Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>OS(O)(=O)=O.CCCCC>[C:8]([C@@H:11]1[O:5][C:1](=[O:6])[C@H:2]([CH3:4])[O:3]1)([CH3:10])([CH3:9])[CH3:7]
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCC
Product: C[C@@H]1O[C@H](C(C)(C)C)OC1=O
Temperature: -80 °C

Procedure:
A mixture of L-Lactic acid (106 g of 85% in H2O), pivalaldehyde (220 mL), p-toluene sulfonic acid mono hydrate (2.0 g) and H2SO4 conc. (8 drops) in pentane (800 mL) was refluxed with azeotropic removal of the water formed using a Dean-Stark trap. The supernatant was decanted, washed with water, dried over MgSO4 and concentrated. The resulting residue was dissolved in hexane (800 mL) and cooled to -80° C. for 20 h. Crystals were collected by filtration in a cold room (5° C.) and washed with cold hexane (-78° C.). The crystals were dissolved in Et2O, dried over MgSO4 and concentred to give the title compound as a colorless oil. 1H NMR(CD3COCD3): δ0.95 (9H, s), 1.38 (3H,d), 4.47 (1H, m), 5.24 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].[Br:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>O1CCCC1.[Cu]>[Br:1][C:2]1[C:3]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[Br:15])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C([O-])c1cccc(Br)c1I
Reactant: Nc1ccccc1Br
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Br)c1Nc1ccccc1Br
Yield: 36.9 %

Procedure:
A mixture of 16.0 g (46 mmol) of sodium 3-bromo-2-iodobenzoate [prepared from 15.0 g (46 mmol) of 3-bromo-2-iodobenzoic acid (XX) and 1.1 g (46 mmol) of sodium hydride], 19.5 g (100 mmol) of sodium 2-bromoanilide [prepared from 17.3 g (100 mmol) of 2-bromoaniline (XXI) and 2.4 g (100 mmol) of sodium hydride] and a spatula-tipfull of copper powder in 100 ml of tetrahydrofuran was heated to reflux for 9 h. The solvent was distilled off, the residue extracted with 0.5 M aqueous sodium hydroxide, and the resulting suspension subjected to centrifugation. The centrifugate was acidified with diluted hydrochloric acid, the precipitated solid was filtered off and dried under high vacuum. Fractional sublimation under high vacuum yielded 6.3 g (37% of theory) of 3-bromo-2-(2-bromophenylamino)benzoic acid (XXII) as a yellow powder with a melting point of 181-182° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH3:31])=[O:29].[Li+].[OH-]>C(Cl)Cl.O.CO>[CH2:1]([CH:8]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]1[C:28]([O:30][CH3:31])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCNC(Cc2ccccc2)C1
Reactant: COC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of methyl 2-benzylpiperidine-4-carboxylate (7.36 g, 31.55 mmol) and DIPEA (11.02 mL, 63.09 mmol) in DCM (200 mL) was added methyl chloroformate (3.18 mL, 41.01 mmol) in 100 mL DCM over 1 h. The reaction mixture was stirred for 40 min, then washed with satd NaHCO3, dried using a phase separator and evaporated. The residue was dissolved in THF (80 mL) followed by addition of LiOH (1.0 g, 42.0 mmol), MeOH (60 mL) and water (60 mL). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 72 h. After evaporation of solvents, the residue was taken up in water. The pH was adjusted to <2 by addition of HCl (10%). The aqueous phase was then extracted with DCM (×5). The combined organic layers were dried by using a phase separator and evaporated to give 2-benzyl-1-(methoxycarbonyl)piperidine-4-carboxylic acid as an oil. MS m/z 276 (M−H)−.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11]1.C(N(CC)CC)C>CS(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:10]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)C1CNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CC(C(=O)O)C2)cc1
Temperature: 100 °C
Yield: 48.4 %

Procedure:
To a stirred solution of 4-fluoro benzaldehyde (5 g, 40.28 mmol) in DMSO (70 mL) was added azetidine-3-carboxylic acid (8.14 g, 80.56 mmol) followed by addition of triethyl amine (20.38 g, 201.41 mmol) at room temperature. Resulting reaction mixture was heated at 100° C. for 24 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was cooled to room temperature and quenched with ice cold water (150 mL). Aqueous layer was extracted with EtOAc (3×150 mL). Combined organic layer was washed with water (2×300 mL), dried over sodium sulphate; filtered and evaporated in vacuo to afford brown colored solid (4 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ: 3.54-3.59 (m, 1H), 4.03 (t, 2H, J=6.8 Hz), 4.16 (t, 2H, J=8.36 Hz), 6.52 (d, 2H, J=8.36 Hz), 7.69 (d, 2H, J=8.6 Hz), 9.68 (s, 1H); LC-MS (M−H): =203.70
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:20][C:21]1[N:22]([CH2:48][C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[C:23]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:24][C:25]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34].[CH3:59][C:60]1[N:61]([CH2:87][C:88]([O:90]CC2C=CC=CC=2)=[O:89])[C:62]([C:81]2[CH:82]=[N:83][CH:84]=[CH:85][CH:86]=2)=[CH:63][C:64]=1[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[S:72]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)(=[O:74])=[O:73]>CO.[Pd]>[CH3:20][C:21]1[N:22]([CH2:48][C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[C:23]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:24][C:25]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34].[CH3:59][C:60]1[N:61]([CH2:87][C:88]([OH:90])=[O:89])[C:62]([C:81]2[CH:82]=[N:83][CH:84]=[CH:85][CH:86]=2)=[CH:63][C:64]=1[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[S:72]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)(=[O:73])=[O:74]
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)cc(-c2cccnc2)n1CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CO
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)cc(-c2cccnc2)n1CC(=O)O
Reaction time: 1.5 h
Yield: 95 %

Procedure:
Benzyl 2-(2-methyl-3-(2-(phenylsulfonyl)benzyl)-5-(pyridin-2-yl)-1H-pyrrol-1-yl)acetate was synthesized according to general procedure I (step 1), with the exception that 6 equivalents of triethylsilane and 4.5 equivalents of trimethylsilyl trifluoromethanesulfonate were used. The crude benzyl 2-(2-methyl-3-(2-(phenylsulfonyl)benzyl)-5-(pyridin-2-yl)-1H-pyrrol-1-yl)acetate was taken forward. In a small recovery flask, H2 was flushed over a stirring solution of benzyl 2-(2-methyl-3-(2-(phenylsulfonyl)benzyl)-5-(pyridin-3-yl)-1H-pyrrol-1-yl)acetate (350 mg, 0.652 mmol), Pd/C (20 mg, 0.019 mmol) in MeOH (2 ml) followed by subjection to 1 atm (balloon) positive pressure of H2. After 1.5 hours, the reaction vial was flushed with nitrogen gas and the mixture was filtered through a 2 micron filter. The colorless mixture was concentrated to afford 2-(2-methyl-3-(2-(phenylsulfonyl)benzyl)-5-(pyridin-3-yl)-1H-pyrrol-1-yl)acetic acid (277 mg, 95%) as a fine yellow powder. 1H NMR (CDCl3/400 MHz) 11.77 (bs, 1H), 8.7 (s, 1H), 8.44 (d, 1H), 8.25 (d, 1H), 7.86-7.82 (m, 3H), 7.54-7.37 (m, 6H), 7.17 (d, 1H), 5.76 (s, 1H), 4.46 (s, 2H), 4.03 (s, 2H), 1.99 (s, 3H). MS m/z=447.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].NCCC(O)=O.C(O)(=O)C>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:19]2[N:13]([CH3:12])[C:14](=[O:15])[NH:16][C:17]2=[O:18])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: CN1CC(=O)NC1=O
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=C2C(=O)NC(=O)N2C)ccc1O
Yield: 14.8 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (4.6 g, 30 mmoles), 1-methyl hydantoin (3.5 g, 30 mmoles), β-alanine (1.4 g, 16 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 8 hours the mixture is stirred into water (300 ml) and the precipitate filtered off, rinsed successively with water (3×), ethanol (2×), and ether (2×) and dried. Recrystallization from acetonitrile gave the pure product (1.1 g), mp 197°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(Cl)Cl.C(=O)=O.[Br:24]Br>CC(C)=O.O>[Br:24][C:12]1[C:13]2[S:17][CH:16]=[CH:15][C:14]=2[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: COc1ccc(-c2cccc3sccc23)cc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccc(Br)c3sccc23)cc1
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a 25 ml round bottom flask was added 4-(4-methoxyphenyl)-1-benzothiophene (500 mg, 2.08 mmol), CH2Cl2 (10 ml), and the solution was cooled to −20° C. (acetone-water, CO2). Bromine (8.33 ml of 0.25 M stock in CH2Cl2, 2.08 mmol) was slowly added dropwise over 0.5 h and the reaction was stirred for a additional 0.5 h. The reaction was then washed with water, dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 460 mg orange oil. Recrystallization from 3:97 EtOAc-hexanes afforded 350 mg (53%) of product as white crystals: 1H NMR (300 MHz, DMSO-d6): δ 3.83 (3H, s), 7.10 (2H, d, J=8.0 Hz), 7.31 (1H, d, J=7.9 Hz), 7.51 (2H, d, J=8.4 Hz), 7.56 (1H, d, J=5.6 Hz), 7.68 (1H, d, J=7.9 Hz), 7.92 (1H, d, J=5.6 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1(P(O[NH2:36])(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH2:36][N:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:20]
Reactant: CC(C)c1ccc(-c2n[nH]c(=O)c3ccccc23)cc1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Product: CC(C)c1ccc(-c2nn(N)c(=O)c3ccccc23)cc1

Procedure:
4-(4-Isopropylphenyl)phthalazin-1(2H)-one was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give the title compound. MS (APCI+) M/Z 279 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:26])([F:25])[CH2:22][NH:23][NH2:24]>>[CH3:16][C:15]1[CH:14]=[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])[N:23]([CH2:22][C:21]([F:26])([F:25])[F:20])[N:24]=1
Reactant: NNCC(F)(F)F
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(CC(F)(F)F)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and 2,2,2-trifluoro-ethyl hydrazine (70% in water) according to the procedure of Example 28.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12
Reactant: C1COCCN1
Reactant: O=C(O)c1cnc(Cl)c2[nH]ccc12
Product: O=C(c1cnc(Cl)c2[nH]ccc12)N1CCOCC1

Procedure:
Prepared from 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid in a similar manner to Example 19 (e) using morpholine instead of tetrahydro-pyran-4-ylmethylamine to give the title compound (32 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][C:21](=[O:23])[C:20]4[N:24]([CH3:27])[CH:25]=[CH:26][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH:21]([OH:23])[C:20]4[N:24]([CH3:27])[CH:25]=[CH:26][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1ccc2c1C(=O)CN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1ccc2c1C(O)CN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 85.2 %

Procedure:
To a suspension of 42 mg (0.1 mmol) of Compound 21 in 5 ml of ethanol, 38 mg (1 mmol) of sodium borohydride were added gradually under ice-cooled stirring. The resulting mixture was stirred under ice cooling for 1 hour and further at room temperature for 13 hours. Water (5 ml) was added to the reaction mixture. The thus-obtained mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. Post treatment and purification were conducted as in Example 15, whereby 36 mg of the title compound were obtained (yield: 85%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]([CH2:19][CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([CH2:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(=CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reaction time: 15 h
Yield: 75.8 %

Procedure:
In a 2L-flask were placed 4-trifluoromethylaniline (161 g, 1.00 mol), methyl 3-oxopentanoate (143 g, 1.10 mol) and toluene (640 ml). To this solution was added p-toluenesulfonic acid monohydrate (3.2 g, 0.017 mol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 27 kPa, while the water generated was taken out of the reaction system by using a Dean-Stark trap under reflux. After 15 hours, the heating was discontinued, nitrogen leaked in, and the reaction mixture cooled. The solvent was evaporated by means of a rotary-evaporator, and the residue was distilled under reduced pressure to give 207 g of the title compound. The yield was 75.8%.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([OH:20])[CH2:16][CH2:15]2)[CH2:10]1)=O)(C)(C)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[ClH:28].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][C:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)([OH:20])[CH2:18][CH2:19]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a solution of 4-((3R)-3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-1-(4-fluorophenyl) cyclohexanol (1.05 g, 2.8 mmol) in ethyl acetate (50 ml), cooled to 0° C. was added hydrogen chloride gas, bubbled in gently for 5-10 minutes. The reaction mixture was stirred for 20 minutes at 0° C. and the above procedure was repeated twice. Concentration and flushing with ethyl acetate three times gave 4-((3R)-3-aminopyrrolidin-1-yl)-1-(4-fluorophenyl) cyclohexanol dihydrochloride (0.87 g, 89%); 1H NMR (DMSO)δ 11.33 (bd, 1H)), 8.60 (bd, 3H), 7.52 (m, 2H), 7.14 (m, 2H), 5.12 (bs, 1H), 3.35-4.04 (m, 6H), 1.76-2.27 (m, 10H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[NH2:20].[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[NH:20][C:24](=[O:25])[CH2:23][C:22]([F:28])([F:27])[F:21]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: Nc1nc2ccc(F)cn2c1-c1nc2ccccc2s1
Solvent: c1ccncc1
Product: O=C(CC(F)(F)F)Nc1nc2ccc(F)cn2c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-amine (compound m, 250 mg, 0.0009 mol) in pyridine (0.2 mL) was treated with 3,3,3-trifluoropropionyl chloride (0.134 mL, 0.0011 mol) and shaken at room temperature for about 45 min. The solvent was removed and the crude product was purified by column chromatography (50% ethyl acetate/hexane) to give N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3,3-trifluoropropanamide as a white solid. Rf 0.32, 70% ethyl acetate/hexanes; MS m/z 395 (M+H). SH-SY5Y_EC50 (μM): 2.1258.
Reaction SMILES: [CH2:1]1[O:5][CH:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:3][C@@H:2]1[C@H:12]1[O:17][C:15](=[O:16])[C:14]([OH:18])=[C:13]1[OH:19].C(=O)([O-])[O-].[Ca+2:24].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>O>[Ca:24].[CH2:1]1[O:5][CH:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:3][C@@H:2]1[C@H:12]1[O:17][C:15](=[O:16])[C:14]([OH:18])=[C:13]1[OH:19]
Reactant: [Ca+2]
Agent: O=C([O-])[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C1O[C@H]([C@@H]2COC(c3ccccc3)O2)C(O)=C1O
Solvent: O
Product: [Ca]

Procedure:
5,6-O-Benzylidene-L-ascorbic acid (13.2 g) was suspended in water (300 ml), to which was then added calcium carbonate (5 g), whereby the ascorbic acid was dissolved in water. The resulting aqueous solution was freeze-dried to give a calcium salt of 5,6-O-benzylidene-L-ascorbic acid (yield 13 g). This product was a white powdery substance which was readily soluble in water and decomposed near 200° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[CH2:13][CH:14]([CH3:16])[CH3:15].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1.C(Cl)Cl>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCOC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-pyridylacetic acid hydrochloride 10.00 g (57.60 mmol), iso-amyl alcohol 6.09 g (69.12 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 14.35 g (74.88 mmol) in 20 ml of pyridine and 80 ml of methylene chloride was stirred at room temperature for 2 hr.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([CH:12]1[CH2:15][NH:14][CH2:13]1)(=[O:11])=[O:10].CS(O[CH:21]([C:23]1[CH:24]=[N:25][C:26]([NH:55][C:56]2[CH:57]=[N:58][C:59]([O:62][CH3:63])=[CH:60][CH:61]=2)=[C:27]([C:29]2[N:34]=[C:33]([N:35]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([CH3:54])[N:30]=2)[CH:28]=1)[CH3:22])(=O)=O>C(Cl)Cl>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:33]2[N:34]=[C:29]([C:27]3[C:26]([NH:55][C:56]4[CH:57]=[N:58][C:59]([O:62][CH3:63])=[CH:60][CH:61]=4)=[N:25][CH:24]=[C:23]([CH:21]([N:14]4[CH2:15][CH:12]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:13]4)[CH3:22])[CH:28]=3)[N:30]=[C:31]([CH3:54])[N:32]=2)=[CH:51][CH:50]=1
Reactant: CS(=O)(=O)C1CNC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)OS(C)(=O)=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CC(S(C)(=O)=O)C4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 35.5 %

Procedure:
Triethylamine (0.327 mL, 2.345 mmol) and 3-(methylsulfonyl)azetidine (PharmaBlock, Carrboro, N.C.; 241 mg, 1.786 mmol) were sequentially added to a solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl methanesulfonate (375 mg, 0.558 mmol) in CH2Cl2 (5.5 mL) and the resulting mixture was stirred at 25° C. for 21 h. The reaction mixture was then concentrated in vacuo and chromatographically purified (silica gel, 0 to 100% (10% MeOH-EtOAc)/hexanes) to furnish N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(3-(methylsulfonyl)azetidin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (141.0 mg, 0.198 mmol, 35.5% yield) as a yellow oil. m/z (ESI, +ve) 711.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[N:3]1.O.NN>C(O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14][NH2:15])=[N:3]1
Reactant: Cn1cc2c([C@H]3C[C@H]3CN3C(=O)c4ccccc4C3=O)cccc2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1cc2c([C@H]3C[C@H]3CN)cccc2n1

Procedure:
A crudely purified product of cis-2-{[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}-1H-isoindole-1,3(2H)-dione was dissolved in ethanol (6.5 mL), and hydrazine monohydrate (3 mL) was added. The mixture was heated under reflux for 20 min. The solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a crudely purified product.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[C:28]([NH:1][C@H:2]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[CH:6][CH:5]=1)(=[O:30])[CH3:29]
Reactant: CCNC(=O)[C@@H](N)Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)[C@H](Cc1ccc(C(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 4-[(2S)-2-amino-3-(ethylamino)-3-oxopropyl]benzoate was dissolved in dichloromethane (3.5 mL). Pyridine (0.05 mL) and acetic anhydride (0.05 mL) were added. The reaction was allowed to stir overnight at room temperature under nitrogen. The reaction was transferred to a separatory funnel and washed with saturated sodium bicarbonate. The aqueous layer was extracted three additional times with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting material was purified by column chromatography. 1H NMR 600 MHz (CDCl3) δ 7.86 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.4 Hz), 6.89 (s, 1H), 6.47 (s, 1H), 4.68 (m, 1H), 3.15 (m, 2H), 3.06 (m, 2H), 1.93 (s, 3H), 1.55 (s, 9H), 0.99 (m, 3H). MS: cal'd 335 (MH+), exp 335 (MH+).
Reaction SMILES: [Cl-].C(C[P+](C)(C)C)#N.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:19]1([C@@H:25](O)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[F:28][C:29]1([F:57])[CH2:34][CH2:33][N:32]([C:35]([C:37]2[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][C:42]([C:46]([N:48]2[CH2:53][CH2:52][N:51]([CH:54]([CH3:56])[CH3:55])[CH2:50][CH2:49]2)=[O:47])=[CH:41][CH:40]=3)=[O:36])[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:57][C:29]1([F:28])[CH2:34][CH2:33][N:32]([C:35]([C:37]2[N:38]([C@H:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:26])[C:39]3[C:44]([CH:45]=2)=[CH:43][C:42]([C:46]([N:48]2[CH2:49][CH2:50][N:51]([CH:54]([CH3:55])[CH3:56])[CH2:52][CH2:53]2)=[O:47])=[CH:41][CH:40]=3)=[O:36])[CH2:31][CH2:30]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: C[C@H](O)c1ccccc1
Agent: C[P+](C)(C)CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3[C@@H](C)c2ccccc2)CC1
Yield: 32 %

Procedure:
Example 123 was independently synthesized according to example 74 under inversion of the configuration (e.e. >94%), from (cyanomethyl)trimethylphosphonium chloride (prepared according to Tetrahedron Lett. 1996, 37 (14), 2459-62), potassium bis(trimethylsilyl)amide, (S)-1-phenylethanol and (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32) in toluene, to give the compound as a light brown foam (32%).