Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:24][C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[C@@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). R-(+)-α-Methylbenzylamine (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 mmol). The reaction was stirred overnight at room temperature. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted twice with water, once with brine and dried over MgSO4. Filtration and concentration in vacuo afforded a white foam that was purified by flash column chromatography (84.5:15:0.5 CH2Cl2:acetonitrile:NH4OH) to afford a clear oil. The material was rechromatographed (89.5:10:0.5 CH2Cl2:acetonitrile:NH4OH) to afford the title compound as a clear oil. Wt.: 547 mg (7%). 1H NMR (300 MHz, CDCl3) δ7.31 (m, 3H), 7.22 (m, 2H), 3.85 (m, 3H), 2.68 (m, 1H), 2.46 (m. 1H), 2.17 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (m, 2H), 0.97 (d, 3H); LC/MS m/z 319 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH:18]=[C:17]([C:19]2[C:20]([C:47]([O:49]C(C)(C)C)=[O:48])=[N:21][C:22]([N:25]3[CH2:34][CH2:33][C:32]4[C:27](=[C:28]([C:35](=[O:46])[NH:36][C:37]5[S:38][C:39]6[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=6[N:41]=5)[CH:29]=[CH:30][CH:31]=4)[CH2:26]3)=[CH:23][CH:24]=2)[CH:16]=[N:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO>[S:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=[C:37]1[NH:36][C:35]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[CH2:26][N:25]([C:22]1[N:21]=[C:20]([C:47]([OH:49])=[O:48])[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:1]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:18]=3)=[CH:24][CH:23]=1)[CH2:34][CH2:33]2)=[O:46]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(C(c2ccccc2)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(-c3cnn(C(c4ccccc4)c4ccccc4)c3)c(C(=O)O)n1)CC2

Procedure:
A suspension of EXAMPLE 75B (30 mg) and lithium hydroxide (2 mg) in tetrahydrofuran and methanol (2:1, 1 mL) was heated at 60° C. for 16 hours. The reaction mixture was quenched with HCl (0.2 mL, 1M), concentrated and purified by chromatography on silica gel using 0-5% methanol/dichloromethane as eluent to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 13.14 (s, 1H), 12.87 (s, 1H), 8.04 (d, 1H), 7.82 (s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.66 (s, 1H), 7.61 (d, 1H), 7.44-7.51 (m, 1H), 7.40-7.44 (m, 1H), 7.29-7.40 (m, 5H), 7.19 (d, 4H), 6.93 (t, 2H), 4.94 (s, 2H), 3.94 (s, 1H), 3.86 (t, 2H), 2.99 (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]=O)[CH:7]=1.Cl.[NH2:16][OH:17].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]=[N:16][OH:17])[CH:7]=1
Reactant: NO
Reactant: COc1cc(Br)cn2ncc(C=O)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Br)cn2ncc(C=NO)c12
Reaction time: 1 h

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (100 mg, 0.365 mmol), hydroxylamine hydrochloride (27.9 mg, 0.401 mmol) and sodium bicarbonate (33.7 mg, 0.401 mmol) were suspended in absolute ethanol (4 ml) and stirred for 1 h (heavy colorless precipitate forms). The mixture was concentrated to dryness, then diluted in 8 mL of water and stirred for 5 minutes. The solid was filtered, washed with water, then placed under vacuum overnight to afford 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde oxime as a mixture of oxime isomers.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=[O:18].[OH-].[Na+].O>O1CCOCC1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2F)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1ccccc1F
Temperature: 25 °C
Yield: 136 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(2-fluorophenoxy)phenyl]acetate (5.7 g.), sodium hydroxide (1.6 g.), water (25 ml.) and dioxane (25 ml.) was refluxed under heating for 16 hours with stirring. The reaction mixture was left to cool at ambient temperature and dioxane was distilled off under reduced pressure. To the residue was added water and the mixture was washed with diethyl ether. Diethyl ether was added to the aqueous layer and the mixture was adjusted to pH 3 to 4 with 5% sulfuric acid. The diethyl ether layer was separated, washed with water and dried over magnesium sulfate and then the solvent was distilled off under reduced pressure to give 2-[2-amino-3-(2-fluorophenoxy)phenyl]acetic acid (7 g.). This crude substance was recrystallized from a mixture of ethyl acetate and n-hexane to give the pure compound (3.6 g.), mp 122° to 123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31](O)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][C:10]=1[CH3:34].[CH3:35][NH:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][C:10]=1[CH3:34]
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)cc1C
Reactant: CNCCc1ccncc1
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)N(C)CCc4ccncc4)n3Cc3ccccc32)cc1C

Procedure:
Prepared by treatment of 10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E, with 4-(2-methylaminoethyl)pyridine (1.2 equiv.) in the manner of Example 5, Step E.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:3]4/[C:2](=[O:10])[NH:1][C:9]5[C:4]/4=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Yield: 83.7 %

Procedure:
The title compound (61 mg, 84%) was synthesized as a yellow solid according to the method described for (E/Z)-3-((3-iodo-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one (oil temp 75° C., reflux 90 min) using oxindole (26.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H, NH), 10.64 (s, 1H, NH), 8.91 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.73 (d, J=16.8 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H, partially overlapping with the peak at 7.60 ppm), 7.60 (d, J=17.2 Hz, 1H, partially overlapping with the peak at 7.61 ppm), 7.54 (d, J=8.4 Hz, 1H), 7.43 (dd, J=7.8 Hz, 4.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.85 (t, J=7.8 Hz, 1H); MS ESI 365.1 [M+H]+, calcd for [C23H16N4O+H]+ 365.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]1.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 40 °C

Procedure:
To a round 25 ml bottomed flask containing trans-methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate (60 mg, 0.23 mmol) and water (4 ml) was added sodium hydroxide (32 mg, 0.78 mmol) and the solution heated to 40° C. for 1 hr. The solution was poured into a separating funnel containing ethyl acetate (15 ml) and water (10 ml). To the aqueous layer was then added aqueous hydrochloric acid (10 ml, 1.0M) and ethyl acetate (20 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound (34 mg, 60%) as a solid. m/z (ES+) 251 (M+H+); δH(CD3OD) 1.20 (2H, m), 1.48 (2H, m), 1.89 (4H, m), 2.25 (2H, d), 2.81 (1H, m), 6.27 (2H, m), 6.91 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:37])[C:28]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)=[O:29].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:25][O:26][C:27](=[O:37])[C:28](=[O:29])[C:30]1[CH:31]=[CH:32][C:33]([O:24][CH2:23]/[CH:22]=[CH:21]/[C:9]2[C:10]([CH:18]([CH3:20])[CH3:19])=[N:11][C:12]3[C:17]([C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:34][CH:35]=1
Reactant: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/CO
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2c(C(C)C)nc3ccccc3c2-c2ccc(F)cc2)cc1
Yield: 62.5 %

Procedure:
As in Example 15, (E)-3-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-2-propen-1-ol (1.0 g) was coupled with 4-hydroxyphenylglyoxylic acid methyl ester (0.565 g) in the presence of diethyl azodicarboxylate (0.683 g) and triphenylphosphine (1.02 g) in tetrahydrofuran (30 mL). The usual work up, followed by purification of the crude product by flash chromatography over silica gel (50 g; diethyl ether-hexane; 1:4) and crystallization from diethyl ether to provide 0.94 g of (E)-4-[3-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-2-propenyloxy]-alpha-oxobenzeneacetic acid methyl ester, mp 109°-111° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11](=[O:13])[NH2:12].[C:14]1([CH2:20][C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ON1C2C=CC=CC=2N=N1.OC1C2N=NNC=2C=CC=1>ClCCl.CN(C)C=O>[C:11]([C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[S:6][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[NH2:12]
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Agent: Oc1cccc2[nH]nnc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)Cc2ccccc2)sc2c1CCCC2
Temperature: 20 °C
Reaction time: 170 h

Procedure:
A mixture of commercially available 2-amino-3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophene (5 mg, 0.026 mmol), phenylacetic acid (7 mg, 0.05 mmol), N-hydroxybenzotriazole (8.5 mg, 0.065 mmol), and N-cyclohexylcarbodiimide-N′-methylpolystyrene (loading about 1.5 mmol/g resin, 50 mg) in dichloromethane (2 ml)/dimethylformamide (0.5 ml) was agitated at 20° C. for 170 h. Afterward tris-(2-aminoethyl)-amine polystyrene (loading about 4 mmol/g resin 40 mg) was added for scavenging the hydroxybenzotriazole and the excess of acid, and the agitation was maintained for additional 24 h.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:12][C:10]1[C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=[CH:2][CH:11]=1
Reactant: Cc1cc(Cl)nc2c(N)nc3ccccc3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccnc2c(N)nc3ccccc3c12

Procedure:
To a solution of 3-chloro-1-methylbenzo[f][1,7]naphthyridin-5-amine (from step 3) in ethyl acetate/methanol (1:2, 0.03 M) was added 10% wt palladium on carbon (0.2 eq.). The reaction vessel was shaken on a hydrogen Pan apparatus under 50 psi of hydrogen overnight. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 1-methylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (CDCl3): δ 8.63 (d, 1H), 8.44 (d, 1H), 7.71 (dd, 1H), 7.54 (m, 1H), 7.45 (d, 1H), 7.30 (m, 1H), 6.20 (bs, 2H), 3.01 (s, 3H). LRMS [M+H]=210.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3.C(N(CC)CC)C.C1(N[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])C=CC=CC=1>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[N:8]3
Reactant: Cc1nc2cccc3nc(SCCCCCN)c1n23
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3nc(SCCCCCNS(=O)(=O)C(F)(F)F)c1n23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg (1.82 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 30 ml of acetonitrile were added 0.51 ml (3.66 mmol) of triethylamine and 1.302 g (3.66 mmol) of N-phenyltrifluoromethanesulfonamide. The mixture was stirred for two hours at room temperature. The solvent was distilled off. To the residue was added methylene chloride, which was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 608 mg (82.1%, a pale yellow solid) of the desired compound.
Reaction SMILES: Cl.[N+:2]([CH:5]=[C:6]([S:16][CH3:17])[NH:7][CH2:8][CH:9](OCC)OCC)([O-:4])=[O:3].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH3:17][S:16][C:6]1[NH:7][CH:8]=[CH:9][C:5]=1[N+:2]([O-:4])=[O:3]
Reactant: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CSc1[nH]ccc1[N+](=O)[O-]
Yield: 53.7 %

Procedure:
Dry hydrogen chloride was passed through a stirred solution of 1-nitro-2-methylthio-2-(2,2-diethoxyethylamino)-ethylene (9.7g, 0.04 mol) in dry ether (250 ml) at 5-10° for 3 hours. The resulting mixture was basified by pouring it into potassium carbonate solution (300 ml). The mixture was filtered to give a yellow solid, and the aqueous phase of the filtrate was separated and extracted with ether (2×150 ml). The combined ether solutions were evaporated to a residue. This residue and the solid filtered off earlier were recrystallised from acetone-chloroform to give 2-methylthio-3-nitropyrrole (3.4g, 54%) m.p. 212-213°.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:16][CH:17]([C:19]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:20])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Pyrrolidine (271 μL, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(pyrrolidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (550 mg, 72%). 1H NMR (CD3OD, 400 MHz) δ 3.93-3.65 (m, 5 H); 3.43-3.28 (m, 4 H) and 2.00-1.81 (m, 4 H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][N:20]2[CH2:42][CH2:41][C:23]3([NH:27][C:26](=[O:28])[N:25]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=4)[C:24]3=[O:40])[CH2:22][CH2:21]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][S:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:25]2[C:24](=[O:40])[C:23]3([CH2:22][CH2:21][N:20]([CH2:19][C@@H:10]4[C@@H:11]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:12][NH:8][CH2:9]4)[CH2:42][CH2:41]3)[NH:27][C:26]2=[O:28])=[CH:35][CH:34]=1)(=[O:37])=[O:38]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CN2CCC3(CC2)NC(=O)N(Cc2ccc(S(C)(=O)=O)cc2)C3=O)[C@@H](c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(CN2C(=O)NC3(CCN(C[C@H]4CNC[C@@H]4c4ccccc4)CC3)C2=O)cc1
Yield: 75.5 %

Procedure:
83 mg (0.139 mmol) of (3S,4S)-3-[3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 3 mL of DCM and 1 mL of TFA and the solution was stirred overnight. The mixture was then evaporated to dryness and the residue was redissolved in 2 mL of toluene and evaporated again at 40° C. The crude compound was then dissolved in 5 mL of 5% methanol in DCM and filtered through a ChemElute™ loaded with 1 mL of 2 M NaOH. The filtrate was evaporated to yield 3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (52.1 mg, 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[H-].[Na+].FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O>O1CCCC1>[F:25][C:24]([F:27])([F:26])[CH2:23][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(CC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (2 g, 9.99 mmol, 1.00 equip), tetrahydrofuran (20 mL), To this was added sodium hydride (480 mg, 20.00 mmol, 2.00 equip) at 0° C. The resulting solution was stirred for 0.5 h at 0° C., and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.784 g, 11.99 mmol, 1.20 equip) was added. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to yield tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate as yellow oil. LCMS (ES, m/z) 283 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)(=[O:32])=[O:31].O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:40][CH:39]=3)[N:10]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Cc1c(Br)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)cn2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
To a solution of 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (Int. 15, 55 mg, 0.148 mmol) in DMF (3 mL) was added cesium carbonate (58 mg, 0.177 mmol) followed by 4-(methylsulfonyl)benzyl bromide (40 mg, 0.163 mmol) and the mixture was stirred at RT for 20 hrs. Further amounts of cesium carbonate (25 mg) and 4-(methylsulfonyl)benzyl bromide (20 mg) were added and stirring was continued for 2 hrs. Water was added and the mixture was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as a yellow solid (49 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[O:23]=[C:15]1[C:14](=[C:10]2[C:11]3[C:7](=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:13][CH:12]=3)[CH2:8][O:9]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(CCCO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.3 %

Procedure:
To a stirred suspension of 3-[5-(3-hydroxy-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (440 mg, 1.43 mmol) and triethylamine (289 mg, 2.86 mmol) in THF (7 ml), was added methanesulfonyl chloride (327 mg, 2.86 mmol). The mixture was stirred for 20 minutes and poured into an ice water (150 ml, containing 0.5 ml of AcOH). The solid was filtered, washed with water and dried under vacuum to afford a crude product. The crude product was purified by silica gel column chromatography, eluted with 5% MeOH in CHCl3, to give methanesulfonic acid 3-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-propyl ester as a yellow solid (437 mg, 79%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:30])=[C:5]([C@@H:10]2[S:15](=[O:17])(=[O:16])[CH2:14][C@@H:13]3[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N+:12]3([O-])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CO>[C:1]([C:3]1[C:4]([CH3:30])=[C:5]([C@@H:10]2[S:15](=[O:16])(=[O:17])[CH2:14][C@@H:13]3[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c([C@H]2C[N+]3([O-])CCN(C(=O)OC(C)(C)C)C[C@H]3CS2(=O)=O)ccc(F)c1C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CS2(=O)=O)ccc(F)c1C#N
Temperature: 80 °C

Procedure:
The above compound from step A (23 mg, 0.052 mmol) was combined with TRIPHENYLPHOSPHINE (24.71 mg, 0.094 mmol) in DMF (0.4 M) and warmed to 80° C. for 20 minutes. LC-Ms showed the completion of the reaction. The reaction mixture was diluted with methanol and purified with mass-directed reverse phase HPLC eluting with 10% acetonitrile/water with 0.1% TFA to 100% acetonitrile with 0.1% TFA to yield the title compound: 1H-NMR (500 MHz, CD3OD): δ ppm 9.05 (m, 1H), 7.24 (m, 1H), 4.63 (bs, 1H), 4.03 (m, 2H), 3.32-3.45 (m, 2H), 3.05 (m, 3H), 2.92 (m, 1H), 2.75 (m, 2H), 2.63 (S, 3H), 2.25 (m, 1H), 1.48 (s, 9H); LC-MS: M+1=424.