Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([CH:19]([NH:22][C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[CH:28]3)=[O:24])[CH2:20][CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:30]2[C:31]3[C:27](=[CH:26][C:25]([C:23]([NH:22][CH:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:20][CH3:21])=[O:24])=[CH:33][CH:32]=3)[CH:28]=[CH:29]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CCC(NC(=O)c1ccc2c(ccn2C(=O)c2ccc([N+](=O)[O-])cc2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Example 25, using 4-nitrobenzoylchloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 428 (M+H)
Reaction SMILES: O=C1N2CC3C(C2=C([C:15]([O:17][CH2:18][C:19](=O)[N:20]([CH3:22])C)=O)C=C1C1C=CC=CC=1)=CC=CC=3.CN(C)CCOC(C1C=C(C2C=CC=CC=2)C(=O)N2CC3C(=CC=CC=3)C=12)=O.FC1C=CC=C2C=1C1=C(C(OC)=O)C=C(C3C=CC=CC=3)C(=O)N1C2.[Cl:83][C:84]1[CH:85]=[CH:86][CH:87]=[C:88]2[C:92]=1[C:91]1=[C:93]([C:104](OC)=[O:105])[CH:94]=[C:95]([C:98]3[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=3)[C:96](=[O:97])[N:90]1[CH2:89]2>>[Cl:83][C:84]1[CH:85]=[CH:86][CH:87]=[C:88]2[C:92]=1[C:91]1=[C:93]([C:104]([N:20]3[CH2:19][CH:18]([O:17][CH3:15])[CH2:22]3)=[O:105])[CH:94]=[C:95]([C:98]3[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=3)[C:96](=[O:97])[N:90]1[CH2:89]2
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1c(Cl)cccc1C2
Reactant: CN(C)C(=O)COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1c(F)cccc1C2
Product: COC1CN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2c(Cl)cccc2C3)C1

Procedure:
A method according to claim 14 wherein the compound is selected from methyl 4,6-dihydro-4-oxo-3-phenyl-4H-pyrido[2,1-a]isoindole-1-carboxylate; (dimethylcarbamoyl)methyl 4,6-dihydro-4-oxo-3-phenylpyrido-[2,1-a]isoindole-1-carboxylate; 2-(dimethylamino)ethyl-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate; and methyl 10-fluoro-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate; and methyl 10-chloro-4, 6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N+:37]([O-:39])=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:30]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCNc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCN(C(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 33 g of 4-chloro-3-nitro-benzoyl chloride in 100 ml of benzene is added dropwise in the course of one hour to a solution, which has been heated to the reflux temperature, of 54.3 g of N-n-hexadecyl-2-nitroaniline in 80 ml of benzene. After a further two hours, the reaction has ended. The reaction solution is poured into 600 ml of hexane and the mixture is left to stand overnight. The resulting crystals are filtered off with suction and washed with hexane. This gives 48 g of the compound with a melting point of 83° to 85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>CN(C=O)C>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:10]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11]2)=[C:2]([NH:1][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[CH:3]=1)#[N:6]
Reactant: CCN=C=O
Reactant: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(C#N)ccc1C1CCc2cncn21
Temperature: 70 °C

Procedure:
To a solution of 3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.090 g, 0.420 mmol), given as example 6B, and DMF (5 mL) is added ethylisocyanate (0.040 mL, 0.510 mmol). The solution is heated to 70° C. in a microwave reactor for 1.5 h followed by heating at 70° C. in an oil bath overnight. The solution is then concentrated and the residue purified via flash chromatography (1-10% MeOH/CH2Cl2) to give 1-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)phenyl]-3-ethylurea. MS (ESI) m/z 296.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (t, J=7.2 Hz, 3 H), 2.47-2.62 (m, 1 H), 2.82-3.04 (m, 2 H), 3.05-3.17 (m, 1 H), 3.21-3.33 (m, 2 H), 5.63 (app t, J=6.8 Hz, 1 H), 5.80 (br s, 1 H), 6.82 (s, 1 H), 6.91 (d, J=8.1 Hz, 1 H), 7.30 (dd, J=8.1, 1.5 Hz, 1 H), 7.39 (s, 1 H), 7.53 (br s, 1 H), 7.97 (d, J=1.3 Hz, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]1([P:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][NH2:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:17][CH2:16][CH2:15][P:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc[nH]1
Reactant: NCCP(c1ccccc1)c1ccccc1
Product: C(=NCCP(c1ccccc1)c1ccccc1)c1ccc[nH]1
Yield: 99.3 %

Procedure:
Replicate the preparation of the ligand used in Ex. 7 except use 0.2 g (2.103 mmol) of pyrrole-2-carbaldehyde and use 0.506 g (2.208 mmol) of 2-(diphenylphosphino)ethanamine instead of N1,N1-dimethylethane-1,2-diamine to give 0.640 g (99%) of N-((1H-pyrrol-2-yl)methylene)-2-(diphenylphosphino)ethanamine as a white solid, which is analytically pure by GC-MS and 1H-NMR: 1H NMR (400 MHz, C6D6) δ 9.49 (s, 1H), 7.62 (s, 1H), 7.49-7.32 (m, 5H), 7.11-6.92 (m, 5H), 6.44-6.29 (m, 2H), 6.22-6.14 (m, 1H), 3.58 (td, J=8.8, 1.0 Hz, 2H), 2.37 (dd, J=8.4, 7.1 Hz, 2H).
Reaction SMILES: CN(C)C=O.Cl.Cl[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[NH2:22][C:23]1[CH:42]=[CH:41][C:26]([O:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([OH:40])=[C:35]([C:38]#[N:39])[CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[CH:25][C:24]=1[F:43]>C(OCC)(=O)C.O>[NH2:22][C:23]1[CH:42]=[CH:41][C:26]([O:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:40][CH2:8][CH:9]4[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]4)=[C:35]([C:38]#[N:39])[CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[CH:25][C:24]=1[F:43]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Reactant: CN1CCCC(CCl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC(COc2cc3nccc(Oc4ccc(N)c(F)c4)c3cc2C#N)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 10.9 %

Procedure:
After adding dimethylformamide (4 ml), 3-chloromethyl-1-methylpiperidine hydrochloride (621 mg) and potassium carbonate (840 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (400 mg), the mixture was stirred at 20° C. for 3 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (60 mg).
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11]2=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:16]=[C:10]2[C:9]1=O)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:9]1[C:10]2=[N:16][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[C:11]2[CH:12]=[CH:13][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Product: Clc1ccc(-c2c3ccnc(Cl)c3nn2-c2ccccc2Cl)cc1
Yield: 77 %

Procedure:
A stirred suspension of 6-benzyl-2-(2-chlorophenyl)-3-(4-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7(6H)-one (1A-3, 925 mg, 2.07 mmol) in POCl3 (20 ml) was heated at reflux for 5 days. After the reaction was cooled and concentrated, in vacuo, an ethyl acetate solution of the residue was washed with saturated aqueous NaHCO3 and then brine. The solution was dried (Na2SO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 40S column using 0–40% ethyl acetate in hexanes to afford I-9A-1a as an off-white solid (600 mg, 77%): +ESI MS (M+1) 374.3; 1H NMR (400 MHz, CD2Cl2) δ 8.00 (d, J=6.2 Hz, 1H), 7.60–7.45 (m, 5H) 7.38 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][C:19]=4[NH:24][C:25](=[O:27])[CH3:26])[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC(=O)Nc1cccc2c1CCNC2
Product: CC(=O)Nc1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH:15]1[CH2:21][C:22]([O:24]CC)=[O:23])(=[O:13])=[O:12]>CO.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH:15]1[CH2:21][C:22]([OH:24])=[O:23])(=[O:13])=[O:12]
Reactant: CCOC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1Cl
Reaction time: 16 h

Procedure:
Lithium hydroxide (0.92 mg, 21.9 mmol) was added to a cooled solution of ethyl 2-(1-(2,4-dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetate (2.7 g, 7.3 mmol) in methanol (25 ml) and water (6 ml), and stirring was carried out for 16 h at room temperature (TLC monitoring). The solvent was removed using a rotary evaporator and the residue was taken up in water. The aqueous phase was washed with diethyl ether and acidified with HCl, and the product was extracted with ethyl acetate. The organic phase was then washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(Br)cc1Oc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A 100 mL round-bottom flask, was charged with 4-bromo-2-phenoxybenzaldehyde (1.00 g, 3.61 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.674 g, 3.62 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.30 g, 10.8 mmol, 3.01 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with H2O (10 mL). The resulting mixture was extracted with dichloromethane (2×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (8/92) to provide 1.20 g (74% yield) of tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 447 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[NH:13][CH3:14].I[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.NC1CCCCC1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC#N.O.[Cu]I>[NH2:20][C:19]1[CH:21]=[CH:22][C:16]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([NH:13][CH3:14])[CH:4]=3)[C:9]2=[O:12])=[CH:17][CH:18]=1
Reactant: Nc1ccc(I)cc1
Reactant: CNc1cc2c(cc1F)C(=O)NCC2
Agent: [Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)cc1)CC2
Temperature: 110 °C
Yield: 60.4 %

Procedure:
A mixture of 7-fluoro-6-(methylamino)-3,4-dihydroisoquinolin-1(2H)-one (70 mg, 0.36 mmol), 4-iodoaniline (119 mg, 0.543 mmol), CuI (27 mg, 0.14 mmol), 1,2-diaminocyclohexane (44 uL, 0.36 mmol) and K3PO4 (153 mg, 0.722 mmol) in dioxane (1.5 mL) was heated at 110° C. overnight, then diluted with CH3CN (5 mL) and H2O (5 mL) and filtered. The filtrate was purified by RP-HPLC to give the noted intermediate compound as a solid (62 mg). ES-MS (M+H)+=286.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH:15]=[CH2:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]>C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=Cc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.4 %

Procedure:
6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester (1.27 g, 5.11 mmol) was dissolved in benzene (10 mL) and EtOAc (10 mL). Tristriphenylphosphine rhodium chloride (150 mg) was added and the reaction was placed under an atmosphere of hydrogen. Stirring at room temperature was continued. After 14 hours, the solvents were removed in vacuo and the crude material was purified by silica gel chromatography to provide 1.14 g (88%) of the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ=1.19 (t, J=7.8 Hz, 3H), 2.10 (s, 3H), 2.60 (q, J=7.8 Hz, 2H), 3.89 (s, 6H), 6.87 (s, 1H), 10.79 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([I:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C.[CH2:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][NH:51]1>CCOC(C)=O.CN(C=O)C.C1COCC1>[I:17][C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:16][C:12]=1[C:13]([N:51]1[CH2:52][CH2:53][C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:50]1)=[O:15]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)c1ccc(I)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(I)c(C(=O)N2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
A 100 mL flask was charged with 3-(tert-butoxycarbonyl)benzoic acid (Matrix, 1.75 g, 7.87 mmol), palladium(II) acetate (0.177 g, 0.787 mmol), iodobenzene diacetate (2.54 g, 7.87 mmol), iodine (2.00 g, 7.87 mmol), and tetrabutylammonium iodide (2.91 g, 7.87 mmol). DCE (30 mL) was added and the dark reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was concentrated in vacuo, diluted with 2M aq. sodium carbonate solution, and then extracted with ether (2×). The aqueous layer was made acidic with concentrated HCl and then extracted with EtOAc (2×). The pooled EtOAc extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give crude 5-(tert-butoxycarbonyl)-2-iodobenzoic acid (1.7 g, 62%) which was used directly without further purification. A 200 mL round bottom flask was charged with crude 5-(tert-butoxycarbonyl)-2-iodobenzoic acid (1.7 g, 4.88 mmol) and HATU (2.23 g, 5.86 mmol). THF (30 mL), DMF (30.0 mL), and 2,6-lutidine (1.1 mL, 9.77 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Next, 1,2,3,4-tetrahydroisoquinoline (0.93 mL, 7.3 mmol) was then added. After stirring at room temperature 1 h, the reaction mixture was suspended in EtOAc, and then washed with sat. aq. sodium bicarbonate solution, 10% aq. LiCl solution, and then sat. aq. bicarbonate solution again. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 120 g column eluting with 0-40% EtOAc/hexanes) to give the title compound (1.46 g, 65%) as a white foam. 1H NMR (CDCl3) δ 7.96-7.90 (m, 1H), 7.81-7.80 (m, 1H), 6.70-6.67 (m, 1H), 7.27-7.13 (m, 4H), 5.09-4.83 (m, 1H), 4.45-4.33 (m, 1H), 4.06-4.01 (m, 1H), 3.50-3.44 (m, 1H), 3.05-2.83 (m, 2H), 1.58 (s, 9H); MS(ESI+) m/z 464.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[N:4][CH:3]=1.[Li]CCCC.CCCCCC.[Sn:18](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22]>CCOCC>[CH3:1][C:2]1[O:6][C:5]([Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:4][CH:3]=1
Reactant: Cc1cnco1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ncc(C)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
A solution of 5-methyloxazole (5.0 g, 60.2 mmol) in Et2O (100 mL) was cooled to −78° C. under N2 and treated with a 1.6 M solution of BuLi in hexane (41.4 mL, 66.2 mmol) dropwise. The mixture was stirred at −78° C. for 30 min and a solution of Bu3SnCl (16.31 mL, 60.2 mmol) in Et2O (50 mL) was then added dropwise. The mixture was stirred at −78° C. for another 30 min and then allowed to warm to RT. The reaction mixture was filtered on celite, and the filtrate concentrated in vacuo. Purification by distillation (0.1 Torr, 128-130° C.) afforded the title compound (3.5 g) as a yellow liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88 (m, 12 H) 1.14-1.22 (m, 6 H) 1.27-1.38 (m, 6 H) 1.52-1.61 (m, 6 H) 2.17-2.21 (m, 3 H) 7.49-7.54 (m, 1 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH:16]([C:20]([OH:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.C(N(CC)CC)C.[NH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[O:38]>C(Cl)Cl.O>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:37](=[O:38])[CH2:36][NH:35][C:20]([CH:16]2[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:15]2)=[O:22])=[CH:44][CH:43]=1
Reactant: COc1ccc(C(=O)CN)cc1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CNC(=O)C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
Oxalyl chloride (2.385 mL, 27.2 mmol) was added to a suspension of 4-(phenylmethyl)-2-morpholinecarboxylic acid (4.02 g, 18.16 mmol) and DMF (0.703 mL, 9.08 mmol) in CH2Cl2 (100 mL) at 0° C. in 10 minutes, and the reaction mixture was stirred at 25° C. for 2 hours. The mixture was concentrated, and the resulting residue was dissolved in CH2Cl2 (100 mL) and triethylamine (5.57 mL, 40.0 mmol). 2-Amino-1-[4-(methyloxy)phenyl]ethanone (3.0 g, 18.16 mmol) was added to the brown solution at 0° C., and the reaction mixture was stirred at 25° C. for 3 hours. Water (150 mL) was added to the reaction mixture, and the aqueous mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to afford the title compound (3.4 g) as a brown solid. LC-MS (ES) m/z=369 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([O:10]C2C=CC(Cl)=CC=2)=O)=[N:5][N:4]=1)#[N:2].[Cl:18]C1C=CC(O)=CC=1>>[C:1]([C:3]1[S:7][C:6]([C:8]([Cl:18])=[O:10])=[N:5][N:4]=1)#[N:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1nnc(C(=O)Oc2ccc(Cl)cc2)s1
Product: N#Cc1nnc(C(=O)Cl)s1

Procedure:
4-Chlorophenyl 5-cyano-1,3,4-thiadiazole-2-carboxylate can be prepared by reacting 4-chlorophenol (12.9 g.) with 17.4 g. 5-cyano-1,3,4-thiadiazole-2-carbonyl chloride as in Example 1 to give 22 g. light tan product.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:16])[CH2:14]Br)=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)=[O:4].[CH3:20][NH:21][CH3:22]>C(O)C>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:16])[CH2:14][N:21]([CH3:22])[CH3:20])=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)=[O:4]
Reactant: COC(=O)Nc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Reactant: CNC
Solvent: CCO
Product: COC(=O)Nc1ccc(NC(=O)CN(C)C)c([N+](=O)[O-])c1

Procedure:
N-(4-methoxycarbonylamino-2-nitrophenyl)-2-bromoacetamide (25 g) in ethanol (250 ml) was treated with a solution of dimethylamine in ethanol (35.5 g of a 30% w/w solution) and the mixture refluxed for one hour. The ethanol was evaporated and the residual solid shaken with water and filtered to give N-(4-methoxycarbonylamino-2-nitrophenyl)-2-dimethylaminoacetamide (21.1 g), m.p. 186°-189° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[C:9]([C:11]1([NH:14][C:15]([C@@H:17]2[CH2:21][C@@H:20]([S:22]([C:25]3[CH:30]=[CH:29][C:28](F)=[CH:27][C:26]=3[Cl:32])(=[O:24])=[O:23])[CH2:19][C@H:18]2[C:33]([N:35]2[CH2:38][C:37]([F:40])([F:39])[CH2:36]2)=[O:34])=[O:16])[CH2:13][CH2:12]1)#[N:10]>CN(C)C=O>[C:9]([C:11]1([NH:14][C:15]([C@@H:17]2[CH2:21][C@@H:20]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:27][C:26]=3[Cl:32])(=[O:23])=[O:24])[CH2:19][C@H:18]2[C:33]([N:35]2[CH2:38][C:37]([F:40])([F:39])[CH2:36]2)=[O:34])=[O:16])[CH2:13][CH2:12]1)#[N:10]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
To a mixture of 2,2,2-trifluoroethanol (0.014 mL, 0.20 mmol) and sodium hydride (dispersion in oil, 55% w/w (9 mg, 20 mmol) in N,N-dimethylformamide (2 mL) was added (1R,2R,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amid (Example 119, 80 mg, 0.16 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 16 h, then was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate then the combined organic layers were washed with water and brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichloromethane/methanol (98:2 v/v) as eluant to afford the title compound (32 mg, 31%) as an off-white gum. MS (EI): 570.0 (M+H)+.