Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)[CH3:6].[OH:28][CH2:29][C:30]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>ClCCl.C1CCCCC1>[Cl:24][C:9]1[CH:8]=[C:7]([CH:5]([O:28][CH2:29][C:30]2([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (600 mg, 1.27 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.41 g, 1.40 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 8 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (40 μL, 0.26 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate, and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), 1M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (18% ethyl acetate/hexanes) gave 380 mg (50%) as a yellow film. 1H-NMR (CDCl3, 300 MHz) δ 7.96 (s, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.28-7.35 (m, 4H), 7.17-7.23 (m, 1H), 6.86 (m, 1H), 5.62 (s, 2H), 4.93 (q, J=6.2 Hz, 1H), 3.72 (m, 2H), 3.55-3.60 (m, 2H), 3.38 (d, J=9.2 Hz, 1H), 3.34 (d, J=8.8 Hz, 1H), 2.97-3.08 (m, 2H), 2.10-2.21 (m, 2H), 1.91-1.97 (m, 2H), 1.42 (d, J=6.2 Hz, 3H), 1.41 (s, 9H), 0.82-0.87 (m, 2H), 0.08 (s, 9H). Mass spec.: 600.22 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[H-].[Na+].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].O>O1CCCC1>[C:37]([O:36][C:34]([CH2:33][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C:2]1=[O:1])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NC1CN(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)CN(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Under argon atmosphere a solution of 2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.94 g) that obtained from Referential Example 3 in anhydrous tetrahydrofuran (30 ml) was added to a suspension of 60% sodium hydride (400 mg) in anhydrous tetrahydrofuran (30 ml) at 0° C., the mixture was stirred at room temperature for one hour. Tert-butyl bromoacetate (1.46 g) in anhydrous tetrahydrofuran (15 ml) to this solution, the resultant mixture was stirred at room temperature for one hour. Water (300 ml) was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added for trituration to the residue, filtered, to thereby obtain 1.74 g of the titled compound (Yield: 69.4%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](=[NH:21])[NH2:20])[CH:16]=2)[CH2:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C[O-].[Na+]>CO>[CH2:2]([CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[N:20]=[CH:11][C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:18][N:21]=3)[CH:16]=2)[CH2:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC1Cc2ccc(C(=N)N)cc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCc1cnc(-c2ccc3c(c2)CC(CCCCCCCC)C3)nc1
Yield: 104.6 %

Procedure:
0.80 g (2.59 mM) of 2-octyl-5-amidinoindan hydrochloride, 0.30 g (5.55 mM) of sodium methylate, 0.62 g (2.73 mM) of α-octyloxy-β-dimethylaminoacrolein and 12 ml of methanol were placed in a 30 ml-round bottomed flask, followed by refluxing for 18 hours and 20 minutes under stirring. After the reaction, the reaction mixture was cooled on an ice water bath to precipitate a crystal. The crystal was recovered by filtration and purified by silica gel column chromatography (eluent: toluene), followed by recrystallization from a mixture solvent (acetone/methanol) to obtain 0.57 g of 2-octyl-5-(5-octylpyrimidine-2-yl) indan (Yield: 50.4%). ##STR133##
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[Li]CCCC.I[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O1CCCC1.[Cl-].[Cl-].[Zn+2]>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:15][CH:16]=1)#[N:19]
Reactant: C#CC(=O)OCC
Reactant: N#Cc1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(C#N)cc1
Temperature: -12.5 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a stirred solution of ethyl prop-2-ynoate (5.98 g, 60.96 mmol, 1.00 equiv) in anhydrous tetrahydrofuran (60 mL) maintained under nitrogen at −65° C. was added dropwise a 2.5M solution of n-BuLi (28 mL, 1.50 equiv) in hexanes. The reaction mixture was stirred at −65-40° C. for 1 h then a 0.7M solution of ZnCl2 (170 mL, 2.00 equiv) in THF was added. The resulting solution was stirred at room temperature for 30 min. 4-iodobenzonitrile (6.87 g, 30.00 mmol, 0.50 equiv) was then added in portions followed by the addition of Pd(PPh3)Cl2 (1.05 g, 1.00 equiv). The resulting mixture was stirred at 50° C. for 5 h and then quenched by the addition of 150 mL of saturated NH4Cl solution. The mixture was extracted with 3×100 mL of ether. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of methanol in dichloromethane to give 3.25 g (27%) of ethyl 3-(4-cyanophenyl)propiolate as a white solid.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:9]=[O:10].[OH-].[K+]>O>[OH:10][CH2:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: C=O
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cc(CO)c(=O)[nH]1
Temperature: 50 °C
Yield: 81 %

Procedure:
A mixture of uracil (9 g, 80.3 mmol), paraformaldehyde (3 g) and 0.42N potassium hydroxide (125 mL) was heated 90 hours at 50° C. The reaction mixture was diluted with water (350 mL), stirred with Dowex® 50 ion-exchange resin (30 g, H form, 100-200 mesh), filtered, concentrated in vacuo to a volume of 20 mL and refrigerated. The solids were collected and recrystallized from water (50 mL) to give 5-hydroxymethyl-2,4(1H,3H)-pyrimidinedione (9.5 g, 65.04 mmol), m.p. 260°-300° C. (dec).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]([NH2:25])=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[C:24]([N:25]3[CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][CH2:3]3)=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: CN(CCCl)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2c[nH]nc2C(=O)Nc2ccc(F)cc2)CC1
Temperature: 200 °C
Yield: 19.8 %

Procedure:
Bis(2-chloroethyl)methylamine hydrochloride (97 mg; 0.5 mmol) was added to a stirred solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (100 mg; 0.45 mmol), tetrabutylammonium iodide (20 mg; 0.045 mmol) and diisopropyethylamine (200 ul) 1.13 mmol) in DMF (5 ml), and the resulting mixture was heated at 200° C. (100 W) for 30 minutes in a CEM Discover™ microwave synthesiser. The DMF was removed under vacuum, then purified by flash column chromatography, eluting with dichloromethane/methanol/acetic acid/water (90:18:3:2). Product containing fractions were combined and evaporated, treated with HCl in ethyl acetate and then re-evaporated with toluene (2×20 ml) to give an off white solid (27 mg). (LC/MS: Rt 1.64, [M+H]+ 378).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]1([C:23]#[C:24][C:25](OCC)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:26]=[C:25]1[CH:24]=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]2[C:2]([S:3][C:4]3[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=32)=[N:1]1
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CCOC(=O)Cc1ccc2nc(N)sc2c1
Product: CCOC(=O)Cc1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Temperature: 200 °C
Yield: 25.8 %

Procedure:
A stirred mixture of 5 g of ethyl 2-aminobenzothiazole-6-acetate and 6 g of ethyl phenylpropiolate was heated at 200° C. in an oil bath for 1 hour and the crude mixture was then purified on a column of 200 g of silica using CHCl3 as eluant. The product obtained was highly colored and was crystallized from CHCl3 and crystallized from ethanol to obtain 1.99 g (26% yield) of ethyl 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate as orange plates.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[N:3]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:28][CH2:29]3)[N:3]=[C:4]([CH:16]([CH3:18])[CH3:17])[N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CC(C)c1nc(Cl)cc(-c2ccc(F)c(Cl)c2)n1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1

Procedure:
Dissolve 4-chloro-6-(3-chloro-4-fluorophenyl)-2-isopropyl-pyrimidine (56 mg, 0.2 mmoles) and 1-(3-(trifluoromethyl)-pyridin-2-yl)piperazine (46 mg, 0.2 mmoles) in DMA (1.5 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (55 mg, 0.4 mmoles) to this mixture and heat at 120° C. for 18 hours. Cool, dilute with water (5 mL), extract with EtOAc (3×2 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product and purify by flash column chromatography using 7% EtOAc/hexane to afford the title product as colorless viscous oil. NMR (CDCl3) δ 1.33 (6H, d, J=1.8), 3.05 (1H, m), 3.40 (4H, m), 3.87 (4H, m), 6.68 (1H, s), 7.03 (1H, m), 7.19 (1H, t), 7.89 (2H, m), 8.07 (1H, d, J=2.3), 8.45 (1H, m). Mass spec m/z=480.22.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(=O)NC(C)C)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 86.4 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 82 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid and 36 mg of isopropylamine. Thus, 78 mg (86%) of the title compound was obtained as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:23]([OH:25])=O)[C:14]3[CH:15]=[N:16][N:17]([CH:20]([CH3:22])[CH3:21])[C:18]=3[CH:19]=2)[CH2:7][CH2:6]1)[CH3:3].[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36]>>[CH3:1][N:2]([CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[C:13]([C:23]([NH:26][CH2:27][C:28]3[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=3[CH2:34][CH2:35][CH3:36])=[O:25])[C:14]3[CH:15]=[N:16][N:17]([CH:20]([CH3:22])[CH3:21])[C:18]=3[CH:19]=2)[CH2:9][CH2:10]1)[CH3:3]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(N3CCC(CN(C)C)CC3)cc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(N2CCC(CN(C)C)CC2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared using the procedure described for example 37 (step c) from 6-(4-((dimethylamino)methyl)piperidin-1-yl)-1-isopropyl-1H-indazole-4-carboxylic acid and 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.33 Hz, 3H), 1.14-1.32 (m, 2H), 1.42 (m, 6H), 1.45-1.55 (m, 2H), 1.57-1.68 (m, 1H), 1.72-1.89 (m, 3H), 2.03-2.21 (m, 12H), 2.63-2.79 (m, 2H), 3.54-3.66 (m, 1H), 3.81 (m, 2H), 4.37 (d, J=4.80 Hz, 2H), 4.94 (quin, J=6.63 Hz, 1H), 5.91 (s, 1H), 7.05 (s, 1H), 7.32 (d, J=1.77 Hz, 1H), 8.14 (s, 1H), 8.44 (t, J=5.05 Hz, 2H) 11.24-11.80 (m, 1H); LCMS: (M+H)+=507.1
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>CN(C)C=O>[C:6]([NH:5][CH2:4][CH2:3][NH:2][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(=O)CC(=O)NCCN
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCNC(=O)CC(C)=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
Crude N-(2-aminoethyl)acetoacetamide hydrobromide (50 g, 0.18 mole) was dissolved in N,N-dimethylformamide (500 ml). Triethylamine (78 g, 0.4 mole) and methacryloyl chloride (19 g, 0.18 mole) were added simultaneously at 0° C. The reaction solution was then stirred at 0° C. for 1 hour and at 20° C. for 20 hours. The resulting solution was filtered, the solvent removed, and the residue dissolved in chloroform (500 ml). The solution was then washed with 10% hydrochloric acid (200 ml), then water (200 ml) and dried over anhydrous magnesium sulfate. The solvent was then removed. The residue was recrystallized from ethanol/ether (1:1). The resulting compound had a m.p. of 86°-90° C. The yield was 25%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[O:6].[CH3:31][NH2:32].C1COCC1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:32][CH3:31])=[O:25])[N:21]=1)=[O:6]
Reactant: CN
Reactant: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Solvent: C1CCOC1
Product: CNC(=O)Cc1csc(NC(=O)Nc2cc(C)ccc2C(=O)c2ccccc2OC)n1
Yield: 75 %

Procedure:
2-(2-{3-[2-(2-Methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-N-methyl-acetamide (164 mg, 75%) was prepared from (2-{3-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-acetic acid (213 mg, 0.5 mmol) and 1 N solution of methylamine in THF (0.5 mL, 0.5 mmol) following the general procedure K.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:35])[NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:35])[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:7]3[N:8]([CH3:11])[C:9]4[C:5]([C:6]=3[C:20]#[N:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:17]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CN3CCC(NC(=O)OC(C)(C)C)CC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and piperidin-4-yl-carbamic acid tert-butyl ester are processed according to the method described in Example 170 to give {1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester. MS (ESI) m/z 480.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([C:19]3[NH:20][C:21]([CH3:25])=[C:22]([Cl:24])[CH:23]=3)=[O:18])[C@H:12]([O:26][CH3:27])[CH2:11]2)=[N:7][C:6]=1[C:28]([NH:30]C(C)(C1C=CC=CC=1)C)=[O:29])=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:30][C:28]([C:6]1[N:7]=[C:8]([N:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([C:19]3[NH:20][C:21]([CH3:25])=[C:22]([Cl:24])[CH:23]=3)=[O:18])[C@H:12]([O:26][CH3:27])[CH2:11]2)[S:9][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:29]
Reactant: COC(=O)c1sc(N2CC[C@H](NC(=O)c3cc(Cl)c(C)[nH]3)[C@H](OC)C2)nc1C(=O)NC(C)(C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(N2CC[C@H](NC(=O)c3cc(Cl)c(C)[nH]3)[C@H](OC)C2)nc1C(N)=O
Temperature: 85 °C

Procedure:
Cis(±)methyl-2-(4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-1,3-thiazole-5-carboxylate (Example 21; 0.058 g, 0.1 mmol) was dissolved in equal volumes of TFA and DCM. The reaction was heated in a sealed tube to an external temperature of 85° C. overnight. The reaction mixture was concentrated to remove the DCM and excess TFA. The residue was partitioned with EtOAc and NaHCO3 and the organic extracts were dried with MgSO4 and concentrated to a yellow solid (0.050 g, 100%). MS (ES) MH+: 456 for C18H22ClN5O5S.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:13][O:14]C(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(C)oc12
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c2cc(C)oc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 30.2 %

Procedure:
To a well stirred solution of 7-methoxy-2-methylbenzo[b]furan (from step 2) (6.5 g, 40.07 mmol) in DCM (70.0 mL) was added stannous chloride (17.7 g, 68.26 mmol) followed by slow addition of 1,1-dichloromethyl methyl ether (4.6 g, 40.07 mmol) at −10-0° C. and stirred for 1-2 hrs. Ice cold water (100 mL) was added with vigorous stirring, the organic layer was separated and washed with water (2×50 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (7.0 g). The crude product was purified by silica gel column using petroleum ether: ethyl acetate (9:1) as an eluent to afford the product as pale yellow oil (2.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1.Cl.C(OCC)(=O)C>CC(C)=O>[Br:20][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:12]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Oc1ccc2cc(Br)ccc2c1Br

Procedure:
6-Bromo-2-naphthol (500 mg, 2.242 mmol, 1 eq) and NBS (558.7 mg, 3.319 mmol, 1.4 eq) are stirred at RT in 4.4 ml of acetone and 22 μl of 1 N HCl for 15 min. Ethyl acetate is added, and this organic phase is washed three times with 1 N HCl. After drying over magnesium sulfate, filtering and concentrating in vacuum on a rotary evaporator, the desired product is obtained in quantitative yield (677 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13](Cl)(=[O:15])=[O:14].CN.[CH2:19]([N:21](CC)CC)C>O1CCCC1.C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH:21][CH3:19])(=[O:15])=[O:14]
Reactant: CCN(CC)CC
Reactant: Nc1cc(Cl)c(S(=O)(=O)Cl)cc1S(=O)(=O)Cl
Agent: CN
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(S(=O)(=O)Cl)c(Cl)cc1N
Reaction time: 0.75 h

Procedure:
Cool a solution of 4-amino-6-chloro-1,3-benzenedisulfonyl chloride (32.3 g) in tetrahydrofuran (THF, 150 ml) to -78° C. under a nitrogen atmosphere. Add a solution of 1.45 Molar methylamine in benzene (100 ml) containing triethylamine (10.1 g) dropwise with stirring over 45 minutes. After the addition is complete, stir at room temperature for 3 hours. Vacuum evaporate the solvent and partition the residue between ethyl acetate (EtOAc) (500 ml) and 10% aqueous citric acid (50 ml). Separate the organic layer and wash with saturated aqueous NaHCO3 (100 ml) followed by brine (100 ml). Dry the solution over Na2SO4, filter and vacuum evaporate the solvent. Triturate the residue with ether (100 ml) and collect the product by filtration. Vacuum dry at room temperature to give the title compound, m.p. 153°-155° C. Rf (silica gel; CH2Cl2 :EtOAc,97:3)=0.40.
Reaction SMILES: [N:1]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14](O)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH2:27][C@H:28]([C:37]([NH:39][CH2:40][C:41]([O:43][C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45])=[O:42])=[O:38])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33]C=1.C1(N=C=NC2CCCCC2)CCCCC1>>[N:1]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:27][C@H:28]([C:37]([NH:39][CH2:40][C:41]([O:43][C:44]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:45])=[O:42])=[O:38])[CH2:29][C:30]1[CH:31]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](CCc1ccccc1)C(=O)NCC(=O)OC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OC(=O)c1ccccc1
Yield: 66 %

Procedure:
Condensation of BocPro-PheOH (3.12 g.) and HPhe-Gly-OBz (3.50 g.) using dicyclohexylcarbodiimide and N-hydroxynorbornenedicarboximide gave BocPro-Phe-Phe-GlyOBz in 66% yield. Debenzylation of BocPro-Phe-Phe-GlyOBz (3.70 g.) by hydrogenation with palladium catalyst gave BocPro-Phe-Phe-GlyOH in 100% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:3][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of piperidin-4-one hydrochloride (1567 g, 11.56 mol) and triethylamine (1400 g, 13.87 mol) in dichloromethane (12 L) was added benzyl chloroformate (1965 g, 11.55 mol) dropwise at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC (EtOAc/petroleum ether=1:5) showed the reaction was complete. The mixture was washed with water (3 L) and brine (1 L), dried over sodium sulfate and concentrated to afford benzyl 4-oxopiperidine-1-carboxylate as a colorless oil.