Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3](Cl)[CH2:4]Cl.[OH:7][CH:8]1[CH:12]([OH:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[O:7]1[CH:8]2[CH2:9][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:11][CH:12]2[O:13][CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC(O)C(O)C1
Reactant: ClCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CC2OCCOC2C1
Temperature: 55 °C
Yield: 39 %

Procedure:
A mixture of NaOH aqueous solution (35 w/w %, 21 mL, aq.), ClCH2CH2Cl (21 mL), benzyl 3,4-dihydroxypyrrolidine-1-carboxylate (1.16 g, 4.9 mmol, 1.0 eq) and TBAB (0.31 g, 0.98 mmol, 0.2 eq) was heated at 55° C. for 48 h in a round-bottom flask. The reaction mixture was cooled to room temperature and poured into water (50 mL), extracted with EtOAc (50 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified with a silica gel column chromatography (1:1 (v/v) PE/EtOAc) to give the product as colorless oil (0.50 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[CH:7](C(OC)=O)[N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Mg+2].[Cl-].[Cl-].N#N.[CH3:28][CH:29]([N:31]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:32]1=[O:44])[CH3:30].[NH4+].[Cl-]>CN1C(=O)CCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:41]3[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][N:31]([CH:29]([CH3:28])[CH3:30])[C:32]4=[O:44])[CH2:39][CH2:40]3)=[CH:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1C(=O)c2ccc(Cl)cc2N1c1ccc(F)cc1
Reactant: CC(C)N1CCN(CCN2CCNCC2)C1=O
Agent: N#N
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(CCN2CCN(c3cn(-c4ccc(F)cc4)c4cc(Cl)ccc34)CC2)C1=O
Temperature: 130 °C
Yield: 50.2 %

Procedure:
To 6-chloro-2-methoxycarbonyl-1-(4-fluorophenyl)-3-indolinon (7.5 g) in NMP (75 ml) was added MgCl2, 6H2O (9 g). The mixture was heated at 130° C. under N2 for one hour and finally the temperature was raised to 190° C. while H2O vapours were carried away by a gentle stream of N2. 1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-piperazine (12 g) in NMP (30 ml) were added and the temperature kept at 190°-200° C. for another hour. After cooling to room temperature the reaction mixture was poured into ethyl acetate (200 ml) and a saturated NH4Cl solution (500 ml) added. The organic phase was separated, dried (anh. MgSO4), filtered and the solvent evaporated. The remaining oil was purified by column chromatography on silica gel (eluent ethyl acetate/ethanol/triethylamine 90/10/4) yielding 5.7 g of pure title compound 6a. Mp: 176° -177° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11]1.C1COCC1.O.[Li+].[OH-]>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]1
Reactant: COC(=O)C1(c2nc3ccccc3o2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C1(c2nc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred solution of methyl 1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylate (0.132 g, 0.6077 mmol) in 3 mL 3:2 THF:H2O at room temperature under nitrogen was added LiOH (0.02911 g, 1.215 mmol). After stirring at ambient temperature overnight the reaction was diluted to 30 mL with ethyl acetate and washed with 2N HCl, water and brine. The organics were dried (MgSO4), filtered and concentrated to a white solid (100 mg, 81% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C2C(COC([N:32]=[C:33]=[S:34])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:33](=[S:34])[NH2:32])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC1CCNCC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CC1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of piperidin-4-ylacetic acid tert-butyl ester (10.72 g, 50.0 mmol) in chloroform (100 ml) was added to a solution of 9-fluorenylmethoxycarbonyl isothiocyanate (14.07 g, 50.0 mmol) in chloroform (100 ml) and the mixture was stirred at room temperature for 1 hour. Then, piperidine (80 ml) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, water was added, and it was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over magnesium sulfate and the residue obtained by vacuum concentration was washed with isopropyl ether and the title compound was obtained (11.35 g, 98%).
Reaction SMILES: C(OC(N1C[CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[C:33]([O:37][C:38]([N:40]1CCNC[C:41]1(C)C)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH2:13][N:12]([CH2:16][C:17]2[S:18][C:19]3[C:24]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[N:23][C:22]([Cl:31])=[N:21][C:20]=3[N:32]=2)[CH2:11][C:10]1([CH3:14])[CH3:9])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1(C)C

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (100 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:10]2[N:9]=[C:8]([C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH3:7])[CH:13]=[CH:12][N:11]=2)=[CH:16][CH:17]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(N)cc3)n2)s1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1

Procedure:
By treatment of [4-(2,4-dimethylthiazol-5-yl)-pyrimidin-2-yl]-(4-aminophenyl)-amine with chloroacetyl chloride. Mp. 217-219° C. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 4.22 (s, 2H, CH2), 7.05 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.50 (d, 2H, J=8.8 Hz, Ph-H), 7.70 (d, 2H, J=8.8 Hz, Ph-H), 8.49 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 9.65 (s, 1H, NH), 10.20 (s, 1H, NH). MS (ESI+) m/z 374.47 [M+H]+ (C17H16ClN5OS requires 373.86).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:8][N:7](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6]1)=[O:4].[ClH:22]>CO.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[ClH:22].[CH3:1][NH:2][C:3]([CH:5]1[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [C+4]
Solvent: CO
Product: CNC(=O)C1CNC1
Reaction time: 5 h

Procedure:
To a solution of crude 1-benzhydrylazetidine-3-carboxylic acid methylamide (2.72 g) in methanol (200 ml) were added hydrochloric acid (3.0 ml) and 20% palladium hydroxide carbon (1.0 g), followed by stirring under hydrogen atmosphere (0.40 MPa) for 5 hours. The reaction mixture was filtered to remove the catalyst, which was washed with methanol, and the filtrate was concentrated. To the resultant residue was added hexane, allowed to stand for a while, the supernatant was removed using a pipette. The remain was evaporated to provide a crude product of azetidine-3-carboxylic acid methylamide hydrochloride (ESI-MS (m/z): 115[M+H]+). To the crude product was added water (20 ml), followed by stirring in an ice water bath, and to the reaction mixture were added tetrahydrofuran (10 ml), di-tert-butyl dicarbonate (2.34 g) and sodium hydrogencarbonate (2.25 g), followed by stirring at room temperature for 12.5 hours. The reaction mixture was partitioned between ethyl acetate (200 ml) and brine (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol=10:1 to 5:1) to provide the titled compound (696 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:16].[K+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([NH2:15])=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Agent: [K+]
Solvent: CC(C)O
Product: NC(=O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 82 °C

Procedure:
Propan-2-ol (100 ml), tetrahydro-4-(3-bromophenyl)-2H-pyran-4-nitrile (20.0 g, 0.075 mole, 1 eq.), potassium hydroxide (13.74 g, 0.245 mole, 3.26 eq.) were added to a reaction flask set for boiling at reflux under a nitrogen atmosphere, and the reaction mixture was heated with stirring at reflux, about 82° C. for 5-6 hours under nitrogen. After reaction completion, the mixture was cooled (<30° C.) and quenched with water (100 ml). The resultant slurry was filtered and the product residue, washed with water (30 ml), and dried under vacuum at 45-50° C. to yield a white solid. Yield 19.05 g, 89.2%. mp 245-247° C.; m/z 285 (m+1); 1H NMR (300 MHz, DMSO) δ7.43 (m, 5H), 7.14 (s, 1H), 3.76 (d, 2H), 3.47 (t, 2H), 2.44 (d, 2H), 1.79 (m, 2H).; IR (drifts) vmax 3363, 3174, 3062, 2973, 2935, 2879, 2828, 1685, 1631, 1588.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]1[CH2:16][O:15][CH2:14][CH2:13][NH:12][CH2:11]1.Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[CH2:11][CH2:10][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C1CNCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1ccc(CN2CCCOCC2)cc1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 4-bromobenzaldehyde (616 mg, 3.3 mmol) in dichloroethane (50 mL) was added homomorpholine hydrochloride (548 mg, 4 mmol) and acetic acid (0.1 mL). Sodium triacetoxyborohydride (3.4 g, 16 mmol) was added and the reaction was stirred overnight. The reaction was quenched with sat. NH4Cl (30 mL). Ethyl acetate (250 mL) was added and the solution was washed with sat. NaHCO3 (2×50 mL), brine (50 mL), dried over MgSO4 and concentrated to dryness. The residue was flushed through a silica plug with (5% MeOH/CH2Cl2) to give a white solid (850 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=7.3 Hz, 2H), 7.10 (d, J=7.3 Hz, 2H), 3.66-3.57 (m, 2H), 3.55-3.50 (m, 2H), 3.46-3.42 (m, 2H), 3.16-3.10 (m, 2H), 2.55-2.45 (m, 4H), 1.75-1.65 (m, 2H).
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[C:8](C)[C:9]3[NH:15][C:14]4[CH:16]=[CH:17][N:18]=[CH:19][C:13]=4[C:10]=3[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[I-].[Na+].C[Si](Cl)(C)C.C[Si](C)(C)N[Si](C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:48]([N:50]([CH2:53][CH2:54][CH2:55][NH2:56])[CH2:51][CH3:52])[CH3:49]>C(#N)C>[CH2:48]([N:50]([CH2:51][CH3:52])[CH2:53][CH2:54][CH2:55][NH:56][C:3]1[C:12]2[C:7](=[CH:8][C:9]3[NH:15][C:14]4[CH:16]=[CH:17][N:18]=[CH:19][C:13]=4[C:10]=3[CH:11]=2)[CH:6]=[CH:5][N:4]=1)[CH3:49]
Reactant: COc1nccc2c(C)c3[nH]c4ccncc4c3cc12
Reactant: CCN(CC)CCCN
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CCN(CC)CCCNc1nccc2cc3[nH]c4ccncc4c3cc12
Reaction time: 1 h

Procedure:
0.87 g (0.0033 mole) of 10-methoxy 6-methyl 5H-pyrido[3',4':4,5]pyrrolo[2,3-g]isoquinoline and 0.495 g (0.003 mole) of sodium iodide are suspended in 25 ml of acetonitrile and 4.2 ml (0.33 mole) of trimethylsilylchloride, and then heated at 40° C. for 17 hours. 10.5 ml (0.050 mole) of hexamethyldisilazane, 0.113 g (6×10-4 mole) of anhydrous p-toluenesulfonic acid and 22.4 ml (0.14 mole) of diethylaminopropylamine are then added. After distillation of the acetonitrile, the mixture is heated at reflux for 20 hours. It is evaporated to dryness under a partial vacuum and the residue is stirred with 20 ml of water and 5 ml of diisopropyl ether for 1 hour. The precipitate obtained is filtered off and dried under vacuum at 50° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][CH:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=4)[CH2:16][CH:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][CH:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[N:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:16][CH:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(OCC2CCC3CN(c4ccc(Cl)nn4)CCN3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1ccc(OCC2CCC3CN(c4cccnn4)CCN3C2)cc1

Procedure:
A mixture of 0.150 g (0.363 mmol) of (7RS,9aSR)-7-(4-fluorophenoxy)methyl-2-(6-chloropyridazin-3-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 32). 0.10 mL (0.72 mmol) of triethylamine, and 20 mg of 10% Pd/C in 10 mL of ethanol were shaken under 50 psi of hydrogen for 18 h. The mixture was filtered through Celite and the filtrate was evaporated. The residue was dissolved in chloroform, washed with water, dried (magenesium sulfate), filtered and evaporated. mp (.HCl) 246–250° C. HRMS calcd for C19H23FN4O: 342.1851, found: 342.1826.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cccn2nc(N)nc12

Procedure:
8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 0.0047 mol) and 2-methoxybenzeneboronic acid (1.1 g, 0.0070 mol) in a manner analogous to Step 2c. The reacting product was isolated as a brown solid (1.0 g) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.50 (d, J=6.5 Hz, 1H), 7.51 (dd, J=7.6, 1.5 Hz, 1H), 7.43-7.36 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.91 (t, J=7.0 Hz, 1H), 5.96 (br s, 2H), 3.73 (s, 3H). MS=241 (MH)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[C:18]([C:20](=[O:37])[NH:21][C@H:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:23]([C:25]([O:27]CC)=[O:26])[OH:24])[CH:17]=[CH:16][C:15]=2[F:38])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C1COCC1.[OH-].[Na+]>CCOC(C)=O>[CH2:30]([C@@H:22]([NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:38])=[C:14]([C:9]2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=1)=[O:37])[C@H:23]([C:25]([OH:27])=[O:26])[OH:24])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(-c2ccccc2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O)c1ccc(F)c(-c2ccccc2C(=O)O)c1
Reaction time: 1 h
Yield: 15.1 %

Procedure:
5′-((1R,2R)-1-Benzyl-2-ethoxycarbonyl-2-hydroxy-ethylcarbamoyl)-2′-fluoro-biphenyl-2-carboxylic acid t-butyl ester (100 mg, 192 μmol, 1.0 eq.) was combined with 1:1 TFA/DCM (1 mL each) and stirred for 1 hour. The solvents were evaporated and THF (3 mL) and 1 M aqueous NaOH (577 μL, 3.0 eq.) were added. The mixture was stirred for 2 hours and EtOAc was added. The aqueous was extracted out and the organic was washed with NaOH (0.2 mL), stirred and the aqueous extracted. The aqueous was acidified to pH ˜5 with concentrated HCl yielding a gummy solid, which was dissolved in AcOH and purified by preparative HPLC to yield the title compound (12.7 mg, 99% purity). MS m/z [M+H]+ calc'd for C24H20FNO6, 438.13. found 438.
Reaction SMILES: C(S)C.[H-].[Na+].[C:6]1([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22]C)=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]=2[C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>CN(C)C=O>[C:6]1([C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]=2[C:24](=[O:33])[C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccc(OC)cc3CC2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C(C1=C(c2ccccc2)c2ccc(O)cc2CC1)c1ccc(O)cc1
Temperature: 60 °C
Yield: 77.9 %

Procedure:
To a cold 300 mL of dimethylformamide and under a nitrogen atmosphere was added 9.3 g of ethylmercaptan. To this mixture was added 7.2 g of 50% sodium hydride (150 mmol) in oil. To this mixture was added 11.1 g (30 mmol) of 1-phenyl-2-(4-methoxybenzoyl)-3,4-dihydro-6-methoxynaphthalene and the reaction mixture was heated to 60° C. for two hours. The reaction was acidified with the addition of 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water and evaporated to dryness. The final product was crystallized from a mixture of methanol-acetone to yield 8 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 37.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (195 mg, yield: 37.8%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH:2]=[N:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][C:11]=1[CH3:16])[CH3:7]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Nc1ccc(F)cc1C

Procedure:
A solution of ethyl glyoxalate (50% solution in toluene-40.8 mL) in toluene (180 mL) was heated to reflux for 1.5 hours under a Nitrogen atmosphere, in a flask equipped with a Dean Stark apparatus. Then, a solution of 4-fluoro-2-methyl-aniline (10 g) in dry toluene (20 mL) was slowly added. The mixture was heated to reflux for 3 hours, then it was concentrated in vacuo. The residue was purified by flash chromatography (toluene/CH/AcOEt 4:4:2) to give the title compound (13.06 g) as a yellow oil.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[N:15][CH:16]=2)[CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].C[O:19][C:20](=O)[C:21]#[CH:22]>CO>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:9]2[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:22]=[CH:21][C:20](=[O:19])[N:6]3[CH2:7][CH2:8]2)=[CH:16][N:15]=1
Reactant: C#CC(=O)OC
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Solvent: CO
Product: O=c1ccc([N+](=O)[O-])c2n1CCN2Cc1ccc(Cl)nc1
Yield: 52.3 %

Procedure:
A mixed solution of 2-nitromethylene-3-(2-chloro-5-pyridylmethyl)-imidazolidine (12.7 g), propiolic acid methyl ester (4.2 g) and methanol (100 ml) was refluxed under heating for about 20 hours. Subsequently methanol was distilled off under reduced pressure, and the residue was refined by a silica-gel column chromatography to give the desired 1,2,3,5-tetrahydro-1-(2-chloro-5-pyridylmethyl)-8-nitroimidazo[1,2-a]pyridin-5-one (8 g).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2=[CH:18][N:19]=[C:20]([C:22](O)=[O:23])[CH:21]=[C:16]2[CH:15]=[CH:14]1.N.Cl>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[CH:21]=[C:16]4[CH:15]=[CH:14][S:13][C:17]4=[CH:18][N:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2ccsc2cn1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccsc2cn1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[2,3-c]pyridine-5-carboxylic acid (Tetrahedron Lett. 1999, 40, 7935) according to methods A and C; yield 73 mg, 0.18 mmol (51%): 1H NMR (300 MHz, methanol-d4) δ 2.12-2.33 (m, 5H), 2.55 (s, 2H), 3.53 (d, J=12 Hz, 2H), 3.59 (s, 2H), 3.99 (d, J=13 Hz, 2H), 4.40 (s, 1H), 7.94 (d, J=5 Hz, 1H), 8.65 (d, J=5 Hz, 1H), 9.15 (s, 1H), 9.59 (s, 1H); MS (DCI/NH3) m/z 296 (M+H)+; Anal. C17H19N3OS.2.HCl.0.6H2O: C, H, N.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH2:21].C(N(CC)CC)C>C(O)(C)C>[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][C@@H:15]2[NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: NC1CC2CCC1C2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC2CCC1C2
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.064 g, 0.30 mmol) (Example 1, Step 2), bicyclo[2.2.1]heptan-2-amine (from Aldrich, 0.050 g, 0.45 mmol) and triethylamine (0.083 mL, 0.60 mmol) in isopropyl alcohol (1.4 mL) was heated at 90° C. for 2 h. The mixture was concentrated to give the desired product, which was used in the next step without further purification. LCMS calculated for C14H16N3O2S (M+H)+: m/z=290.1. Found: 290.0.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[CH3:21])=[O:14])[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].CCN(C(C)C)C(C)C.[CH2:31]([C:33]1[C:38]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][C:40]2=[O:45])=[CH:37][CH:36]=[CH:35][C:34]=1[S:46](Cl)(=[O:48])=[O:47])[CH3:32]>C(Cl)Cl>[CH2:31]([C:33]1[C:38]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][C:40]2=[O:45])=[CH:37][CH:36]=[CH:35][C:34]=1[S:46]([NH:1][C@H:2]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[CH3:21])=[O:14])[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6])(=[O:47])=[O:48])[CH3:32]
Reactant: C[C@H]1COCCN1C(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Reactant: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCOC[C@@H]1C
Reaction time: 1.25 h

Procedure:
5-Chloro-thiophene-2-carboxylic acid [(S)-2-amino-3-((S)-3-methyl-morpholin-4-yl)-3-oxo-propyl]-amide, Intermediate 3 (95 mg, 0.287 mmol) was dissolved in 2 ml DCM and DIPEA (151 μl, 0.861 mmol). 2-ethyl-3-(3-oxo-morpholin-4-yl)-benzenesulfonyl chloride, Intermediate 7 (91 mg, 0.3 mmol) in 2 ml DCM was slowly added and the reaction was stirred for 75 min. After that the solution was evaporated to dryness and purified by prep. HPLC. After lyophilization the title compound was obtained as colorless, amorphous solid. Yield: 108 mg, 63%