Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[C:15]([CH3:27])([CH3:26])[CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:35]([N:37]([CH2:42][CH3:43])[S:38](Cl)(=[O:40])=[O:39])[CH3:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:38](=[O:40])(=[O:39])[N:37]([CH2:42][CH3:43])[CH2:35][CH3:36])[CH:20]=4)[C:15]([CH3:27])([CH3:26])[CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(=O)(=O)Cl
Reactant: CC1(C)CN=C(C2(c3ccc(Cl)cc3)CCC2)c2cc(OCCN)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2(C)C
Temperature: 2.5 °C

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-4,4-dimethyl-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine (145 mg, 0.38 mmol, cf. example 67) was dissolved in dry dichloromethane (8 mL). Triethylamine (60 μL, 0.45 mmol). The solution was cooled to 0-5° C. and diethylsulfamoyl chloride (71.5 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with dichloromethane (20 mL) and washed with a 1:1 mixture of water and saturated ammonium chloride solution (20 mL). The organic layer was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane then dichloromethane:ethyl acetate=180:5). Yield: 96 mg (0.19 mmol, 48.9%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:26]=[CH:25][C:14]3[N:15]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[N:37]([CH:40]([CH3:42])[CH3:41])=[C:38]=[O:39]>CN1C(=O)CCC1>[CH:40]([NH:37][C:38]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:27])[CH:9]=4)[CH:26]=[CH:25][C:14]=3[N:15]=2)[CH2:20]1)=[O:39])([CH3:42])[CH3:41]
Reactant: CC(C)N=C=O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)NC(C)C)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and DIPEA (17 μL, 100 μmol) in 300 μL of NMP was added 2-isocyanatopropane (5 μL, 50 μmol). The reaction solution was stirred at room temperature for 18 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-4-(2-(1-(isopropylcarbamoyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (5.9 mg, 12 μmol as white powder. ES/MS m/z 469.2 (MH+).
Reaction SMILES: [C:1]([C:11]1[N:15]([CH3:16])[C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[C:1]([C:11]1[N:15]([CH3:16])[C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1

Procedure:
A solution of 3.00 g. (0.0105 mole) of methyl 5-(p-anisoyl)-1-methylpyrrole-2-acetate in 12 ml. (0.012 mole) of 1N sodium hydroxide solution and 5 ml. of 95% ethanol is refluxed for 30 minutes. The solution is diluted with water, and the ethanol is evaporated in vacuo. The solution is filtered, and the filtrate acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration, dried and recrystallized from methanol-water to give white 5-(p-anisoyl)-1-methylpyrrole-2-acetic acid, m.p. 170-171° C. Analysis: Calcd. for C15H15NO4 : C, 65.92; H, 5.53; N, 5.13%. Found: C, 66.01; H, 5.62; N, 5.12%
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][N:27]([CH2:29][C:30]1[N:31]([CH3:36])[C:32]([SH:35])=[N:33][N:34]=1)[CH3:28].O.OC1N=CN=C2C=1NC(S)=N2>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:35][C:32]3[N:31]([CH3:36])[C:30]([CH2:29][N:27]([CH3:28])[CH3:26])=[N:34][N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: CN(C)Cc1nnc(S)n1C
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(CN(C)C)n3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-[(dimethylamino)methyl]-4-methyl-4H-1,2,4-triazole-3-thiol, as described in Step 1 of Example C(83), was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.50-1.69 (m, 8H) 2.02 (m, 2H) 2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.72 (d, J=18.1 Hz, 1H) 2.87 (s, 6H) 2.92 (d, J=15.0 Hz, 1H) 3.63 (s, 3H) 3.80 (s, 3H) 4.53 (s, 2H) 7.01 (d, J=8.5 Hz, 1H) 7.18 (dd, J=8.4, 2.1 Hz, 1H) 7.31 (d, J=1.9 Hz, 1H). MS (APCI) calcd for C25H33ClN4O4S: 521.08; found M=521.2.
Reaction SMILES: CN1CCOCC1.C1(C2C=CC=CC=2)C=CC(S([N:17]2[CH2:21][CH2:20][S:19][CH:18]2[C:22](O)=[O:23])(=O)=O)=CC=1.ClC(OCC(C)C)=O.[NH2:39][C@H:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:41][CH2:42][OH:43]>C1COCC1>[OH:43][CH2:42][CH2:41][C@H:40]([NH:39][C:22]([CH:18]1[NH:17][CH2:21][CH2:20][S:19]1)=[O:23])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N[C@@H](CCO)c1ccccc1
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(N[C@@H](CCO)c1ccccc1)C1NCCS1
Temperature: -25 °C
Reaction time: 0.08 h

Procedure:
N-methyl morpholine (NMM) (3.24 g, 2.5 eq, 32.15 mmol) was added to a solution of a compound of general formula (VIII) (Intermediate 8, 4.50 g, 1 eq, 12.86 mmol), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid, in dry THF (100 ml) and the reaction mixture was cooled down to −25° C. To the reaction mixture was then added drop wise, over a period of 5 minutes, isobutyl chloroformate (1.84 g, 1.05 eq, 13.50 mmol) in solution in dry THF (20 ml). The resulting mixture was stirred at −25° C. for 30 minutes, after which time an amine of general formula (IV) or (IV*) (commercial or Intermediate 2, 2.14 g, 1.1 eq, 14.15 mmol), e.g., (3S)-3-amino-3-phenyl-1-propanol, was added in dry THF (20 ml) over a period of 5 minutes. The mixture was allowed to gradually warm to room temperature and stirred overnight at room temperature. The solvent was removed and the residue re-dissolved in ethyl acetate (200 ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml). The combined organic phases were dried with magnesium sulfate and concentrated in vacuo, yielding the crude product of general formula ([), e.g., 3-(1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide, as a white solid (6.21 g, 96%). Silica gel chromatography, eluting in isocratic conditions (50% ethyl acetate in hexanes), which gave the separation of the desired two pure diastereoisomers of general formula (I), e.g., (2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (more polar compound, 3.1 g), and (2R)-3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[(1S)-3-hydroxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide (less polar compound, 3.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[K+].[CH2:14]([OH:17])[CH2:15]Br.O>CN(C)C=O>[N+:9]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][CH:14]([OH:17])[CH3:15])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)Oc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
2.5 mols (434 g) of 4-chloro-3-nitrophenol are dissolved in 1,300 ml of dimethylformamide heated to 70° C. beforehand. 3 mols of powdered potassium hydroxide (210 g of 80% pure potassium hydroxide) are added to this solution and 3 mols (534 g) of glycol bromohydrin are then introduced in the course of 30 minutes, with stirring, whilst keeping the temperature at 70° C. When the addition has ended, the reaction medium is kept at 70° C. for 1 hour. 1 mol of powdered potassium hydroxide (70 g of 80% pure potassium hydroxide) and 1 mol of glycol bromohydrin (178 g) are then added. After heating for 1 hour, a further 1 mol of potassium hydroxide and 1 mol of glycol bromohydrin are added. The heating is continued for a further 1 hour and the cooled reaction medium is then poured into 7.5 liters of iced water. The expected product precipitates. It is filtered off and washed carefully with a 3N solution of sodium hydroxide and then with water. After drying in vacuo, it melts at 96° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][CH:4]=[N:3]1.[Br:8][CH:9]([CH:12]=O)[CH:10]=O>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]2=[N:7][CH:12]=1
Reactant: O=CC(Br)C=O
Reactant: Cn1nccc1N
Solvent: CC(=O)O
Product: Cn1ncc2cc(Br)cnc21
Yield: 27.9 %

Procedure:
Dissolve 1-methyl-5-aminopyrazole (Butt Park LTD; 1.0 g, 10.3 mmol) and 2-bromomalonaldehyde (Aldrich; 1.55 g, 10.3 mmol) in glacial acetic acid (160 mL) and reflux under nitrogen for 48 h. Concentrate under reduced pressure and purify via chromatography (silica gel, 90% dichloromethane/10% diethyl ether) to obtain 610 mg (27%) of the title compound as an off-white solid. TOF MS ES+ exact mass calculated for C7H7N3Br (p+H): m/z=211.9823, Found: 211.9838.
Reaction SMILES: C([O:5]C(C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)C(O)=O)(C)(C)C.[C:29]([O:33][C@@H:34]([C:37]1[C:38]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH2:48][CH3:49])[CH:41]=[CH:40]2)[CH2:35][OH:36])([CH3:32])([CH3:31])[CH3:30].C(OC(C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)CO)(C)(C)C>>[C:29]([O:33][C@@H:34]([C:37]1[C:38]([C:50]2[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([CH2:48][CH3:49])[CH:41]=[CH:40]2)[C:35]([OH:5])=[O:36])([CH3:30])([CH3:31])[CH3:32]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Reactant: CCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Agent: Cc1ccc2c(-c3ccc(Cl)cc3)c(C(CO)OC(C)(C)C)c(Cl)cc2n1
Product: CCc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound tert-butoxy-[7-chloro-5-(4-chloro-phenyl)-2-methyl-quinolin-6-yl]-acetic acid of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)ethanol was used instead 2-tert-butoxy-2-[7-chloro-5-(4-chloro-phenyl)-2-methyl-quinolin-6-yl]ethanol. 1H-NMR 300 MHz, (CD3OD) δ 8.31 (d, 1H), 7.98 (s, 1H), 7.76 (d, 1H), 7.70-7.60 (m, 3H), 7.42-7.35 (m, 1H), 5.25 (s, 1H), 3.21 (q, 2H), 2.78 (s, 3H), 1.48 (t, 3H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C24H27ClNO3: 412.9. Found: 412.2, 414.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[CH3:9][CH:10]1[CH2:15][CH2:14][C:13]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:12][CH2:11]1
Reactant: CC1CCC(=O)CC1
Reactant: C#Cc1ccccn1
Product: CC1CC=C(C#Cc2ccccn2)CC1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), 4-methylcyclohexanone (6.0 mmol, 672 mg); yields 2-[(4-methyl-1-cyclohexe-n-1-yl)ethynyl]pyridine as a transparent oil (250 mg, 21% overall yield). 1H NMR (CDCl3, 300 MHz) Δ8.57 (m, 1H), 7.59 (m, 1H), 7.39 (m, 1H), 7.20 (m, 1H), 6.30 (m, 1H), 2.22 (m, 3H), 1.25 (m, 1H), 0.99 (m, 3H). MS (EI ionization) 197 (M+).
Reaction SMILES: BrC1C=CC(Cl)=C(S(Cl)(=O)=O)C=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:24]([F:27])([F:26])[F:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1.[CH2:28]1[O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1>>[O:37]1[C:36]2[CH:35]=[CH:34][C:32]([NH:33][S:20]([C:18]3[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=3[C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:21])=[CH:31][C:30]=2[O:29][CH2:28]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1C(F)(F)F
Agent: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Product: O=S(=O)(Nc1ccc2c(c1)OCO2)c1cc(Cl)ccc1C(F)(F)F

Procedure:
This compound is prepared analogously to Intermediate E (step 2) by replacing S-bromo-2-chloro-benzenesulfonyl chloride with 5-chloro-2-trifluoromethyl-benzenesulfonyl chloride and by replacing aniline with 3,4-(methylenedioxy)aniline to afford the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][N:13]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:12]1=[O:28].[O:29]=[C:30]1[N:39]([CH:40]2[CH2:45][CH2:44][N:43]([C:46](Cl)=[O:47])[CH2:42][CH2:41]2)[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31]1>ClCCCl>[CH:25]1([CH2:24][N:13]2[CH2:14][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:17][C@@H:11]([NH:10][C:46]([N:43]3[CH2:44][CH2:45][CH:40]([N:39]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:29])[CH2:41][CH2:42]3)=[O:47])[C:12]2=[O:28])[CH2:27][CH2:26]1
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
Diisopropylethylamine (0.16 mL, 0.90 mmol) was added to a solution of (3R,6S)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one (116 mg, 0.45 mmol) and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride (132 mg, 0.45 mmol) in 1,2-dichloroethane (10 mL) and the mixture heated to reflux. After 1 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→5% methanol/dichloromethane) gave the title compound (32 mg). MS 516 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:27])[F:28])=[N:20][C:21]([C:22]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 88.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (60 mg, 0.109 mmol), morpholine (19 mg, 0.218 mmol) and bis(2-oxo-3-oxazolidinyl) phosphonic chloride (53.5 mg, 0.218 mmol) were dissolved in 5 mL of dichloromethane under stirring, and triethylamine (0.1 mL, 0.65 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight until thin lay chromatography showed the starting material disappeared, and was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 3a (60 mg, yield 89%) as a white solid.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([O:18][CH3:19])[C:7]=2[CH2:6][CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>O>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([O:18][CH3:19])[C:7]=2[CH2:6][CH2:5]1
Reactant: CCN1C(=O)C(N=[N+]=[N-])CCc2c1ccc([N+](=O)[O-])c2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)C(N)CCc2c1ccc([N+](=O)[O-])c2OC

Procedure:
Combined (+/−)-3-Azido-1-ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (280 mg), Triphenylphosphine Resin (1.0 mmol/g loading; 1.83 g), Tetrahydrofuran (25 mL) and Water (0.25 mL) and stir at rt overnight. Filter and concentrate. Strip down from benzene to remove water. (+/−)-3-Amino-1-ethyl-6-methoxy 7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as an orangish oil isolated (251 mgs). 1H-NMR (CDCl3, 400 MHz): 7.84 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 4.36-4.28 (m, 1H), 3.97 (s, 3H), 3.71-3.62 (m, 1H), 3.36-3.31 (m, 1H), 3.23-3.18 (m, 1H), 2.52-2.39 (m, 2H), 2.03-1.99 (m, 1H), 1.66 (broad s, 2H), 1.21 (t, J=7.3 Hz, 3H). LC/MS: (M+H)+ found 280.18.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([C:16](=[O:21])[NH:17][CH2:18][C:19]#[N:20])[CH2:11][S:12][C:13](=O)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:24]([C:26]1[CH:27]=C([CH:31]=[CH:32][CH:33]=1)CBr)#[N:25]>CN(C)C=O.O>[CH2:1]([S:8][CH2:9][CH:10]([CH2:11][S:12][CH2:13][C:14]1[CH:31]=[CH:32][CH:33]=[C:26]([C:24]#[N:25])[CH:27]=1)[C:16]([NH:17][CH2:18][C:19]#[N:20])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(=O)SCC(CSCc1ccccc1)C(=O)NCC#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCNC(=O)C(CSCc1ccccc1)CSCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.8 %

Procedure:
A solution of thioacetic acid S-[3-benzylsulfanyl-2-(cyanomethyl-carbamoyl)propyl] ester (0.105 g) in dimethylformamide (1 mL) and water (0.8 mL) was cooled on ice and treated with 1 N aqueous potassium hydroxide (0.65 mL). 3-Cyanobenzylbromide (0.129 g) in dimethylformamide (0.8 mL) was added. The reaction mixture was allowed to warm to room temperature while stirring overnight. The reaction mixture was then poured into ice water and extracted with ethyl acetate (50 mL) and washed with water and saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and evaporated to give 2-benzylsulfanylmethyl-3-(3-cyano-benzylsulfanyl)-N-cyanomethyl-propionamide (0.135 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12]I)[C:5]2=[CH:4][CH:3]=1.[NH2:14][C@H:15](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.CN>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][NH:14][CH3:15])[C:5]2=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: Clc1ccc2c(CCI)c[nH]c2n1
Agent: CN
Solvent: CCO
Product: CNCCc1c[nH]c2nc(Cl)ccc12
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A mixture of 1 g (3.26 mM) of 6-Chloro-3-(2-iodo-ethyl)-1H-pyrrolo[2,3-b]pyridine and 0.49 g (3.26 mM) Nal were mixed together in 100 mL of an ethanol solution saturated with methyl amine gas. This solution was heated to 100° C. in a steel bomb for 12 hours. The reaction mixture was cooled to room temperature and the solvent evaporated. The residue was chromatographed on silica using a mixture of 10:1 CH2Cl6 : CH3OH as the elutant. The appropriate fractions were combined and evaporated. The residue was crystallized from isopropyl ether-methanol to yield 140 mg of [2-(6-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-methyl-amine. MP=214-215° C. NMR (D6DMSO) δ11.75 (s, 1H), 8.08 (d, 1H), 7.41 (s, 1H), 7.15 (d, 1H), 3.20 (t, 2H), 3.02 (t, 2H), 2.60 (s, 3H). 13C NMR (D6DMSO) 147.5, 143.2, 129.9, 124.8, 118.2, 114.8, 108.7, 48.4, 32.6, 21.6. Mass spectrum: m/e=210, 212(P+1, P+3).
Reaction SMILES: [O:1]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[CH:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[O:19])=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc2c(c1)CCC2Oc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc3c(c2)CCC3Oc2ccccc2)c(O)n1
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of 1-phenoxy-2,3-dihydro-1H-indene-5-carboxylic acid (100 mg, 0.39 mmol) in dichloromethane (50 mL) were added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) and triethylamine (71 mg, 0.7 mmol). And then the mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (61 mg, 0.4 mmol) was added. The mixture was stirred at room temperature for 12 hours. The resultant mixture was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-phenoxy-2,3-dihydro-1H-indene-5-carboxamide (Compound I-45) (35 mg, 23%) as white solid. LRMS (M+H+) m/z: calcd 388.18. found 388. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.41-7.29 (m, 3H), 7.05-6.93 (m, 3H), 5.89-5.86 (m, 2H), 4.30 (d, J=4.8 Hz, 2H), 3.10-2.84 (m, 2H), 2.64-2.56 (m, 1H), 2.16 (s, 3H), 2.11 (s, 3H), 2.09-1.98 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[O:43][CH:44]([CH3:46])[CH3:45])[C:5]([NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]3[C:35]([CH:36]([OH:38])[CH3:37])=[CH:34][CH:33]=[CH:32][N:31]3[CH:39]=2)=[CH:24][CH:23]=1)[CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[O:6].O.NN>C(O)C>[NH2:10][CH2:9][C@@H:8]([NH:7][C:5](=[O:6])[C:4]1[CH:40]=[CH:41][C:42]([O:43][CH:44]([CH3:45])[CH3:46])=[C:2]([Cl:1])[CH:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]3[C:35]([CH:36]([OH:38])[CH3:37])=[CH:34][CH:33]=[CH:32][N:31]3[CH:39]=2)=[CH:24][CH:23]=1
Reactant: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 57 °C
Yield: 99.8 %

Procedure:
A mixture of 3-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57° C. overnight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound (1.67 g, 100%) as a pale yellow powder. MS (ES+) m/e 507 [M+H]+.