-chloro-3-pyrazinyloxy)-2-propanol, melting point 132°-133° C. The neutral fumaric acid salt prepared therefrom using the calculated amount of fumaric acid crystallises from a mixture of methanol and diethyl ether, melting point 167°-168° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C([N-]C(C)C)(C)C.[Li+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH2:16]([CH:4]([CH2:3][CH2:2][CH3:1])[C:5]([OH:7])=[O:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC(=O)O
Reactant: ClCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(Cc1ccccc1)C(=O)O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
N-Valeric acid (1 g) was dissolved in 75 ml of tetrahydrofuran and treated with 2 equivalents of lithium diisopropylamide at room temperature. The solution was then heated to 40° C. for 30 minutes followed by the addition of 1.1 ml of benzyl chloride. After 1.5 hours at 40° C., the reaction mixture was cooled to room temperature, poured into 300 ml of water and extracted with diethyl ether (2×200 ml). The aqueous solution was then acidified with 1M hydrochloric acid and extracted with diethyl ether (2×300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by radial chromatography (40-50% ethyl acetate in hexane, 2 mm plate) to yield 1.63 g of 2-benzylpentanoic acid (87% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]1[CH:60]=[C:59]([NH2:61])[CH:58]=[N:57]1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:61][C:59]2[CH:58]=[N:57][N:56]([CH3:55])[CH:60]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1cc(N)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 1-methyl-1H-pyrazol-4-ylamine (1 M solution in MeOH, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (51 mg, 41%) which was obtained as a white solid. MS: m/e=388.1 [M−H]−.