Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([F:36])=[CH:34][CH:33]=[C:32]([OH:37])[C:31]=5[F:38])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:49][C:50]#[CH:51].[Cl-].[NH4+]>CN(C)C=O.C1(C)C=CC=CC=1>[F:39][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([F:36])=[CH:34][CH:33]=[C:32]([O:37][CH2:51][C:50]#[CH:49])[C:31]=5[F:38])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(F)ccc(O)c4F)C3)cs2)CC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(F)c(C2CC(c3csc(C4CCN(C(=O)Cn5nc(C(F)F)cc5C(F)F)CC4)n3)=NO2)c1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2,6-difluoro-3-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (1.82 g) and potassium carbonate (657 mg) in N,N-dimethylformamide (15 ml) are added, at room temperature, potassium iodide (289 mg) and 3-bromoprop-1-yne (755 mg)) (80 wt % in toluene). The reaction mixture is stirred at 80° C. for 4 h. Then the mixture is admixed with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2,6-difluoro-3-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone, (1.68 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][C:13]([C:18]([OH:20])=O)([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>C(#N)C>[C:18]([C:13]12[CH2:14][CH:15]3[CH2:16][CH:11]([CH2:10][CH:9]([N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]1)[CH2:12]2)(=[O:20])[NH2:21]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(C(=O)O)(C3)C2
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C2CC3CC1CC(C(N)=O)(C3)C2
Reaction time: 1 h
Yield: 87 %

Procedure:
A 50 mL RB flask fitted with magnetic stirrer was charged with 5 mL of acetonitrile and 2-(tert-butoxycarbonyl)-2-azatricyclo[3.3.1.13,7]decane-5-carboxylic acid, Intermediate-10 (0.16 g, 0.56 mmol). Under N2 atm, pyridine (60 mg, 0.6 mmol) and Boc-anhydride (0.148 g, 0.6 mmol) was added to the reaction mixture and was stirred for 1 hr. After 1 hr, ammonium bicarbonate solid (75 mg, 0.9 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction (reaction was monitored by TLC), reaction mixture was concentrated under vacuum. The resulted crude material was extracted with ethyl acetate (25 ml×3). The organic layer was washed with ammonium chloride solution and saturated sodium bi carbonate solution. It was then dried over anhydrous sodium sulfate and concentrated to give Intermediate-11, as an oily mass (0.14 g, yield=87%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 52.8 %

Procedure:
To a solution of 1-benzhydryl-azetidin-3-ol (640 mg) in methylene chloride (6.0 mL) was added 4 Å molecular sieves. The reaction vessel was purged with nitrogen followed by addition of NMO (800 mg) and then TPAP (42 mg). The reaction was stirred over night and then filtered through a plug of silica to yield 335 mg of the title compound as a clear, colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm 4.03 (s, 4H), 4.61 (s, 1H), 7.25 (m, 2H), 7.32 (m, 4H), 7.50 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:15]1[C@@H:19]([CH2:20][OH:21])[O:18][C:17](=[O:22])[NH:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>CC(C)=O>[CH2:8]([C@H:15]1[C@@H:19]([CH2:20][O:21][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[O:18][C:17](=[O:22])[NH:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2OC(=O)N[C@H]2Cc2ccccc2)cc1
Temperature: 22 °C
Reaction time: 6.5 h
Yield: 93.9 %

Procedure:
5.6 ml of triethylamine are added at 22° C. to a stirred suspension of 5.55 g of the alcohol from Example 8 in 27 ml of acetone and 6.64 g of p-toluenesulphonyl chloride and stirred at 22° C. for 6.5 hours. The suspension is treated with water, stirred at 10° C., filtered, the residue is washed with a water/acetone solution (3:2) and dried to give 9.09 g (94%) of 99% p-toluenesulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester, m.p. 148.7-150.3° C., [α]D20 : +3.0(1% acetone).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:25]=[CH:26][CH:27]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(OC(=O)c2ccccc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(OC(=O)c2ccccc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-benzoyloxybenzaldehyde in an analogous manner to that described in Example 1 to give 9-(3-benzoyloxyphenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from ethanol gave a pale yellow crystalline solid of melting point 274-275° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C[AlH]CC(C)C)C.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)c(OCc2ccccc2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: OCc1ccc(Br)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To 3.35 g (10 mmol) of 7 in 25 ml of CH2Cl2 under Ar in a dry ice-acetone bath was slowly added 20 ml 1.0 M DIBAL with stirring. After stirring for 2 h, 20 ml of 1 N HCl and 50 ml of CH2Cl2were added, and the mixture was stirred for 0.5 h, then washed (water and brine), and dried (Na2SO4). Concentration and chromatography (EtOAc/hexane) afforded 2.78 g (91%) of 8 (white solid): 1H NMR (300 MHz, CDCl3) δ 4.63 (d, J=5.7 Hz, 2 H), 6.83 (d, J=8.1 Hz, 1 H), 7.00 (s, 1 H), 7.40−7.33 (m, 3 H), 7.5−7.42 ppm (m, 3 H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:36])[C@@H:5]([NH:15][C:16](=[O:35])[C@@H:17]([NH:28][C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[OH-].[Li+]>O.C1COCC1>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH2:6][C@H:5]([NH:15][C:16](=[O:35])[C@@H:17]([NH:28][C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:27])=[CH:23][CH:24]=1)[C:4]([OH:36])=[O:3])([CH3:14])([CH3:12])[CH3:13]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 2-(S)-[2-(S)-allyloxycarbonylamino-3-(4-carbamimidoyl-phenyl)-propionylamino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester hydrochloride (3.06 g, 5.8 mmol) in 100 ml of water and 30 ml of THF was added lithium hydroxide hydrate (0.49 g, 11.6 mmol). The solution was stirred at room temperature for 12 hours, evaporated, and freeze-dried. The residue was purified by chromatography on Sephadex LH20 employing n-butanol/glacial acetic acid/water (17/1/2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water, and the aqueous solution was freeze-dried. Yield: 2.7 g (97%). MS: m/z=477.4 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:15]1[CH:16]=[CH:17][C:12]([CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)CCCCl)cc1
Temperature: 6.5 °C
Reaction time: 14 h
Yield: 86.9 %

Procedure:
Slurry aluminum chloride (140.9 g, 1.075 mol) and 4-chlorobutyryl chloride (148 g, 1.05 mol) in methylene chloride (1.0 L) add, by dropwise addition, cumene (125 g, 1.04 mol) over a thirty minute period under a nitrogen atmosphere while maintaining the internal temperature between 5-8° C. with an ice bath. Allow the stirred solution to come to room temperature and continue stirring under nitrogen for 14 hours. Cautiously add the methylene chloride solution to 1 L of crushed ice with stirring and add additional methylene chloride (400 mL). Separate the organic phase and wash with 10% hydrochloric acid (3×300 mL), water (3×300 mL), 10% sodium bicarbonate (3×300 mL) and water (3×300 mL). Dry (MgSO4), filter and wash with methylene chloride (150 mL). Evaporate the solvent to give the title compound (203 g, 86%) as a clear oil which crystallizes on standing; mp 35-37° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][Si](C(C)(C)C)(C)C)[N:3]=1.[ClH:41]>O1CCOCC1>[ClH:41].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(NC(=O)CCN3CCCCC3)c2)c(C#N)c(N)n1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(-c2cccc(NC(=O)CCN3CCCCC3)c2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 9 %

Procedure:
To a stirred solution of N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]-phenyl}-3-(1-piperidinyl)propanamide (0.150 g, 0.270 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in dioxane (2 mL). The mixture was stirred at room temperature for 12 hrs. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give N-{3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide hydrochloride (0.011 g, yield 9%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C1COCC1.[OH-].[Na+].C(OCC)(=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Ethyl cyanoacetate (5 mmol), and p-chloro-acetophenone (5 mmol) are dissolved in toluene (5 mL). Morpholine (5 mmol) is added followed by activated molecular sieves (4A). The reaction is stirred at 80° C. for 12 hours. The reaction is cooled to room temperature, filtered and concentrated. The residue is taken up in toluene (5 mL), ethanol (5 mL) and sulfur is added (0.16 g; 5 mmol). The reaction mixture is heated with mixing at 70° C. for 12 hours. The reaction is cooled to room temperature and the solvents are evaporated. The residue is purified by HPLC to provide ethyl 2-amino-4-(4-chlorophenyl)-thiophene-3-carboxylate. Ethyl 2-amino-4-(4-chlorophenyl)-thiophene-3-carboxylate (5 mmol) is treated with 4-fluorobenzoyl chloride (5 mmol) in THF (10 mL). The reaction is stirred at room temperature for 10 hours. The reaction is diluted with 1N NaOH (10 mL) and ethyl acetate (15 mL). The layers are separated, the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography to provide ethyl 2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylate. Ethyl 2-(fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylate is hydrolyzed under a variety of conditions (e.g. LiOH, water; LiOH, H2O2, water; or NaOH, water) to provide 2-(4-fluorobenzamido)-4-(4-chlorophenyl)thiophene-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[C@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.Cl>[Cl-].[Na+].CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1ccnc1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: C[C@@H](S)[C@](O)(Cn1ccnc1)c1ccc(F)cc1F

Procedure:
A methanol solution (75 ml) containing (2R,3S)-2-(2,4-difluorophenyl)-2-(1-imidazolyl)methyl-3-methyloxirane (2.5 g), methyl 3-mercaptopropionate (5.5 ml) and 28% sodium methoxide-methanol (8.1 ml) was refluxed for 1.5 hours. Then, methyl 3-mercaptopropionate (5.5 ml) and 28% sodium methoxide-methanol (8.1 ml) were added and the mixture was further refluxed for 2 hours. The reaction mixture was cooled with ice, neutralized with 5N hydrochloric acid (16 ml), diluted with saturated aqueous sodium chloride solution (100 ml) and extracted with ethyl acetate (200 ml×3). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (40 ml), followed by addition of 1N aqueous sodium hydroxide solution (8 ml) and water (100 ml). The aqueous layer was further extracted with methylene chloride (40 ml×3). The methylene chloride layers were combined and extracted 5 times with water (30 ml) containing 1N hydrochloric acid (8 ml). The aqueous layers were combined, neutralized with sodium hydroxide and extracted with methylene chloride (40 ml×4). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (4 cm×15 cm) using methanol-methylene chloride (5:95) as the eluent. The desired fraction was concentrated and diethyl ether was added to the residue to yield (2R,3R)-2-(2,4-difluorophenyl)-1-(1-imidazolyl)-3-mercapto-2-butanol (0.84 g) as colorless prisms.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][CH3:18])[C@H:14]([CH2:19][NH2:20])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:21][C:22]1[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1>>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][CH3:18])[C@H:14]([CH2:19][NH:20][C:27]([C:25]2[S:26][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:28])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Solvent: CC(=O)O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(=O)c1ccc(Cl)s1

Procedure:
80.4 Using general procedure E, (3R,4S)-3-aminomethyl-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester acetate was coupled with 5-chlorothiophene-2-carboxylic acid to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester. Colorless foam. MS 318.9 ([M−isobutene+H]+)
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:30][C:31]1[C:32]([I:39])=[N:33][N:34]([CH:36]([CH3:38])[CH3:37])[CH:35]=1>O1CCCC1>[I:39][C:32]1[C:31]([CH2:30][C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]2)=[CH:35][N:34]([CH:36]([CH3:38])[CH3:37])[N:33]=1
Reactant: CC(C)n1cc(CBr)c(I)n1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cn(C(C)C)nc2I)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (0.54 mL, 2.11 mmol) in tetrahydrofuran (15 mL) in a dry 100 mL round bottom flask under nitrogen was cooled to −78° C. and then treated with lithium bis(trimethylsilyl) amide (1 M toluene, 2.13 mL, 2.13 mmol). After stirring for 45 minutes at −78° C., 4-(bromomethyl)-3-iodo-1-isopropyl-1H-pyrazole (535 mg, 1.63 mmol) was added as a suspension in 10 mL tetrahydrofuran. The mixture was stirred 1 hour at −78° C. and then allowed to stir 18 hours at room temperature. The reaction mixture was quenched with 20 mL saturated aqueous ammonium chloride, stirred 30 minutes at room temperature, diluted with 50 mL water and then extracted with ethyl acetate (2×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10-80% ethyl acetate/heptanes, 25 g silica gel) to yield 1-tert-butyl 4-ethyl 4-((3-iodo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (645 mg) as a clear oil. +ESI (M-tBu) 450.1; 1H NMR (400 MHz, CDCl3, δ): 7.02 (s, 3H), 4.44 (spt, J=6.6 Hz, 1H), 4.17 (m, 2H), 3.92 (m, 2H), 2.86 (m, 2H), 2.62 (s, 2H), 2.08 (m, 2H), 1.46 (m, 17H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14]4[C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=[C:13]4[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.CN(C=O)C.[Br:29]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:29][C:10]1[N:9]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]3[C:17]([C:20]([F:23])([F:21])[F:22])=[N:18][N:19]=[C:13]3[CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1nnc2n1CCN(c1ncc3c(Cl)nccn13)C2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCN(c1nc(Br)c3c(Cl)nccn13)C2
Yield: 89.6 %

Procedure:
To a 100 ml one neck round bottom flask was charged with 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (540 mg, 1.571 mmol) along with DMF (5 ml). The mixture was stirred and 1-bromopyrrolidine-2,5-dione (308 mg, 1.728 mmol) was added in on batch. The resulting reaction mixture was then stirred at room temperature for 18 hrs overnight. The mixture was diluted with ethyl acetate and washed with NaHCO3 (sat), water, dried over MgSO4, filtered and concentrated. The residue was purified by MPLC (24 g silica gel, 50% to 100% ethyl acetate in hexanes, 18 CV) to afford light color solid product 7-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (595 mg, 1.408 mmol, 90% yield). LC-MS: C12H8BrClF3N7, 421. found 422.02 [M+H]+, RT=1.30 min.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:44][CH3:45])=[C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=4[C:36]([NH2:38])=[O:37])[C:17]4[CH:22]=[CH:21][N:20](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:19]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[O-].[Na+].[Na+].[Cl-]>CO.C1COCC1.CCOC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:44][CH3:45])=[C:10]([NH:13][C:14]3[NH:19][C:18]4=[N:20][CH:21]=[CH:22][C:17]4=[C:16]([NH:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=4[C:36]([NH2:38])=[O:37])[N:15]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(C)=O)CC2
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
A solution of of 2-({2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (104 mg, 0.17 mmol) in methanol (10 mL) and THF (20 mL) was treated with a solution of sodium methoxide (0.5M in MeOH, 3.3 mL, 1.7 mmol). The resulting mixture was stirred at rt for 2 days, then diluted with EtOAc (100 mL) and a saturated NaCl solution. The organic layer was washed with a saturated NaHCO3 solution, concentrated onto Celite and purified by silica gel chromatography using 0-5% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a yellow solid (63 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.13 (s, 3H), 3.09-3.19 (m, 2H), 3.78 (s, 3H), 4.06-4.15 (m, 2H), 6.23 (s, 1H), 6.88 (J=9.71 Hz, 9.34 Hz, 1H), 6.95 (s, 2H), 7.27-7.37 (m, 1H), 7.58 (s, 1H), 8.02 (s, 1H), 8.10 (s, 1H), 8.50 (d, J=8.42 Hz, 1H), 8.62 (s, 1H), 10.52 (s, 1H), 11.29 (s, 1H); ESIMS (M+H)+=475.99.
Reaction SMILES: S(=O)(=O)(O)O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12][NH:13][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[C:15](N)=[O:16].[ClH:25].[CH3:26][OH:27]>>[ClH:24].[CH3:26][O:27][C:15](=[O:16])[CH:14]([NH:13][CH2:12][CH2:11][C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25]
Reactant: NC(=O)C(NCCc1cccs1)c1ccccc1Cl
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Yield: 83 %

Procedure:
In 40 ml of methanol under cooling 11.5 ml (0.215 mol) of 100% sulfuric acid is dissolved, the solution is heated under reflux conditions for 30 minutes, then after cooling to room temperature 12.4 g (0.042 mol) of dextrorotatory [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide is added and the mixture is heated under reflux for 6-7 hours, till the end of the reaction. Methanol is distilled off in vacuo, to the residue 75 ml of 1,2-dichloroethane and 75 ml of water are added, the mixture is shaken well and the phases are separated. The aqueous phase is extracted with 2×20 ml of 1,2-dichloroethane, the united organic phase is extracted with 50 ml of 5% sodium hydroxide solution then with 50 ml of water, dried over anhydrous sodium sulfate. The drying material is filtered off and 1.5 g (0.041 mol of dry hydrogen chloride gas is introduced under cooling into the solution. The precipitated crystalline product is filtered off, washed with 1,2-dichloroethane and dried. Weight: 12.1 g, mp.: 185-186° C. (decomposition), [α]22D=+107° . Yield: 83%. Optical purity: in general 99-100%.