Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:33])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:41][CH2:42][C:43](Cl)=[O:44]>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH:33][C:43](=[O:44])[CH2:42][Cl:41])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To an ice-cold mixture of 1-benzenesulfonyl-N*4*-(1-benzyl-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine 1.30 g, 2.80 mmol) and triethylamine (0.59 mL, 4.20 mmol) in DCM (50 mL) was added chloroacetyl chloride (0.25 mL, 3.10 mmol) and the mixture was stirred 2 h. The reaction mixture was diluted with DCM, washed with water, brine, and dried over sodium sulphate. The residue was purified by flash (silica gel. 0-5% MeOH/DCM) to afford N-[1-Benzenesulfonyl-4-(1-benzyl-piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-chloro-acetamide (1.10 g, 72%): LCMS (method E, ESI): RT=1.2 min; m+1=538.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=O)C.[CH:21]([NH2:23])=O>>[O:3]=[C:4]1[NH:23][CH:21]=[N:11][C:10]2[S:9][C:8]3[CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15][C:7]=3[C:6]1=2
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2c1CCC(C(=O)OCC)C2
Product: CCOC(=O)C1CCc2c(sc3nc[nH]c(=O)c23)C1
Temperature: 140 °C

Procedure:
In a 100 mL round-bottom flask was placed 3.5 g (11.75 mmol, 1 equiv) of 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3,6-dicarboxylic acid diethyl ester in 10 mL of formamide. The flask was equipped with a reflux condenser and heated at 140° C. for 16 h. The mixture was then allowed to cool to rt and a brown solid precipitated from solution. The resulting precipitate was filtered and rinsed with EtOAc (200 mL) and dried in a hi-vac oven for 2 h. After drying 3.25 g (99%) of the desired product as a brown solid was obtained and used without further purification in the next step. LCMS RT=2.80 min; [M+H]+=279.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:29])[NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[N:21]([CH3:26])[C:20]([CH3:28])([CH3:27])[CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:17][CH:18]2[CH2:19][C:20]([CH3:27])([CH3:28])[N:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH2:23]2)=[O:29])=[CH:12][CH:11]=1)[NH2:8]
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NNC(=O)OC(C)(C)C)cc2)CC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Reaction time: 1.5 h

Procedure:
N′-[4-(1,2,2,6,6-Pentamethyl-piperidin-4-ylcarbamoyl)-phenyl]-hydrazinecarboxylic acid tert-butyl ester was dissolved in 4M HCl in dioxane (30 ml) and left to stir for 1-2 hrs. The solution went quickly from a deep orange colour to a bright orange colour. After 1 hr reaction time, the solvent was removed under vacuum to reveal an orange oil that under a vacuum for several minutes crystalised out to give orange crystals in a sticky orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].Br[CH2:14][CH:15]1[CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:12])[CH3:11])=[C:2]([O:1][CH2:14][CH:15]2[CH2:17][O:16]2)[CH:7]=1
Reactant: BrCC1CO1
Reactant: CC(=O)Nc1ccc(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C)cc1OCC1CO1
Temperature: 55 °C
Yield: 41.7 %

Procedure:
A mixture of N-(2-hydroxy-4-methylphenyl)acetamide (10 g, 60 mmol), 2-(bromomethyl)oxirane (9.86 g, 72 mmol, 6.0 ml) and potassium carbonate (16.8 g, 120 mmol) in DMF (100 ml) was heated at 55° C. for 2 h. Then the reaction mixture was diluted with ethyl acetate and washed with aq. HCl (1.5%), aq. sat. NaHCO3, and brine. Evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 35 to 70%) afforded the title compound (5.65 g, 25 mmol, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)[CH3:2].[NH:17]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:26])[C:20]=2[CH:19]=[CH:18]1.C(=O)([O-])[O-:28].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:17]2[C:25]3[CH2:24][CH2:23][CH2:22][C:21](=[O:26])[C:20]=3[CH2:19][C:18]2=[O:28])=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C1CCCc2[nH]ccc21
Reactant: O=C([O-])[O-]
Reactant: C=CC(=O)Nc1ccc(C(=O)OCC)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)CCN2C(=O)CC3=C2CCCC3=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
In the second step, 4-acryloylaminobenzoic acid ethyl ester (200 mg, 0.91 mmol), 1,5,6,7-tetrahydro-4H-indol-4-one (123 mg, 0.91 mmol) and potassium carbonate (126 mg, 0.91 mmol) were combined in dry N,N-dimethylformamide (3 mL) and stirred at room temperature for 24 hours, then heated to 60 C for 6 hours. Water (20 mL) was added and the resulting precipitate was vacuum filtered washing with water. The isolated solid was dried under vacuum to yield 180 mg (56%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: COc1cccc(CBr)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CC(C#N)(C#N)CCC(F)(F)F)c1OC
Yield: 83.7 %

Procedure:
Using 0.23 g of 2,3-dimethoxybenzyl bromide, 3 ml of N,N-di-methylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.26 g of 2-(2,3-dimethoxybenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (40)).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]([O:20]CC)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH2:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]([OH:20])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc2ccccn2c1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc2ccccn2c1CCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 128.9 %

Procedure:
Ethyl 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylate (883 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, subjected to DIAION HP-(manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.03 g). The obtained 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (341 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (522 mg).
Reaction SMILES: [CH:1]1([NH:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9](=[O:12])([O-])[O-].[Na+].[Na+].[Cl:15][C:16]1[N:23]=[CH:22][CH:21]=[CH:20][C:17]=1CCl>O1CCOCC1.O>[OH:8][N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9](=[O:12])[C:17]1[CH:20]=[CH:21][CH:22]=[N:23][C:16]=1[Cl:15]
Reactant: ONC1CCCCC1
Reactant: ClCc1cccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1cccnc1Cl)N(O)C1CCCCC1
Reaction time: 0.25 h

Procedure:
12.6 parts of N-cyclohexylhydroxylamine and 14 parts of sodium carbonate in 125 parts of dioxane and 30 parts of water are placed in a reactor. At 0° to 5° C and over a period of 15 minutes, 17.6 parts of 2-chloronicotinyl chloride in 30 parts of dioxane is dripped into the reaction solution, which is then allowed to after-react for 1 hour. The solution is concentrated and the residue taken up in chloroform, followed by extraction with water, drying and concentration. Crystallization from a mixture of benzene and ligroin yields 15 parts of 2-chloronicotinic acid-N-hydroxy-N-cyclohexylamide, m.p.: 151° to 153° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:12][NH:13][C:14]([NH2:16])=[S:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:28]([CH2:30][C:31](OCC)=[O:32])#[N:29].Cl>C(O)(C)C.CC(C)=O.O>[NH2:29][C:28]1[N:13]([CH2:12][C:11]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[C:14](=[S:15])[NH:16][C:31](=[O:32])[CH:30]=1
Reactant: COc1ccc(CNC(N)=S)cc1OCc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cn2c(N)cc(=O)[nH]c2=S)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
1-(3-Benzyloxy-4-methoxy-benzyl)-2-thiourea (72.58 g, 240 mmole) was added to a solution of 97% t-BuOK (30.54 g, 264 mmole) in isopropanol (300 ml), the mixture heated under reflux until dissolution was complete, then ethyl cyanoacetate (26.1 .ml, 245 mmole) was added. After 5 hours at reflux, the mixture was cooled slightly, another batch of t-BuOK (2.78 g, 24 mmole) and ethyl cyanoacetate (5.12 ml, 48 mmole) was added, and the mixture heated under reflux for a further 15 hours. The reaction mixture was cooled to room temperature, poured onto water (1.21) and neutralized with cooling to pH 8 with 5M HCl (43 ml). After 1 hour stirring the solid was collected at 10° C. and washed first with water (180 ml), then saturated sodium bicarbonate solution (60 ml), isopropanol (60 ml) and finally cold water (500 ml). The crude material was suspended in 0.5M NaOH (1.4 l) and isopropanol (350 ml). The insoluble part was filtered off and washed with 0.1M NaOH and water to give recovered thiourea (10.45 g, 14.4%). The filtrate was neutralized to pH 8 with 2M phosphoric acid (175 ml ), crystallized over night, the solid collected and washed with the above three component liqours and water to give the crude thiouracil (73.33 g). This product was suspended in hot acetone (600 ml), concentrated to 500 ml and collected at 0-5° C. to give 6-amino-1-(3-benzyloxy-4-methoxy-benzyl)-2-thiouracil (65.73 g, 74.1%), mp 239-240° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:13]([C:14](=O)[CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1)=[O:4].Cl.[NH2:35][OH:36]>>[F:32][C:2]([F:33])([F:1])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:13](/[C:14](=[N:35]/[OH:36])/[CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1)=[O:4]
Reactant: NO
Reactant: C[C@]12CC[C@H](SCCCCNC(=O)C(F)(F)F)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Product: C[C@]12CC[C@H](SCCCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 40 %

Procedure:
Following the reaction conditions described in Example 1 and starting from 3β-(4-trifluoroacetamidobutylthio)androstane-6,17-dione and hydroxylamine hydrochloride, 3β-(4-trifluoroacetamidobutylthio)-6-(E)-hydroxyiminoandrostane-17-one (240 mg, 40%) was obtained. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.35 (1H, s), 9.40 (1H, t), 3.20 (4H, m), 2.55-0.90 (25H, m), 0.76 (3H, s), 0.67 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].[C:13]([NH2:18])(=[O:17])[C@@H:14]([CH3:16])O>>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C@@H:5]1[NH:18][C:13](=[O:17])[CH:14]([CH3:16])[O:6]1
Reactant: COc1cccc(OC)c1C=O
Reactant: C[C@@H](O)C(N)=O
Product: COc1cccc(OC)c1[C@@H]1NC(=O)C(C)O1

Procedure:
prepared by reaction of 2,6-dimethoxybenzaldehyde with (R)-(+)-lactamide; LC-MS: tR=0.45 min; [M+H]+=238.21.
Reaction SMILES: FC(F)(F)C(O)=O.C(Cl)Cl.C(OC(=O)[NH:17][C@H:18]([C:39]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[C:41]([F:47])[CH:40]=1)[C@H:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20])(C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Si:22]([O:21][C@H:19]([CH3:20])[C@H:18]([NH2:17])[C:39]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[C:41]([F:47])[CH:40]=1)([C:35]([CH3:36])([CH3:37])[CH3:38])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 91.1 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a methylene chloride solution (2 mL) of [(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester (370 mg). This reaction solution was stirred at room temperature for 11 hr. To this reaction solution, a saturated sodium hydrogencarbonate aqueous solution and ethyl acetate were added. The organic layer was separated, washed with a saturated sodium hydrogencarbonate aqueous solution and then with saturated saline. Then, the organic layer was concentrated under reduced pressure to give 275 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[F:34][C:35]([F:41])([F:40])[S:36](Cl)(=[O:38])=[O:37].CCOC(C)=O>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][S:36]([C:35]([F:41])([F:40])[F:34])(=[O:38])=[O:37])=[CH:18][CH:19]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OCc1ccccc1

Procedure:
To a solution of 15.15 g (4.1 mmol) N-(CBZ)-(L)-tyrosine, tert-butyl ester in 150 mL of dry methylene chloride at 0° C. was added 12.9 g (164 mmol) of pyridine followed by the dropwise addition of 12.68 g (4.5 mmol) of trifluoromethylsulfonyl chloride. The reaction mixture was stirred at room temperature for 4 hours at which time TLC (25% EtOAc in hexanes) indicated complete consumption of starting material. The reaction mixture was shaken with 1N HCl (3×100 mL), saturated NaHCO3 solution (2×50 mL), and brine (1×50 mL). The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give N-(CBZ)-4-(trifluoromethylsulfonyloxy)-(L)-phenylalanine, tert-butyl ester.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: COc1ccc(N)cc1OC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1OC
Yield: 74 %

Procedure:
Prepared from VII and 3,4-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 74%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3267, 2839, 2226, 1644, 1610, 1583, 1507, 1460, 1443, 1379, 1308, 1260, 1227, 1201, 1166, 1150, 1129, 1020, 967, 935, 861, 839; 1H NMR (300 MHz, DMSO-d6) δ 8.34 (m, 1H), 7.79 (m, 1H), 7.71 (m, 1H), 6.90 (d, 1H, J=8.1 Hz), 6.54 (m, 2H), 4.26 (s, 6H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0850.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:17][CH2:18][C:19]1[O:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+].Cl>O.C(COC)OC.C(N(CC)CC)C>[C:24]([C:22]1[O:23][C:19]([CH2:18][NH:17][C:2]2[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:20][CH:21]=1)([OH:26])=[O:25]
Reactant: NCc1ccc(C(=O)O)o1
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cc(C(=O)O)c(NCc2ccc(C(=O)O)o2)cc1Cl
Reaction time: 24 h

Procedure:
A mixture of 2,4-dichloro-5-methylsulfonylbenzoic acid (3.50 g.; 0.013 mole), 5-aminomethyl-2-furancarboxylic acid hydrochloride (4.83 g.; 0.027 mole), triethylamine (11.5 ml.), and glyme (25 ml.) is heated to 140°-150° C. for 24 hours. Solid sodium bicarbonate (5.0 g.) is added and refluxing is continued for another 24 hours. The mixture is poured into water (150 ml.) and acidified by the addition of 6N hydrochloric acid. The tan solid is collected, washed with water, and dried, 1.20 g., m.p. 269°-272° C. Recrystallization from acetonitrile gives 2-(5-carboxyfurfurylamino)-4-chloro-5-methylsulfonylbenzoic acid, m.p. 263.5°-265.5° C. (dec.).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:9][CH2:10][NH:11][C:12](=[O:24])[O:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:16]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:2][C:3]1([CH2:9][CH2:10][NH:11][C:12](=[O:24])[O:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:16]=2)[CH2:4][CH2:5][N:6]([C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH2:7][CH2:8]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CNC(=O)c1cc(COC(=O)NCCC2(C)CCNCC2)on1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(COC(=O)NCCC2(C)CCN(c3nccc(C(F)(F)F)n3)CC2)on1
Yield: 74.3 %

Procedure:
The process is performed according to the procedure described in Example 12 (step 12.5.). Starting with 0.30 g (0.83 mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl [2-(4-methylpiperidin-4-yl)ethyl]carbamate hydrochloride, 0.23 g (1.25 mmol) of 2-chloro-4-trifluoromethylpyrimidine and 430 μL (2.49 mmol) of N,N-diisopropylethylamine, dissolved in 2.77 mL of acetonitrile, 0.29 g of expected product is obtained in the form of a powder.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:8]=1[N+:22]([O-])=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>[C].[Pd].O1CCCC1>[CH2:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:8]=1[NH2:22])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)CNc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.2 %

Procedure:
To a tetrahydrofuran solution (5 mL) of 2-(4-neopentylamino-3-nitrophenyl)benzoxazole (see Working Example 81-1) (242 mg, 0.744 mmol) was added 10% palladium-carbon (40 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 15 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (196 mg, 89% yield).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@H:13]([OH:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:9]1[C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:11]2[CH2:12][NH:8]1
Reactant: [H][H]
Reactant: O[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Solvent: CCO
Product: O[C@@H]1CC[C@@H]2CNC[C@@H]21

Procedure:
(3aR,4R,6aS)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ol (2.88 g, 13.25 mmol) from Example 28 and ethanol (40 mL) were added to 20% Pd(OH)2—C, wet (0.576 g, 4.10 mmol) in a 250 mL stainless steel pressure bottle and stirred for 2 hours at 30 psi hydrogen gas at 50° C. The mixture was filtered through a nylon membrane, and the solvent was removed in vacuo to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 4.82 (s, 4H), 4.37 (dd, J=10.5, 4.8, 1H), 3.52 (dd, J=10.8, 1.7, 1H), 2.96-2.86 (m, 1H), 2.76 (dd, J=10.8, 6.9, 1H), 2.71 (dd, J=10.8, 1.8, 1H), 2.56-2.45 (m, 2H), 1.89 (td, J=11.7, 5.3, 1H), 1.80 (ddd, J=12.5, 10.3, 6.8, 1H), 1.66-1.58 (m, 1H), 1.50-1.42 (m, 1H); MS (ESI+) m/z 128 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[OH:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH:55]([C:57]2[CH:58]=[CH:59][C:60]([Cl:63])=[CH:61][CH:62]=2)[OH:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(Cl)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
To a solution of 50 mg (0.31 mmol) of 1H-indole-7-carboxylic acid and 97 mg of TBTU (0.31 mmol) in 4 ml DMF, were added 0.27 ml (1.55 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 99 mg (0.31 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 40 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 89 mg (61%) of a white solid. MS (ISP) 461.4 (M+H)+.