Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:3]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:4]3[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]3)=[O:9])[CH2:11]2)[O:28][N:30]=1
Reactant: COCCC(N)=NO
Reactant: O=C1CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCN1
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCNC(=O)C3)C2)n1

Procedure:
250 mg (0.626 mmol) of 1-[(3-oxopiperazin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]-piperidine-3-carboxylic acid (Example 206A) and 108 mg (0.689 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 1. Yield: 72.0 mg (23% of theory).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:13]1([NH:12][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
4-Nitropyrazole-3-carboxylic acid (2.5 g; 15.9 mmol) was added to a stirred solution of aniline (1.6 ml; 17.5 mmol), EDC (3.7 g; 19.1 mmol), and HOBt (2.6 g; 19.1 mmol) in N,N-dimethylformamide (DMF) (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate/saturated NaHCO3 solution. The resultant solid was collected by filtration, washed with water and diethyl ether then dried under vacuum to give 2.85 g of the title compound (sodium salt) as a yellow/brown solid. (LC/MS: Rt 2.78, [M+H]+ 232.95).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].N1C=CC=CC=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[Cl:23][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=1)[CH3:13]
Reactant: CC(C)=CCc1ccc(C(C)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)=CCc1ccc(C(C)Cl)cc1
Yield: 97.6 %

Procedure:
To a solution of 9.5 g of 1-(p-prenylphenyl)-ethanol, 4.0 ml of pyridine and 60 ml of benzene, a solution of 5.9 g of thionyl chloride in 10 ml of benzene was added dropwise at 0°-5° C. with stirring. After stirring at room temperature for an hour, the reaction mixture was washed with water, aqueous sodium hydrogen carbonate and water successively and dried. Removal of the benzene gave 10.1 g of 1-chloro-1-(p-prenylphenyl)ethane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:16]([C:18]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CNS(C)(=O)=O)c1ccc(-c2cccc(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.2 g (8.1 mmol) of 3-formylbenzeneboronic acid and 1.1 g (8.1 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis-(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 16 hours whereupon 5 mL of water was added and heating continued for 1 hour. The mixture was then cooled to ambient temperature and 10 mL of water was added. The organic portion was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (40% ethyl acetate/hexane) afforded 0.7 g (41%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.N1C=CC=CC=1>O1CCCC1>[N:12]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1ccc2ccccc2n1
Reactant: C1CNCCN1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: c1ccc2nc(N3CCNCC3)ccc2c1
Yield: 91.4 %

Procedure:
A mixture of 2-chloroquinoline (10.0 g, 60.5 mmol), piperazine (26.1 g, 303 mmol) and pyridine (15 ml) was heated reflux temperature for 4 h. The hot reaction mixture was poured into a conical flask and diluted with tetrahydrofuran (150 ml). The precipitated solid was filtered off and washed with diethyl ether (3×50 ml) and the combined organic phases were evaporated in vacuo. The residue was suspended in a mixture of diethyl ether (200 ml) and 96% ethanol (80 ml) and undissolved solid was filtered off and washed with diethyl ether. The organic phase was evaporated in vacuo affording a solid which was crushed under water (200 ml) filtered off and washed with water (3×50 ml), diethyl ether (3×40 ml), dried in vacuo at 50° C. affording 11.8 g (92%) of 2-(1-piperazinyl)quinoline as a solid.
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8](=[O:12])[CH:9]([CH3:11])[CH3:10].N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)C>[OH:12][C@H:8]([C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH:1]=[O:7])[CH:9]([CH3:11])[CH3:10]
Reactant: CCCCCC=O
Reactant: CC(C)C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCC[C@H](C=O)[C@@H](O)C(C)C
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of freshly distilled hexanal (120 μL, 1.0 mmol) in 500 μL dimethylformamide was added slowly over the course of 24 h to a stirring suspension of isobutyraldehyde (272 μL, 3.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at room temperature. After 24 h, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (7:3 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 80% yield (127 mg, 0.80 mmol), 98% ee and 96:4 anti:syn. IR (film) 3458, 2960, 2934, 2874, 2725, 1720, 1467, 1328, 1220, 1146, 1024, 991.2, 959.9, 901.1, 775.6 cm−1; 1H NMR (300 MHz, CDCl3) δ9.75 (d, 1H, J=3.3 Hz, CHO); 3.56 (dd (apparent q), 1H, J=6.0, 5.7 Hz, CHOH); 2.46 (dddd, 1H, J=8.4, 5.7, 5.7, 3.3 Hz, CHCH2); 1.99 (d, 1H, J=6.0 Hz, OH); 1.82 (m, 1H, CH(CH3)2); 1.70 (m, 1H, CHCH2); 1.58 (m, 1H, CHCH2); 1.30 (m, 4H, CH2CH2CH3); 0.97 (d, 3H, J=6.6 Hz, CH(CH3)2); 0.93 (d, 3H, J=6.6 Hz, CH(CH3)2); 0.90 (dd (apparent t), 3H, J=6.6, 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ206.1, 76.7, 54.9, 31.3, 29.5, 26.7, 23.2, 20.0, 17.1, 14.2; HRMS (CI) exact mass calcd for [M+H]+ (C10H21O2) requires m/z 173.1541, found m/z 173.1540; [α]D=−15.4 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the acetal derived from 2,2-dimethylpropane-1,3-diol (obtained by the method of Yamamoto, supra) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (110° C. isotherm, 23 psi); (2S, 3S) anti isomer tr=97.8 min, (2R, 3R) anti isomer tr=102.7 min, (2R, 3S) and (2S, 3R) syn isomers tr=94.4, 96.5 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[N:3]1>CO>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[N:3]1
Reactant: CCOC(=O)C=C(c1cnn(C)c1)C1CCOCC1
Solvent: CO
Product: CCOC(=O)CC(c1cnn(C)c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 3-(1-methyl-1H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)acrylate (205 mg, 0.78 mmol) was dissolved in methanol (10 ml) and argon was bubbled through the solution for 5 minutes. To the solution was added 10% Pd/C (41 mg) and the flask was fitted with a balloon containing hydrogen. The reaction was stirred at room temperature for 16 hours. The catalyst was removed by filtration through a plug of celite. And solution was concentrated in vacuo. The crude product was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([CH3:33])[S:26][C:25]=2[CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][O:18][C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([CH3:33])[S:26][C:25]=4[CH:34]=3)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: COC(=O)c1c(C)sc2cc(O)ccc12
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc12
Yield: 42.9 %

Procedure:
Example 11(b) was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (417 mg, 1.40 mmole) with methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (417 mg, 2.11 mmole) and Cs2CO3 (2.29 g, 7.02 mmole) in a manner as previously described for example 1 to give 290 mg (43%) of a yellow solid. 1H NMR (DMSO-d6): δ8.58 (1H, d, J=5.4 Hz), 8.39 (1H, d, J=9.0 Hz), 8.07 (1H, s), 8.02 (1H, d, J=2.3 Hz), 7.42 (1H, dd, J=2.3, 9.0 Hz), 6.79 (1H, d, J=5.4 Hz), 4.08–3.99 (3H, m), 3.87–3.86 (2H, m), 3.91 (3H, s), 3.64–3.59 (2H, m), 3.27, 3.24 (3H, s), 2.82 (3H, s).
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:13])[NH:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)=O.Cl.[NH2:15]O.C([O-])=O.[Na+].O>C(O)=O>[C:1]([C:3]1[C:4](=[O:13])[NH:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:15]
Reactant: O=Cc1cc(C(F)(F)F)c[nH]c1=O
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1cc(C(F)(F)F)c[nH]c1=O
Temperature: 25 °C

Procedure:
A solution of 3-formyl-5-trifluoromethyl-2-pyridone (3.5 g), hydroxylamine hydrochloride (1.42 g) and sodium formate (1.39 g) in 98% formic acid (42 ml) was heated to reflux for a period of 20hrs. After cooling to ambient temperature, the reaction mixture was poured into water, and rigorously extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, followed by brine, and dried over anhydrous magnesum sulphate. Removal of the solvent under reduced pressure gave 3-cyano-5-trifluoromethyl-2pyridone as an off-white solid (m.p. 170-175° C.) which was used without further purification. The compound showed (DMSO) 8.54 (1H,d) 8.30 (1H,d).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][CH2:14][C:4]=2[N:5]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=1.[CH2:17]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:18]>>[CH:9]1([O:8][C:6]2[N:7]=[C:2]([NH:28][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:29])=[CH:27][CH:26]=3)[C:3]3[CH2:16][CH2:15][CH2:14][C:4]=3[N:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1nc(OC2CCCC2)nc2c1CCC2
Product: CCOC(=O)Cc1ccc(Nc2nc(OC3CCCC3)nc3c2CCC3)cc1
Yield: 93 %

Procedure:
Following General Procedure B2, 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.075 g, 0.31 mmol) was reacted with 4-aminophenylacetic acid ethyl ester (0.084 g, 0.47 mmol) to afford the title compound (0.110 g, crude) as a white solid. MW=381.47. 1H NMR (CD3OD, 300 MHz) δ 7.61 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 5.55-5.45 (m, 1H), 4.13 (q, J=7.6 Hz, 2H), 3.57 (s, 2H), 2.79 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.14-1.95 (m, 4H), 1.89 (s, 1H), 1.87-1.76 (m, 4H), 1.72-1.61 (m, 2H), 1.24 (t, J=7.1 Hz, 1H); APCI MS m/z 382 [M+H]+.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:10][C:11]1[C@@:16]([CH2:21][CH:22]([CH2:24][OH:25])[OH:23])([C@H:17]([CH2:19][OH:20])[OH:18])[O:15][C:13](=[O:14])[C:12]=1[OH:26])[CH2:7][CH2:8][CH3:9].[CH2:27](Br)[CH:28]=[CH2:29]>O>[CH2:6]([O:10][C:11]1[C@@:16]([CH2:21][CH:22]([CH2:24][OH:25])[OH:23])([C@H:17]([CH2:19][OH:20])[OH:18])[O:15][C:13](=[O:14])[C:12]=1[O:26][CH2:29][CH:28]=[CH2:27])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCOC1=C(OCCCC)[C@@](CC(O)CO)([C@@H](O)CO)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Under an argon atmosphere, water and sodium hydrogen carbonate (0.98 g) were added to 3-O-butylglyceryl ascorbic acid (3.56 g) obtained in Example 6, and the mixture was stirred at room temperature for 30 minutes. To the mixture, allyl bromide (1.68 g) was added, and the resultant mixture was heated up to 60° C. and stirred for 5 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 3.53 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:30/3/0.3), and concentration was performed under reduced pressure to obtain to obtain 3-O-butylglyceryl-2-O-allyl ascorbic acid (3.00 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1.[CH:16](I)([CH3:18])[CH3:17]>CN(C=O)C>[CH:16]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:15])([CH3:3])[CH2:5][C:6]1=[O:14])([CH3:18])[CH3:17]
Reactant: CC1(C)CC(=O)Nc2ccccc21
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CC(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of NaH (0.121 g, 3.0 mmol) in dry DMF (2 mL) was added a solution of 4,4,-dimethyl-2-oxoquinoline (Compound 38, 0.529 g, 3.0 mmol) in dry DMF (10 mL). The mixture was stirred at room temperature for 30 min followed by addition of isopropyl iodide. The reaction mixture was left at room temperature for 72 h. Then ice-cubes were added to the reaction and the mixture was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with saturated solution of NaCl, dried over MgSO4 and concentrated to give a pale yellow oil. Purification by column chromatography (silica gel, 30% ethyl acetate in hexane) yielded the title compound as a colorless oil (472 mg, 72%). 1H NMR d 1.32 (s, 6H), 1.57 (d, J=7.1 Hz, 6H), 2.45 (s, 2H), 4.74 (q, J=7.0 Hz, 1H), 7.06-7.32 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16](Cl)=[O:17])[CH:5]=[CH:4][C:3]1=2.[OH:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=1>>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:23][CH:22]=3)=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#CC(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Product: CC(C)(C)OC(=O)c1ccc(OC(=O)C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a similar manner to that of Example 1(d), by reaction of 1.4 g (5 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propynoyl chloride with 950 mg (4.9 mmol) of tert-butyl 4-hydroxybenzoate, 1.75 g (83%) of the expected tert-butyl ester are obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrCC1CO1
Reactant: Oc1ccccc1-c1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1c[nH]c(-c2ccccc2OCC2CO2)c1
Yield: 48.6 %

Procedure:
7.0 g of 2-(hydroxyphenyl)-pyrrole, 7.3 g of epibromohydrin and 11.4 g of dry potassium carbonate in 50 ml of acetone are refluxed for 7 hours. After the mixture has cooled, it is filtered and the filter residue is washed with acetone. The combined filtrates and freed from solvent by distilling off the latter. The residue is twice chromatographed on silica gel, using methylene chloride as the eluant, and thereby gives 4.6 g (48% of theory) of 2-[2- (2,3-epoxypropoxy)-phenyl]-pyrrole as a colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([CH3:10])([CH3:9])[CH3:8]>C1C=CC=CC=1>[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]([Cl:2])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=O)Nc2ccccc2C(C)(C)C)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C(Cl)=Nc2ccccc2C(C)(C)C)cc1
Yield: 95.9 %

Procedure:
Phosphorus pentachloride (6.88 g, 33 mmol) was dissolved in 50 mL of benzene. Under a gentle argon purge, N-(2-tert-butylphenyl)-4-methylbenzamide (Amide II) (8.02 g, 30 mmol) was added slowly with stiffing at room temperature. The yellow solution was refluxed for 2 hours. Benzene was removed in vacuo, yielding a yellow solid (8.22 g, 96%). 1H NMR (400 MHz, C6D6): 8.17 (d, 2H), 7.38 (d, 1H), 7.11 (t, 1H), 7.06 (t, 1H), 6.90 (d, 2H), 6.85 (d, 1H), 1.98 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:39][CH3:40])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](OCC)=O)=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[N:15]=[CH:14]2.C(CP(=O)(OCC)OCC)#[N:42]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:39][CH3:40])=[C:10](\[C:26]1[CH:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:34]#[N:42])=[CH:30][CH:31]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[N:15]=[CH:14]2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(F)cc2Cl)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Product: CC/C(=C(/c1ccc(/C=C/C#N)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl

Procedure:
The title compound was prepared from (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde (Compound 193, Step 1) and diethyl (cyanomethyl)phosphonate following General Procedure E. LCMS: 428 [(M-THP+H)+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[S:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1.C(Cl)CCl>CN(C=O)C>[S:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Reactant: Nc1ccc(C(=O)N2CCSC2)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCSC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (46 mg, 0.14 mmol) and 4-(thiazolidin-3-ylcarbonyl)phenylamine (30 mg, 0.14 mmol) in DMF (2 mL), EDC (54 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (15 mg). MS 509.2 and 511.2 (M+H, Cl pattern).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22](OC(N1CCN(C(=O)C2C=CC(CN3CCOCC3)=CC=2)CC1)=O)([CH3:25])(C)[CH3:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:25]1([N:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Reactant: O=C(c1ccc(CN2CCOCC2)cc1)N1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
(4-Morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone. A solution of 4-(4-morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (1.163 g) in CH2Cl2 (10 mL) was treated with TFA (−4 mL). After 30 min, additional TFA (5 mL) was added, and the mixture was stirred for a further 2 h. The mixture was diluted with diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (0.255 g, 30%). MS (ESI): mass calcd. for C16H23N3O2, 289.18; m/z found, 290.4 [M+H]+. 1H NMR (CDCl3): 7.41-7.35 (m, 4H), 3.95-3.70 (m, 6H), 3.52 (s, 2H), 3.09-2.80 (m, 6H), 2.49-2.42 (m, 4H). Step D. A solution of (4-morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone (0.128 g) in methanol (7.5 mL) was treated with (1-ethoxy-cyclopropoxy)-trimethyl-silane (1.5 mL), acetic acid (0.2 mL), and NaBH3CN (˜400 mg). The mixture was heated at 60° C. for 18 h, and then was cooled to rt and concentrated. The residue was diluted with 1 N NaOH and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to give the title compound (0.0548 g, 38%). MS (ESI): mass calcd. for C19H27N3O2, 329.21; m/z found, 330.4 [M+H]+. 1H NMR (CDCl3): 7.36 (s, 4H), 3.79-3.68 (m, 6H), 3.50 (s, 2H), 3.44-3.32 (m, 2H), 2.74-2.61 (m, 2H), 2.60-2.50 (s, 2H), 2.45-2.40 (m, 4H), 1.66-1.62 (m, 1H), 0.49-0.44 (m, 2H), 0.44-0.39 (m, 2H). Alternative Preparation of Example 1.
Reaction SMILES: S(=O)(=O)(O)[OH:2].ON=[CH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH3:20])[CH3:19])=[O:10]>>[CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:9](=[O:10])[C:8]2=[O:2])([CH3:20])[CH3:19]
Reactant: O=S(=O)(O)O
Reactant: CC(C)c1ccccc1NC(=O)C=NO
Product: CC(C)c1cccc2c1NC(=O)C2=O
Temperature: 80 °C
Yield: 84 %

Procedure:
To concentrated sulfuric acid at 80° C. was added 2-hydroxyimino-N-(2-isopropyl-phenyl)-acetamide in several small portions over 10 minutes. After addition it was heated at 80° C. for 30 minutes., then poured into ice. Filtration, washing with water, and drying under vacuum over P2O5 provided 2.974 g (84%) of the title compound as a solid. ESI (−) MS m/e=188 (MH−).