Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[C:54]1([CH3:65])[CH:59]=[CH:58][C:57]([C:60]#[C:61][C:62](Cl)=O)=[CH:56][CH:55]=1>CC(=O)OCC>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:10]([CH2:35][C:36]([OH:38])=[O:37])[CH2:9][C:8]3[CH:43]=[CH:44][C:5]([C:3]4[N:4]=[C:62]([C:61]#[C:60][C:57]5[CH:58]=[CH:59][C:54]([CH3:65])=[CH:55][CH:56]=5)[O:1][N:2]=4)=[CH:6][CH:7]=3)=[O:34])=[CH:13][CH:14]=2)=[O:33])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:23]=1
Reactant: Cc1ccc(C#CC(=O)Cl)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=N)NO)cc3)cc2)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(C#Cc5ccc(C)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
Prepared using General Procedures 20 and 8. To a stirred solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33 (200 mg, 0.325 mmol) in dioxanes (4 mL) was added DIEA (85 μL, 0.488 mmol) then 3-(p-tolyl)propioloyl chloride (60 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 30 mins then at 120° C. for 3 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (100 mL) and washed with brine (100 mL). The organics were concentrated and the residue diluted with DCM (5 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford 44 mg (19%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(p-tolylethynyl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 471 as an off-white powder. LCMS-ESI (m/z) calculated for C37H29F3N4O6: 682; found 683 [M+H]+, tR=8.49 min (Method 9).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:46][C@@H:47]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]3C=CC=CC=3)=[C:51]([NH:63][CH:64]=[O:65])[CH:50]=2)[OH:48])[CH2:26][C@H:27]([OH:45])[C:28]2[CH:33]=[CH:32][C:31]([O:34]CC3C=CC=CC=3)=[C:30]([NH:42][CH:43]=[O:44])[CH:29]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:68]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:56]([OH:68])(=[O:55])[CH3:57].[C:56]([OH:68])(=[O:55])[CH3:57].[OH:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:27]([OH:45])[CH2:26][N:25]([CH2:46][C@H:47]([OH:48])[C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([NH:63][CH:64]=[O:65])[CH:50]=2)[CH2:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=2)=[CH:29][C:30]=1[NH:42][CH:43]=[O:44]
Reactant: CO
Reactant: O=CNc1cc([C@@H](O)CN(CCCCc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)C[C@H](O)c2ccc(OCc3ccccc3)c(NC=O)c2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(NC=O)c2)C[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of {4-[4-(4-{bis-[2-(4-benzyloxy-3-formylaminophenyl)-2-(R)-hydroxyethyl]-amino}butyl)phenyl]butyl}carbamic acid benzyl ester (10) (0.17 g, 0.19 mmol), palladium dihydroxide (50 mg, 10% Pd(OH)2 on carbon, 50% wet), eight drops of acetic acid, methanol (10 mL), and dichloromethane (5 mL) was stirred at rt for 18 h under atmospheric hydrogen pressure. The catalyst was filtered through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 13 as a white solid (0.10 mg, 98%); m/z (ESI) 579 [C32H42N4O6+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>>[CH2:26]([C:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCBr
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: C=CCCC(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a suspension of sodium hydride (8.7 g, 218 mmol, 60% suspension) in dimethylformaamide (250 mL) at 0° C. was added diethyl 2-(tert-butoxycarbonylamino)malonate (50.0 g, 182 mmol) in dimethylformaamide (250 mL). After stirring for 30 minutes, 4-bromobut-1-ene (29.5 g, 218 mmol, 22.2 mL) was added and the mixture was warmed to 90° C. After stirring an additional 4 h, the solution was cooled to room temperature and the solvents were removed by evaporation. The resulting residue was diluted with ethyl acetate (1.0 L), washed successively with water (2×250 mL), saturated aqueous sodium chloride (1×200 mL) and concentrated. Purification using a combiflash system (330 g silica column, eluted with 15-50% ethyl acetate in heptanes) gave diethyl 2-(but-3-enyl)-2-(tert-butoxycarbonylamino)malonate (54 g, 90%). 1H NMR (CDCl3) δ 5.92 (bs, 1H), 5.79-5.71 (m, 1H), 5.03-4.93 (m, 2H), 4.24-4.19 (m, 4H), 2.36 (m, 2H), 1.96-1.93 (m, 2H), 1.42 (s, 9H), 1.27-1.24 (m, 6H).
Reaction SMILES: [I-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:30][CH:27]4[CH2:29][CH2:28]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1
Reactant: NC1CC1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-chloro-1-[(cyclopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:32](=[O:44])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:45])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH:41]([C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:32]([C@@H:15]2[N:16]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[CH2:17][CH2:18][N:13]([C:11]3[S:12][C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH3:45])[N:10]=3)[CH2:14]2)=[O:44])=[CH:40][CH:39]=1)([CH3:43])[CH3:42]
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)sc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)sc1C(=O)O
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A solution of the compound (224 mg) obtained in Example 5 in trifluoroacetic acid (1.1 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated again under reduced pressure. Diisopropyl ether was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, and dried to give the title compound (97 mg).
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC.[N+]([C@@H:28]1[C@@H:31]([CH2:32][CH:33]=[CH2:34])[N:30]([C:35](=[C:40]([CH3:42])[CH3:41])[C:36]([O:38][CH3:39])=[O:37])[C:29]1=[O:43])#[C-]>C1C=CC=CC=1>[O:43]=[C:29]1[CH2:28][C@@H:31]([CH2:32][CH:33]=[CH2:34])[N:30]1[C:35](=[C:40]([CH3:42])[CH3:41])[C:36]([O:38][CH3:39])=[O:37]
Reactant: [C-]#[N+][C@H]1C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Yield: 99.2 %

Procedure:
2,2'-Azobis(2-methylpropionitrile) (98 mg) and tributyltin hydride (0.95 ml) were added to a solution of methyl 2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (740 mg) in benzene (15 ml), and the mixture was refluxed for 20 minutes. The reaction mixture was chromatographed on silica gel (15 g) eluting with a mixture of hexane and ethyl acetate (5:1-3:1) to give methyl 2-[(4R)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (660 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([CH:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1>CO>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][C:21]1([CH2:20][CH2:19][CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:23][CH2:22]1)[CH2:1][C:2]2=[O:3]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCC(c3ccccc3)CC2)Oc2ccc(Br)cc21
Yield: 65.2 %

Procedure:
In a 50 mL round bottom flask was placed 5-bromo-2-hydroxyacetophenone (1 g, 4.65 mmol) and 4-phenylcyclo-hexanone (810 mg, 4.65 mmol). They were dissolved in MeOH (9.3 mL). To this solution was added pyrrolidine (764 μL, 9.30 mmol) dropwise. To the flask was attached a condenser and the reaction mixture was heated at reflux overnight (˜14 hours). The next morning the volatiles were remove under reduced pressure and the crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, Ethyl Acetate/Hexanes as the eluents). The corresponding fractions were combined and concentrated yielding 6-bromo-4′-phenylspiro[chroman-2,1′-cyclohexan]-4-one (1.12 g, 3.03 mmol, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6](S(C1C=CC=CC=1)=O)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCCCc1cccc2cncn12)S(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C=CCCCc1cccc2cncn12

Procedure:
A solution of 3 g of 5-[5-ethoxycarbonyl-5-(phenylsulfinyl)pentyl]-imidazo[1,5-a]pyridine in 50 ml xylene is heated at reflux temperature for 30 minutes under an atmosphere of nitrogen. The xylene is then removed by distillation under reduced pressure, the residue is dissolved in 15 ml of diethyl ether and purified by column chromatography on silica gel. The product is eluted using a 2:1 mixture of diethyl ether and ethyl acetate as eluent. Evaporation of the solvent yields 5-(5-ethoxycarbonylpent-4-enyl)-imidazo[1,5-a]pyridine as an oil; NMR (CDC13) 1.29 (t,3H), 4.25 (q,2H), 5.88 (d, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:13]2[C:18](=[CH:19][C:20]=1[Cl:21])[N:17]=[C:16]([CH3:22])[CH:15]=[CH:14]2)[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl(O)(=O)(=O)=O>C(OC(=O)C)(C)(C)C>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:2]([CH3:4])([CH3:3])[CH3:1])[C:11]1[C:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:13]2[C:18](=[CH:19][C:20]=1[Cl:21])[N:17]=[C:16]([CH3:22])[CH:15]=[CH:14]2)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)COC(=O)C(C)(C)C)c(Cl)cc2n1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(Cl)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 155.3 %

Procedure:
To a stirred solution of (S)-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)-2-hydroxyethyl pivalate (H) (25 mg, 0.058 mmol) in t-butylacetate (3 mL) was added 70% perchloric acid (0.02 mL, 0.23 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours and quenched by the slow addition of a NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 1J (22 mg, 78%). LCMS-ESI+ (m/z): 488.2, 490.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:5][C:4]=2[N:3]=1.[ClH:35]>C(O)C>[ClH:35].[ClH:35].[NH2:27][CH2:26][CH2:25][O:24][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:13]([CH2:22][CH3:23])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCc1nc2c(N)nc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Agent: Cl
Solvent: CCO
Product: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl 2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (1.8 g, 3.83 mmol) was added to 4.0M ethanolic hydrogen chloride (13 mL) and the reaction was heated to 65° C. for 1 hour. The milky slurry solidified after 20 minutes. Ethanol (10 mL) was added to loosen the solid. After 1 hour, the heat was removed and the reaction was allowed to cool to ambient temperature. Filtration afforded 1.3 g of 7-(2-aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride as a white solid, mp 238° C., decomposition.
Reaction SMILES: [OH-].[K+].Cl.[OH:4][C:5]1[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:13]I.Cl>CS(C)=O>[OH:12][CH2:11][C:6]1[C:5]([O:4][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: OCc1ncccc1O
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cccnc1CO
Yield: 31.3 %

Procedure:
Potassium hydroxide (41.66 g ,0.744 mol) was ground under nitrogen and stirred in DMSO (130 ml, anhydrous) for 20 min. 3-Hydroxy-2-hydroxymethyl pyridine hydrochloride [Aldrich] (47 g, 0.248 mol) was added and stirred for 30 rain in an ice bath. Methyl iodide (35.2 g, 0.248 mol, 15.43 ml) in DMSO (20 ml) was added dropwise to the solution and then allowed to stir overnight at room temperature. 5N HCl was added to pH 1 and the solution was extracted with dichloromethane (5×500 ml). The aqueous was then basified with 5N NaOH to pH 14 and extracted with dichloromethane (3×500 ml). The organics (base wash) were dried over sodium sulfate, and concentrated leaving tan colored crystals. The solid was recrystallized (50% ethyl acetate/hexanes) providing 10.8 g (32%) of the titled product as light tan crystals:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][SiH:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])([CH3:4])[CH3:3].[Br-:14]>Cl[Pd]Cl.C(Br)C=C>[CH3:4][Si:2]([C:5]#[C:6][Si:7]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:9])[CH3:10])[Br:14])([CH3:1])[CH3:3]
Reactant: [Br-]
Reactant: CC(C)[SiH](C#C[Si](C)(C)C)C(C)C
Agent: Cl[Pd]Cl
Solvent: C=CCBr
Product: CC(C)[Si](Br)(C#C[Si](C)(C)C)C(C)C
Temperature: 60 °C

Procedure:
(Trimethylsilylethynyl)diisopropylsilane (14 g, 66 mmol) and allyl bromide (˜40 mL) were added to a round-bottom flask equipped with a stir-bar. A septum and bubbler were attached and the solution was purged with N2 for 15 min. PdCl2 (0.06 g, 0.3 mmol, 0.5 mol %) was added and the reaction was heated at 60° C. for 3 hours, or until analysis by GC-MS showed complete conversion to the bromide. After removing the reaction from the heat, pentane (50 mL) was added and the solution was chilled for 20 min. The PdCl2 was removed by filtration through a fine fitted funnel, then solvent was removed using a rotary evaporator, yielding 18.8 g of (trimethylsilylethynyl)diisopropylbromosilane as a light brown liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N:22]1[C:26](=[O:27])[CH2:25][CH:24]([CH2:28][N:29]2[CH:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[N:30]2)[CH2:23]1.CCN=C=NCCCN(C)C.Cl>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:34]([C:32]1[CH:31]=[N:30][N:29]([CH2:28][CH:24]2[CH2:25][C:26](=[O:27])[N:22]([C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[F:14])[CH2:23]2)[CH:33]=1)=[O:35]
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=C(O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(CC3CC(=O)N(c4ccc(F)cc4F)C3)c2)c1=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 60.4 %

Procedure:
A mixture of 5,6-Diamino-3-propyl-1H-pyrimidine-2,4-dione (0.12 g, 0.67 mmol) and 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid (0.18 g, 0.56 mmol) in methanol (6 ml) was cooled to 0° C. and added EDCI.HCl (0.15 g, 0.78 mmol) and stirred at 25° C. for 20 hours. Solvents were removed under reduced pressure and to this reaction mixture water (10 ml) was added. Solid obtained was filtered off and washed with cold water (20 ml) followed by diethyl ether (25 ml). It was then dried and the crude product was purified by column chromatography using silica gel (100-200 mesh) and 6% methanol in DCM as an eluent to obtain 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.165 g, 60%) as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C.[Cl:54][C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][C:64]=1[O:65][CH:66]([CH3:68])[CH3:67])/[C:58](=[N:60]/O)/[NH2:59]>C(#N)C>[Cl:54][C:55]1[CH:56]=[C:57]([C:58]2[N:60]=[C:17]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:16]4)[O:19][N:59]=2)[CH:62]=[CH:63][C:64]=1[O:65][CH:66]([CH3:68])[CH3:67]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2noc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)C4)n2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.4 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid (190 mg, 0.722 mmol) in acetonitrile (3 mL) in a 5 mL microwave vial was added HOBT (330 mg, 2.16 mmol), DCC (298 mg, 2.16 mmol), and DIEA (0.115 mL, 0.656 mmol). The mixture was stirred at room temperature for approximately 16 hours. Next, (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (150 mg, 0.656 mmol) (prepared by General procedure B) was added and the reaction was heated to 150° C. under microwave irradiation (max 300 W) for 20 minutes. After cooling, the reaction mixture was filtered, concentrated, and purified via Analogix system using RediSep 40 g column, with a gradient of 0-40% EtOAc/Heptane over 30 min. at a flow rate of 30 ml/min. Fractions containing product were combined, rotovapped, and dried in a vacuum oven to give tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindoline-2-carboxylate (46.2 mg, 15.5%) LCMS (Table 1, Method c) Rt=3.40 min, m/z 456.22 (M+H)+; 1H NMR (400 MHz, DMSO) δ ppm 8.16 (d, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.61 (m, 1H), 7.39 (d, 1H), 4.82 (sept, 1H), 4.70 (d, 4H), 1.48 (s, 9H), 1.35 (d, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>COCCOC>[C:15]([CH2:16][CH2:17][N:2]([CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:1])#[N:18]
Reactant: C=CC#N
Reactant: CNCCCc1c[nH]c2ccccc12
Solvent: COCCOC
Product: CN(CCC#N)CCCc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
A mixture of 37.6 g N-methyl-3-(3-indolyl)-propylamine and 21, 2 g acrylonitrile in 65 ml anhydrous 1,2-dimethoxyethane are warmed with stirring at 60°0 for 21/2 hours. N-(2-cyanoethyl-N-methyl-3-(3-indolyl)propylamine (M.pt 48°-49° after crystallization from isopropyl ether) is obtained after working up.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=O)C.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CO>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:14])[CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a stirred solution of 4-acetylamino-2-methyl-benzoic acid (25.5 g) in methanol (250 ml) was added conc. H2SO4 (19 ml) dropwise and the reaction heated to reflux. After 2.5 h, the reaction was cooled to rt. NaHCO3 (aq) was added until alkaline and the obtained mixture was extracted with EtOAc. The organic extracts were washed with NaOH(aq) (2 M) 3 times, then dried and concentrated affording 17.6 g of the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][N:5]([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@:26]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:30](O)=[O:31])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(OC(N1CCC[C@@](CC2C=CC=CC=2)(C(O)=O)C1)=O)(C)(C)C>O1CCCC1.CCOC(C)=O.CCCCCCC>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@@:26]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:30]([N:4]([CH3:3])[N:5]([CH3:7])[CH3:6])=[O:31])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@](Cc2ccccc2)(C(=O)O)C1
Reactant: CNN(C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@](Cc2ccccc2)(C(=O)O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)N(C)C(=O)[C@]1(Cc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1

Procedure:
Trimethylhydrazine dihydrochloride (15,3 g, 104 mmol) was suspended in tetrahydrofuran (250 ml) in a one-neck round-bottom flask (1l) equipped with a large magnetic stirrer, and an addition funnel/nitrogen bubbler. The flask was then placed in a water-bath (temp: 10-20° C.), bromo-tris-pyrrolydino-phosphonium-hexafluorophosphate (40,4 g, 86,7 mmol) was added, and under vigorous stirring dropwise addition of diisopropylethylamine (59 ml, 347 mmol). The mixture (with heavy precipitation) was stirred for 5 min., and a solution of the product from step d which is either (3R)-3-benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester or (3S)-3-benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester (27,7 g, 86,7 mmol) in tetrahydrofuran (250 ml) was added slowly over 1,5 hour. The mixture was stirred overnight at room temperature. The reaction was diluted with EtOAc (1000 ml), washed with H2O (500 ml), aqueous NaHSO4, (200 ml, 10%), aqueous NaHCO3 (200 ml, saturated), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to afford a thin orange oil. The mixture was dissolved in EtOAc (300 ml), added to SiO2 (150 g) and concentrated in vacuo to a dry powder which was applied onto a filter packed with SiO2 (150 g), washed with heptan (1l) and the desired compound was liberated with EtOAc (2,5l). After concentration in vacuo, the product which is either (3R)-3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)-piperidine-1-carboxylic acid tert-butyl ester or (3S)-3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)-piperidine-1-carboxylic acid tert-butyl ester (49 g) as an orange oil was obtained.