Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>C(O)C.O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:30][CH2:27][CH:28]=[CH2:29])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C=CCN
Solvent: CCO
Solvent: O
Product: C=CCNc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 140 °C

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.25 g, 0.669 mmol) was suspended in ethanol (4 mL) followed by addition of allylamine (0.753 mL, 10.03 mmol). The sealed contents were heated (heat block) at 140° C. for ca. 60 h, and then allowed to cool to room temperature. The reaction mixture was diluted with water (100 mL) and then filtered. The collected solid was washed with additional water and then dried in vacuum oven at 45° C. for 18 h. The final product was isolated as an off-white solid, 0.225 g (83%). LCMS E-S (M+H)=394.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.82 Hz, 6H), 2.12 (s, 3H), 2.21 (s, 3H), 4.00 (t, J=5.43 Hz, 2H), 4.32 (d, J=5.05 Hz, 2H), 4.94 (quin, J=6.69 Hz, 1H), 5.09 (dd, J=10.36, 1.77 Hz, 1H), 5.18-5.29 (m, 1H), 5.85-6.01 (m, 2H), 6.68 (s, 1H), 7.37 (t, J=5.56 Hz, 1H), 7.84 (s, 1H), 8.45 (t, J=5.05 Hz, 1H), 11.55 (br. s., 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 120 °C
Yield: 96 %

Procedure:
To a solution of methyl 4-bromo-3-methylbenzoate (ABCR, 15 g, 65 mmol) in toluene (200 mL) and water (200 mL), was added o-tolylboronic acid (10.68 g, 78 mmol) followed by potassium carbonate (45.25 g, 32.7 mmol) and Pd(PPh3)4 (3.78 g, 3.3 mmol). The mixture was degassed with N2 and refluxed at 120° C. for 6 hours. After the completion of reaction, the reaction mixture was cooled to RT. The organic phase was separated and evaporated under reduced pressure. The crude compound was passed through a silica column (60-120) using hexane as eluent to get the title compound as a white solid (15 g, 95%). 1H NMR (DMSO-d6, 400 MHz) δ 7.91 (s, 1H), 7.83-7.81 (m, 1H), 7.33-7.30 (m, 2H), 7.28-7.26 (m, 1H), 7.25-7.22 (m, 1H), 7.07-7.05 (d, 1H), 3.86-3.81 (s, 3H), 2.09-2 (s, 3H), 1.97-1.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:20](=[O:21])[C:19]4[N:18]([CH2:22][C:23]#[C:24][CH3:25])[C:17](Br)=[N:16][C:15]=4[N:14]([CH3:27])[C:12]3=[O:13])=[N:7][C:6]=2[CH:28]=1.[C:29]([O:33][C:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][N:38](N)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O.C[N:51](C)C=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:20](=[O:21])[C:19]4[N:18]([CH2:22][C:23]#[C:24][CH3:25])[C:17]([N:38]5[CH2:39][CH2:40][CH2:41][CH:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[C@@H:37]5[NH2:51])=[N:16][C:15]=4[N:14]([CH3:27])[C:12]3=[O:13])=[N:7][C:6]=2[CH:28]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(F)ccc3s1)c(=O)n2C
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC#CCn1c(N2CCCC(C(=O)OC(C)(C)C)[C@@H]2N)nc2c1c(=O)n(Cc1nc3cc(F)ccc3s1)c(=O)n2C
Temperature: 25 °C
Yield: 77.6 %

Procedure:
By utilizing the well known method, 1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1b (240 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5 ml). (R)-3-tert-butoxycarbonyl-aminopiperidine (130 mg, 0.66 mmol) and potassium carbonate (107 mg, 0.78 mmol) were added to give a reaction mixture. The reaction mixture was reacted at 75° C. for 2 hours, and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was cooled to room temperature. The cooled reaction solution was poured into cool water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-tert-butoxycarbonyl-amino-piperidin-1-yl]-xanthine 1c (230 mg, yellow solid), yield: 77.6%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:21]2[N:17]([CH3:16])[C:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1cccn1C
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(C#N)cc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 5.0 g. (0.03 mole) of p-cyanobenzoyl chloride in 60 ml. of methylene chloride is added to a suspension of 40 g. of aluminum chloride in 30 ml. methylene chloride. The resulting mixture is added dropwise to a chilled solution of 5.0 g. (0.03 mole) of ethyl 1-methylpyrrole-2-acetate in 15 ml. of methylene chloride. The resulting mixture is stirred at room temperature for 20 minutes, and then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated, washed successively with N,N-dimethylaminopropylamine, 3N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo. The resulting solid, which separates from the oily residue on standing, is recrystallized from methanol to give pure ethyl 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate, m.p. 117-120° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:31][C:32](=[O:44])[C:33]([NH:36]C(=O)OC(C)(C)C)([CH3:35])[CH3:34])[C:11]([N:13]1[CH2:30][CH2:29][CH2:28][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:36][C:33]([CH3:35])([CH3:34])[C:32]([NH:31][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([N:13]1[CH2:30][CH2:29][CH2:28][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:14]1)=[O:12])=[O:44]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 1-((2R)-3-(benzyloxy)-1-(2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.18 g, 1.945 mmol) in DCM (15 ml) was treated with TFA (7 ml, 91 mmol) and stirred at RT for 1 hour. The solvent was removed in vacuo and the residue was partitioned between EtOAc (200 ml) and sat. sodium bicarbonate solution (100 ml). The organic portion was dried (MgSO4) and concentrated in vacuo to afford the title compound as a diastereomeric mixture;
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Si:19]([O:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[Si:44]([O:51][C@@H:52]1[CH2:57][CH2:56][C@H:55]([C:58](=[O:69])[C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[CH2:54][CH2:53]1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C1COCC1>[Si:44]([O:51][C@@H:52]1[CH2:53][CH2:54][C@H:55]([C:58]([OH:69])([CH:33]([C@H:30]2[CH2:31][CH2:32][C@@H:27]([O:26][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:28][CH2:29]2)[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[C:59]([O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)=[O:60])[CH2:56][CH2:57]1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](CC(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(=O)C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(C(=O)OCc2ccccc2)C(O)(C(=O)OCc2ccccc2)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M n-butyllithium solution in hexane (0.85 ml, 2.07 mmol) was added to a solution of diisopropylamine (0.23 ml, 2.21 mmol) at −78° C. under an argon stream. The mixture was brought to 0° C., was stirred for 30 min, and was again cooled to −78° C. A solution of benzyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)acetate (500 mg, 1.37 mmol) in anhydrous THF (5.0 ml) was added dropwise at −78° C., and the mixture was stirred for additional one hr. A solution of benzyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-oxoacetate (467 mg, 1.25 mmol) in anhydrous THF (5.0 ml) cooled to −78° C. was added to the resultant enolate solution through a cannula over 10 min. The mixture was stirred at −78° C. for one hr, and the mixture was quenched with acetic acid, was adjusted to pH 4, and was brought to room temperature. The reaction solvent was removed by distillation under reduced pressure, and the residue was diluted with ethyl acetate, and the diluted solution was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as a colorless solid (500 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17](C=O)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[OH-].[NH4+].C1(C)C=CC(S(CN=C=O)(=O)=O)=CC=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40]C1>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:43]2[N:38]=[CH:40][NH:41][CH:42]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: C1CNCCN1
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC2(O)CCCCCC2)c1
Agent: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2c[nH]cn2)ccc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 21.6 %

Procedure:
A solution of 2-chloro-5-formyl-N-(1-hydroxy-cycloheptylmethyl)-benzamide (50 mg, 0.16 mmol) and ammonium hydroxide (0.5 mL, 0.44 mmol) in THF (5 mL) was stirred at room temperature for 6 h. p-Toluenesufonylmethylisocyanate (21 mg, 0.11 mmol) and piperazine (14 mg, 0.16 mmol) were added and the mixture was stirred at room temperature for 5 d. The mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in HCl (20 mL, 1M) and washed with ethyl acetate. The aqueous layer was saponified to pH 12 with sodium hydroxide (6M) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid (12 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClN1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19]C1.[CH:27]([N:30](C(C)C)CC)(C)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: ClN1CC=Nc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ncnc2ccccc12

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g), 4-chloroquinoxaline (0.768 g) and diisopropylethylamine (0.816 ml) were dissolved in tetrahydrofuran (75 ml) and heated to reflux for 6 hours under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium hydrogen carbonate solution, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 50 to 100% ethyl acetate in hexane. The title compound was obtained as a white foam (1.44 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[N-:25]=[C:26]=[O:27].[N-:28]=[C:29]=S>>[OH2:23].[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:26]([NH:25][CH3:29])=[O:27])[CH:4]=2)[NH:8][CH:7]=1.[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:26]([NH:28][CH3:29])=[O:27])[CH:4]=2)[NH:8][CH:7]=1
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: [N-]=C=O
Reactant: [N-]=C=S
Product: CNC(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Product: O

Procedure:
A suspension of 2-[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (1.53 g) in pyridine (50 ml) was cooled in an ice bath and treated dropwise with methylisocyanate (2.5 ml). The mixture was stirred at room temperature for 4 h, and water (15 ml) was added to the resulting white suspension. After 10 min. the yellow solution was acidified with hydrochloric acid (2N), and extracted into ethyl acetate (3×100 ml). The combined organic extract was washed with sodium carbonate solution (2N; 100 ml), dried (magnesium sulphate) and evaporated to dryness, giving a pale yellow solid. On trituration with ether, this afforded the pure title material as a cream crystalline solid (1.22 g) m.p. 210°-212°. The following compounds were similarly prepared from 2[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3-(2H)-dione, hemisulphate, hemihydrate and the appropriate isocyanate or isothiocyanate as detailed in Table I.
Reaction SMILES: [CH2:1]([N:7]([CH3:56])[C:8]([C@@H:10]1[CH2:14][C@H:13]([O:15][C:16]2[C:25]3[C:20](=[C:21]([CH3:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:29]3[S:30][CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=3)[CH:17]=2)[CH2:12][N:11]1[C:38]([NH:40][C@:41]1([C:46](=[O:55])[NH:47][S:48]([C:51]2([CH3:54])[CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH2:43][C@H:42]1[CH:44]=[CH2:45])=[O:39])=[O:9])[CH2:2][CH2:3][CH2:4]C=C>ClC(Cl)C>[CH3:27][O:26][C:22]1[C:21]([CH3:28])=[C:20]2[C:25]([C:16]([O:15][C@@H:13]3[CH2:12][N:11]4[C@H:10]([C:8](=[O:9])[N:7]([CH3:56])[CH2:1][CH2:2][CH2:3][CH2:4][CH:45]=[CH:44][C@H:42]5[C@:41]([C:46]([NH:47][S:48]([C:51]6([CH3:54])[CH2:53][CH2:52]6)(=[O:49])=[O:50])=[O:55])([NH:40][C:38]4=[O:39])[CH2:43]5)[CH2:14]3)=[CH:17][C:18]([C:29]3[S:30][CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[N:33]=3)=[N:19]2)=[CH:24][CH:23]=1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Agent: COc1ccc2c(O[C@H]3C[C@H]4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)NS(=O)(=O)C5(C)CC5)NC(=O)N4C3)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Solvent: CC(Cl)Cl
Product: COc1ccc2c(O[C@H]3C[C@H]4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)NS(=O)(=O)C5(C)CC5)NC(=O)N4C3)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Temperature: 75 °C
Reaction time: 0.42 h

Procedure:
Compound 129 (3.91 g) was dissolved in dichloroethane (980 mL) under Ar at room temperature. The solution was degassed with argon and then heated at 73-77° C. Zhan 1B catalyst (1%) in dichloroethane was slowly added to the reaction solution. At 25 min, another 1% of the catalyst in DCE was added. In total, 8% of the catalyst was added over 4 hrs and 20 min. The reaction mixture was treated with 2-mercaptonicotinic acid (“MNA”) (1 g). The reaction mixture was cooled down to room temperature, concentrated under vacuum to ˜100 mL, and then washed with 0.5M aqueous NaHCO3. To the separated organic phase was added MNA (1 g) and the mixture was stirred at room temperature for 55-65 min. The mixture was washed twice with aqueous 0.5M NaHCO3, dried over Na2SO4, and filtered. Charcoal (11 g) was added to the organic solution and the mixture was stirred at room temperature for 15 hrs. The mixture was concentrated under vacuum to ˜10-15 mL and filtered through a silica plug. The crude solid was triturated in warm methanol to give compound 68b (1.1 g) as an off-white solid in 30% yield and 98% purity.
Reaction SMILES: [C:1]([C:3]1([N:12]([CH3:25])[C:13](=[O:24])[CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:8][CH2:7][N:6]([N:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)#N.S(=O)(=O)(O)[OH:27].[CH3:31][OH:32]>>[CH3:31][O:32][C:1]([C:3]1([N:12]([CH3:25])[C:13](=[O:24])[CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:8][CH2:7][N:6]([N:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=[O:27]
Reactant: CO
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)c(CC(=O)N(C)C2(C#N)CCN(N(C)C)CC2)c(C)c1
Product: COC(=O)C1(N(C)C(=O)Cc2c(C)cc(C)cc2C)CCN(N(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.30 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-N-methyl-2-(2,4,6-trimethyl-phenyl)-acetamide (from Step 2) is dissolved in 2.6 ml methanol, and 1 ml concentrated sulfuric acid is added. The mixture is stirred at room temperature for 3 hours, then at 65° C. for 3 hours, then poured on ice. The mixture is extracted three times with ethyl acetate, washed with brine, dried over sodium sulfate, and the solvent evaporated. Thus, 750 mg 1-Dimethylamino-4-{methyl-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester is obtained. 1H-NMR (CDCl3): 6.80 ppm (s, 2H), 3.60 ppm (s, 5H), 3.15 ppm (s, 3H), 3.15 ppm (s, 3H), 2.85 ppm (m, broad, 4H), 2.45 ppm (s, 6H), 2.30 ppm (m, broad, 2H), 2.20 (s, 3H), 2.15 (s, 6H), 2.10 ppm (m, broad, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH2:47][CH3:48])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH2:49]([I:52])[CH2:50][CH3:51]>C(Cl)(Cl)Cl>[I-:52].[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][N+:42]([CH2:49][CH2:50][CH3:51])([CH2:46][CH2:47][CH3:48])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: CCCI
Reactant: CCCN1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: CCC[N+]1(CCC)CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: [I-]
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To 4.9 mg of (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl)carbonyl-N-{((3S)-1-propyl-3-piperidyl)methyl}pyrrolidine-2-carboxamide, 1 ml of propyl iodide was added at room temperature, followed by 15 hours' stirring at 100° C. under heating. The reaction liquid was diluted with chloroform, the solvent was distilled off under reduced pressure, and the resulting residue was purified with preparative thin-layer chromatography (aluminium oxide 60F254, Art 5713 (Merck), chloroforom/methanol=18/1) to provide 4.1 mg of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1N.C[C:13]([N:15](C)C)=O.Br[N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[N:21](Br)[C:20]1=[O:28].C(OC(C)C)(C)C>O>[CH3:25][C:22]1([CH3:26])[C:23](=[O:24])[N:19]([C:8]2[CH:7]=[CH:6][C:4]([C:13]#[N:15])=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:9]=2)[C:20](=[O:28])[NH:21]1
Reactant: CC(=O)N(C)C
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ccccc1C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reaction time: 0.25 h

Procedure:
100 g of ortho trifluoromethylaniline and 200 ml of dimethylacetamide are introduced and the reaction medium is cooled down to 0°±2° C. 88.8 g of dibromo-dimethyl hydantoin is added over 30 minutes at 0°±2° C., the temperature is maintained at 0°±2° C. and agitation is carried out at 0°±2° C . for 15 minutes. Then the temperature is allowed to rise to 20° C. and the whole is poured into 200 ml of demineralized water at 20°±2° C. Agitation is carried out for 15 minutes, 400 ml of isopropyl ether is added, the aqueous phase is decanted and the organic phase is washed with 2×100 ml of demineralized water, the aqueous phases are reextracted with 100 ml of isopropyl ether and the combined organic phases are dried, filtered and washed with 2×20 ml of isopropyl ether. Concentration is carried out a temperature of 30-40° C. and in this way 149 g of expected product (orangy-brown oil) is obtained.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>O>[CH:6](=[N:1][NH:2][C:3]([NH2:5])=[S:4])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNC(N)=S
Reactant: O=CC=Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NC(=S)NN=CC=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 18.2 g (0.20 m) of thiosemicarbazide in 250 ml of hot water was gradually added to a solution of 26.4 g (0.20 m) of cinnamaldehyde in 250 ml of hot 2 B ethanol. Small, colorless crystals began to ppt from the homogeneous mixture after several minutes of heating on a steam bath. Heating was continued for a half an hour, after which the mixture was cooled to room temperature and the product was collected by filtraton, washed with cold ethanol, and air-dried to yield 25.5 g of small, pale yellow crystals. An additional 18.3 g of product was recovered by concentrating the mother liquors. Recrystallization from ethanol gave 29.3 g (0.14 m) of small, pale yellow crystals, m.p. 137°-139° C.