Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[CH3:18][O-:19].[Na+].CO>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([O:19][CH3:18])=[N:3][CH:4]=1
Reactant: C[O-]
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Nc2nc(OC)ncc2I)cn1
Temperature: 140 °C
Yield: 90.6 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), sodium methoxide (0.5 M solution in methanol, 0.043 mL, 0.749 mmol) and methanol (1 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 15 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-2-methoxy-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (162 mg, 0.452 mmol, 91% yield). 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H); 8.26 (d, J=2.05 Hz, 1H); 7.83 (dd, J=8.84, 2.56 Hz, 1H); 6.87 (s, 1H); 6.78 (d, J=8.77 Hz, 1H); 3.94 (s, 3H); 3.89 (s, 3H). m/z (ESI, +ve ion) 359.0 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0.141 g, 0.509 mmol) (note: this intermediate is disclosed in U.S. Pat. No. 7,112,592 Example 32b) in dry dichloromethane (3 mL) was added 4-amino-1-BOC-piperidine (0.1532 g, 0.765 mmol), triethylamine (0.16 mL, 1.148 mmol), HOBT (0.1145 g, 0.748 mmol), and EDC (0.1455 g, 0.759 mmol) sequentially at room temperature under nitrogen. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by HPLC (30×100 mm Waters Sunfire column; 5 micron; 35 mL/minute; 210 nM; 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes; desired product elutes at 50% CH3CN+0.05% TFA/water+0.05% TFA) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C@@H:16]1[CH2:20][C@@H:19]([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:18](=[O:26])[O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]12[CH2:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][CH:29]2[NH:35]C(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C@@H:16]([OH:17])[CH2:20][C@H:19]([C:18](=[O:26])[NH:35][CH:29]1[CH2:30][CH:31]2[CH2:34][CH:28]1[CH2:33][CH2:32]2)[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CC2CCC1C2
Reactant: CC(C)=CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Product: CC(C)=CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NC1CC2CCC1C2
Yield: 60 %

Procedure:
{(S)-1-[(2S,4R)-4-(3-Methyl-but-2-enyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester (D5) was treated with (±)exo-norbornylamine as described in D3 to afford D6 as a white solid (60%).
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](=[N:5][OH:6])[Cl:13]
Reactant: Cc1ccc(C=NO)c(F)c1I
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(Cl)=NO)c(F)c1I
Temperature: 55 °C

Procedure:
To a solution of 2-fluoro-3-iodo4-methylbenzaldehyde oxime (0.48 g, 1.7 mmol) in DMF (0.5 mL) was added N-chlorosuccinimide (83 mg, 0.62 mmol) and the mixture was heated at 55° C. for 5 min. The mixture was allowed to cool to <50° C., an additional N-chlorosuccinimide (166 mg, 1.24 mmol) was added, then it was heated at 55° C. for 10 min. The reaction mixture was allowed to cool to RT, treated with water (5 mL), and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine, dried and concentrated to afford the intermediate, 2-fluoro-3-iodo-4-methylbenzoyl chloride oxime as a light yellow amorphous solid, which was used without further purification. MS (ESI, pos. ion) m/z: 314.3 (M+1). Cyclopropylamine (0.60 mL, 8.6 mmol) was added dropwise to an ice-cold solution of the above obtained 2-fluoro-3-iodo-4-methylbenzoyl chloride oxime in anhydrous THF (2 mL). The reaction mixture was stirred at ambient for 3 h. The volatiles were removed under reduced pressure and the residue purified on a 40 g ISCO column (eluted with 25-60% ethyl acetate in Hexanes) to provide the title compound as an amorphous off-white solid. MS (ESI, pos. ion) m/z: 335.0 (M+1).
Reaction SMILES: [Mg].[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=2)[N:21]=[C:20]([CH3:29])[CH:19]=1.[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([Mg:42][Br:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>O.C1COCC1>[F:45][C:31]([F:30])([F:44])[C:32]1[CH:33]=[C:34]([Mg:42][Br:43])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=1.[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=3)[N:21]=[C:20]([CH3:29])[CH:19]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: Cc1ccc2nc(C)cc(Cl)c2c1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nc(C)cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Magnesium (1.60 g) was added to THF (60 ml) in a nitrogen atmosphere and 3,5-bis (trifluoromethyl)phenylbromide (17.58 g) was dropped. The resulting mixture was stirred for 30 minutes at room temperature and a THF solution of 3,5-bis (trifluoromethyl)phenylmagnesiumbromide was prepared. In a nitrogen atmosphere, 4-chloro-2,6-dimethylquinoline (2.88 g) and Ni(dpp)Cl2 (500 mg) were added to THF (30 ml) and dispersed. The THF solution of 3,5-bis(trifluoromethyl)phenylmagnesiumbromide prepared as above was dropped to the suspension and the resulting solution was stirred for 4 days at room temperature. Water was poured into the reaction solution, impurities were filtered, and extraction was performed using AcOEt (ethyl acetate). A drying process was applied using Na2SO4 and the solvent was removed under a reduced pressure. The residue was purified through a silica gel column (hexane/ethyl acetate=3/2) to obtain 4-(3,5-bis(trifluoromethyl)phenyl)-2,6-dimethylquinoline (4.40 g) represented by the following chemical formula (49).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([C:14]=1O)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].C(N(C(C)C)CC)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([C:14]=1[NH:49][CH:46]1[CH2:45][CH2:44][N:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:48][CH2:47]1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1c(O)c2cc(Cl)ccc2[nH]c1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2c(C(=O)OC)c(=O)[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 32 %

Procedure:
To a suspension of 6-Chloro-4-hydroxy-2-oxo-1,2dihydro-quinoline-3-carboxylic acid methyl ester (445 mg, 1.8 mmol) and diisopropylethlyamine (607 uL, 3.5 mmol) in acetonitrile (30 mL) was added p-toluenesulfonyl chloride (400 mg, 2.1 mmol). The reaction was stirred at room temperature and monitored by TLC to completion (2 h). 4-amino-piperidine-1-carboxylic acid ethyl ester was then added to the reaction mixture which was stirred at 50° C. for 8 h. The reaction mixture was then diluted up with CH2Cl2 and washed with water. The organic portion was dried with MgSO4 and evaporated. The residue was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide a white solid (235 mg, 32%) which was carried onto the next step without characterization.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5].OO.[OH2:14].C(Cl)Cl.C[OH:19]>C1C=CC=CC=1.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][S:2]([CH:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])(=[O:19])=[O:14]
Reactant: O
Reactant: CSC(C(=O)O)c1cccs1
Reactant: CO
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)C(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
α-Methylthio(2-thienyl)acetic acid (1.731 g) was dissolved in 20 ml of methanol, and 10 mg of sodium tungstate and 3.34 ml of a 30% aqueous solution of hydrogen peroxide were added. The mixture was stirred at room temperature for 70 hours. To the reaction mixture were added 30 ml of water and 30 ml of methylene chloride. The organic layer was separated. The aqueous layer was extracted four times with 30 ml of methylene chloride. The resulting organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford yellow crystals. The crystals were dissolved in benzene, and the insoluble matter was separated by filtration. The residue was concentrated under reduced pressure. Recrystallization of the resulting yellow crystals from benzene/n-hexane afforded 997 mg of α-methylsulfonyl(2-thienyl)acetic acid as pale yellow crystals.
Reaction SMILES: CN(C)N=N[C:5]1[C:13]2[S:12][CH:11]=[C:10]([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.[FH:19]>>[CH3:14][C:10]1[C:9]2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=[C:5]([F:19])[C:13]=2[S:12][CH:11]=1
Reactant: Cc1csc2c(N=NN(C)C)cc([N+](=O)[O-])cc12
Reactant: F
Product: Cc1csc2c(F)cc([N+](=O)[O-])cc12
Temperature: 100 °C

Procedure:
0.5 mole of 1,1-dimethyl-3-(3-methyl-5-nitrobenzothiophen-7-yl)-triazene is introduced in portions into 10 moles of hydrofluoric acid. The apparatus is then closed, 5 bar of nitrogen are forced in and the mixture is warmed to 100° C. The nitrogen formed is let down continuously under 9 bar. When the reaction had ended (about 1 hour), the mixture is cooled to room temperature, the residual pressure is let down and excess HF is distilled off in vacuo. The residue is stirred in methylene chloride and the mixture is washed neutral with water and finally with NaHCO3 solution, dried and concentrated. The product is purified by recrystallisation from light petroleum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:15][C:14]3[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][CH2:10][CH2:9][C:8]=3[C:7]=2[CH:20]=1.Cl.Cl[CH2:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][NH:31][CH:32]2C[CH2:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:37][CH:38]=3)[C:14]3[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][CH2:10][CH2:9][C:8]=3[C:7]=2[CH:20]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3
Reactant: ClCc1ccc(OCCNC2CCCC2)cc1
Agent: Cl
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCC3)cc2)-c2ccccc2SCC1

Procedure:
Following the same procedure in Example 102, using 9-methoxy-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (562 mg) and [2-(4-chloromethyl-phenoxy)-ethyl]-cyclopentyl-amine hydrochloride salt as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][N:5]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[C@H:6]([C:31]([OH:33])=O)[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:14]([NH:22][S:23]([C:26]1[S:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C1C([N+]([O-])=O)=CC=C(O)C=1.C1CCC(N=C=NC2CCCCC2)CC1.O.[NH2:70][NH2:71]>CCOC(C)=O.C(O)C>[CH3:3][CH:2]([CH2:4][N:5]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[C@H:6]([C:31]([NH:70][NH2:71])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:14]([NH:22][S:23]([C:26]1[S:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:1]
Reactant: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)C(=O)O)S(=O)(=O)c1ccc(N)cc1
Reactant: NN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)C(=O)NN)S(=O)(=O)c1ccc(N)cc1
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of Nα-(4-aminobenzenesulfonyl)-Nα-isobutyl-Nε-[N′α-(2-thiophenesulfonyl)-L-phenylalanyl]-L-lysine (650 mg, 1.0 mmol, example 46) dissolved in EtOAc (20 mL) was treated with p-nitrophenol (139 mg, 1.0 mmol) and DCC (206 mg, 1.0 mmol) and was left in a refrigerator overnight. Afterwards, the precipitate was filtered off through celite and the solvent evaporated. The crude residue was used without further purification. A portion of the residue (55 mg, 0.072 mmol) was added to a solution of hydrazine hydrate in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 25 mg, 30% of the desired material.
Reaction SMILES: C(OC(=O)[N:7]([CH2:25][C:26]1[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[C:24]3[CH:23]=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[O:15])=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:33][O:32][C:29]1[N:28]=[CH:27][C:26]([CH2:25][NH:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([C:16]3[C:24]4[CH:23]=[N:22][CH:21]=[N:20][C:19]=4[NH:18][CH:17]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(=O)c3c[nH]c4ncncc34)cn2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncncc34)cn2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.5 %

Procedure:
To (6-methoxy-pyridin-3-ylmethyl)-[5-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (73, 66 mg, 0.14 mmol) in 5 mL of dichloromethane, trifluoroacetic acid (0.5 mL, 6.0 mmol) was added. The reaction was stirred at room temperature for 4 hours, then concentrated under vacuum, and combined with aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate adsorbed onto silica. This was purified by silica gel column chromatography eluting with methanol and dichloromethane. Appropriate fractions were combined, the solvents removed under vacuum, and the resulting solid washed with hexanes and ethyl acetate, with sonicating. The solid was collected by filtration to provide the desired compound as a white solid (P-0008, 4.8 mg). MS (ESI) [M+H+]+=360.9.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2.O[Li].O>C1COCC1.O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][NH:20][C:19]=1/[CH:18]=[C:10]1\[C:11](=[O:17])[NH:12][C:13]2[C:9]\1=[C:8]([C:7]#[C:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH:16]=[CH:15][CH:14]=2
Reactant: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)O)c21

Procedure:
Using Method F above, (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester (50 mg, 0.14 mmol) (from Example 8 above) was hydrolyzed with LiOH-H2O (118 mg, 2.8 mmol) in THF (3 mL) and water (3 mL) for 22 h. (Yield 40 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30]C)=[O:29].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(Cl)Cl.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:28](=[O:29])[OH:30])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)Cl
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 gm, 7.6 mmol) and triethylamine (1.0 gm, 10 mmol) in DCM (50 ml) was treated with methyl chloroformate (860 mg, 9.12 mmol) dropwise at room temperature. The mixture was stirred for 1 hr. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (28 gm of Sorbsil C-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed 2.34 gm. It was converted to a fumarate salt by treatment with fumaric acid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by adding drops of isopropyl ether, yield: 2.31 gm, m.p.=163°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([NH:17][C:18]3[CH:19]=[C:20]([C:21](=[O:22])[NH:23][CH:24]4[CH2:26][CH2:25]4)[CH:27]=[CH:28][C:29]=3[CH3:30])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of 5-(4-chlorophenyl)furan-2-carboxylic acid (45 mg, 0.20 mmol) and 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) (50 mg, 0.22 mmol) in DMF (0.5 mL) DIPEA (0.105 mL, 0.6 mmol) and the resulting mixture was stirred at rt for 1 h then at 80° C. for 1 h. The reaction was cooled to rt and water (3 mL) was added and the crude product was collected by vacuum filtration and dried under vacuum to afford 78 mg of a tan solid. The crude product was recrystallized from CH2Cl2 to afford 48 mg of a light tan solid as the title compound (Example 127). HPLC Ret. Time=3.52 min, LCMS [M+H]+ 395.23.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([OH:8])[CH2:4][N+:5]([O-])=O.[H][H].[ClH:14]>C(O)C.CO.[Pd]>[ClH:14].[NH2:5][CH2:4][C:3]([CH3:9])([OH:8])[C:2]([F:11])([F:10])[F:1]
Reactant: [H][H]
Reactant: CC(O)(C[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(O)(CN)C(F)(F)F
Reaction time: 48 h

Procedure:
Pd/C was added (1 g) to a 200 ml glass vessel. Ethanol (50 ml, dry) was added cautiously under an atmosphere of CO2. 1,1,1-Trifluoro-2-methyl-3-nitropropan-2-ol (10 g, 57.8 mmol) was dissolved in ethanol (50 ml, dry) and added to the glass vessel. The reaction mixture was put under a positive pressure of hydrogen (5 bar) at room temperature and hydrogenated for 2 days. The reaction mixture was filtered through Celite® (filter material) and washed with excess ethanol. The solvent was removed in vacuo to yield a colourless oil. The oil was dissolved in MeOH (50 ml) and treated dropwise with HCl (1 M) in MeOH (30 ml). The solution was left to stir for 30 minutes and concentrated in vacuo azeotroping with MeCN to afford the title compound as a waxy white solid; 1H NMR (DMSO-d6, 400 MHz) δ 8.3 (3H, broad s), 6.9 (1H, broad), 3.0 (2H, q), 1.4 (3H, s).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH:28][C@@H:29]([C@H:32]([OH:37])[C@H:33]([OH:36])[CH2:34]O)[CH:30]=[O:31].[BH4-].[Na+]>CO.C(O)(=O)C>[CH:25]([O:24][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@@H:2]4[NH:1][CH2:34][C@H:33]([OH:36])[C@@H:32]([OH:37])[C@H:29]([OH:28])[CH2:30][OH:31])[N:15]=2)=[CH:23][C:20]=1[C:21]#[N:22])([CH3:27])[CH3:26]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NC[C@H](O)[C@@H](O)[C@H](O)CO)no2)cc1C#N
Temperature: 50 °C
Reaction time: 18 h
Yield: 12.5 %

Procedure:
Prepared using General Procedure 13. To a solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (50.mg, 0.14 mmol) in MeOH (10 mL) was added (2S,3R,4R)-2,3,4,5-tetrahydroxypentanal (20.71 mg, 0.14 mmol) and acetic acid (2 drops) with stirring at 50° C. for 18 h. The reaction was cooled to room temperature and sodium borohydride (52.2 mg, 1.38 mmol) was added slowly with stirring for 2 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3 aqueous (10 mL) and extracted with EA (3×10 mL). The organic layers were washed with brine and dried over Mg2SO4. The product was purified by preparative HPLC to give 8.68 mg (25%) of 2-isopropoxy-5-(3-((S)-1-(((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 119 as a solid. LCMS-ESI (m/z) calculated for C26H30N4O6: 494.5. found 495.2 [M+H]+, tR=2.42 min.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:35][CH2:36][OH:37])[CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:35][CH:36]=[O:37])[CH2:20][C:21]([N:23]([CH3:1])[CH2:24][C:25]2[CH:26]=[C:27]([O:33][CH3:34])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: COc1cc(CNC(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)cc(OC)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CN(C)C(=O)CC(CC=O)c2ccc(Cl)c(Cl)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.6 %

Procedure:
Oxalyl chloride (3.2 g) in CH2Cl2 (125 mL) was cooled to -78° C. and treated with a solution of DMSO (4.12 g) in CH2Cl2 (20 mL) over 15 minutes. This mixture was stirred for 15 minutes whereupon a CH2Cl2 (30 mL) solution of 3,4-Dichloro-beta-(2-hydroxyethyl)-N-[(3,5-dimethoxyphenyl)methyl]benzenepropanamide (9.0 g) was added dropwise. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (6.4 g) in CH2Cl2 (25 mL) and stirred for an additional 30 minutes at -78° C., then allowed to warm to ambient temperature. The reaction mixture was washed with water (125 mL), the organic fraction separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil (12 g). Silica gel chromatography eluting with 10% EtOAc/CH2Cl2 gave the title compound (8.2 g).