Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:12]([O:13][CH3:14])=[C:11]([CH3:15])[C:10]([O:16][CH3:17])=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.CC1[C:33](OC)=[CH:32][C:28](C(Cl)=O)=[C:27]([N+:36]([O-])=O)[C:26]=1[O:39]C.N1(CO)CCCC1>CN(C=O)C.C(Cl)Cl>[CH3:15][C:11]1[C:10]([O:16][CH3:17])=[CH:9][C:5]([C:6]([N:36]2[CH2:33][CH2:32][CH2:28][CH:27]2[CH2:26][OH:39])=[O:8])=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1C
Reactant: COc1cc(C(=O)Cl)c([N+](=O)[O-])c(OC)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: OCN1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1C
Reaction time: 8 h
Yield: 43 %

Procedure:
A catalytic amount of DMF (2 drops) was added to a stirred solution of 189 (3.96 g, 15.32 mmol) and oxalyl chloride (2.14 g, 16.85 mmol) in dry CH2Cl2 (50 mL) under a nitrogen atmosphere. The reaction mixture was allowed to stir overnight and the resulting acid chloride used directly in the next stage of the procedure. 4-methyl-3,5-dimethoxy-2-nitro-benzoyl chloride in anhydrous DCM (50 mL) was added dropwise over 0.5 hours to a stirring solution of pyrrolidine methanol (1.55 g, 15.32 mmol, 1.1 eq) and TEA (3.87 g, 38.3 mmol, 2.5 eq) in anhydrous DCM (50 mL) at 0° C. under a nitrogen atmosphere and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was washed with 1 N HCl (2×100 mL), and the organic layer was washed with distilled H2O (2×100 mL), brine (2×100 mL) and dried over anhydrous MgSO4. Evaporation of excess solvent yielded a yellow glass (190) (2.13 g, 6.56 mmol, 43% -2 steps); 1H NMR (270 MHz, CDCl3) δ6.61 (s, 1H), 4.30-4.28 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.83-3.68 (m, 2H), 3.46-3.26 (m, 2H), 2.19 (s, 3H), 1.94-1.68 (m, 4H); 13C NMR (67.8 MHz, CDCl3) δ167.85, 161.15, 152.62, 135.70, 132.32, 123.17, 103.70, 65.87, 62.61, 61.37, 56.36, 50.20, 28.41, 24.50, 9.34.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12](N)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:19]([BH3-])#[N:20].[Na+].[C:23](O)(=O)C>CO>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:20]([CH3:19])[CH3:23])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl[trans-4-aminocyclohexyl]methylcarbamate (1.15 g, 5.00 mmol), paraformaldehyde (454 mg, 15.0 mmol), and sodium cyanoborohydride (940 mg, 15.0 mmol) in methanol (40 mL) was added acetic acid (catalytic) and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was quenched with water and concentrated to remove methanol. The pH of the aqueous layer was adjusted to 10 with 1 M aqueous sodium hydroxide followed by extraction with methylene chloride. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product (1.2 g, 96%) as a thick oil: ESI MS m/z 257 [C14H28N2O2+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=[CH:12][CH:11]=2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl-]>CN(C=O)C>[NH3:5].[NH2:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=4)=[CH:12][CH:11]=3)[CH:3]=2)=[CH:29][CH:30]=1
Reactant: Cc1cc(Oc2ccc(Nc3cc(Cl)nc(N)n3)cc2)ccn1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(N)nc4)nc(N)n3)cc2)ccn1
Product: N
Temperature: 80 °C
Yield: 5 %
Yield: 114 %

Procedure:
To a mixture of 6-chloro-N4-(4-{[2-methylpyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (2.0 g, 6.1 mmol) and 2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.6 g, 7.3 mmol) in DMF (30 mL) was added aqueous Na2CO3 (2 M, 9.0 mL) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (It) chloride (223 mg, 0.3 mmol). The resulting mixture was degassed for 10 min before it was heated at 80° C. overnight. The resulting mixture was cooled to rt before it was concentrated under vacuo and dissolved in EtOAc. The resulting mixture was washed with water and brine and the organic layer was dried over Na2SO4. Removal of the solvent under vacuo gave the crude material, which was purified with 40 M biotage eluting with 100% EtOAc first and then with 95% CH2Cl2 and 5% 2 N ammonia in MeOH to provide the title compound as an off-white solid (1340 mg, 57%): 1H NMR (DMSO-d6): δ 9.20 (s, 1H), 8.51 (dd, 1H), 8.27 (d, 1H), 7.81-7.88 (m, 3H), 7.03-7.06 (m, 2H), 6.72 (d, 1H), 6.68 (dd, 1H), 6.47 (dd, 1H), 6.33 (s, 1H), 6.32 (s, 2H), 6.23 (s, 2H), 2.39 (s, 3H) ppm; MS ES 386 (M+H)+, RT=1.06 min.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:8])[CH:6]=O)(=O)[CH3:2].[C:9]([O:15][CH3:16])(=[O:14])[CH2:10]C(C)=O>[Fe].CO>[CH3:16][O:15][C:9]([C:10]1[CH:6]=[C:5]([CH3:8])[O:4][C:1]=1[CH3:2])=[O:14]
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)OC(C)C=O
Agent: [Fe]
Solvent: CO
Product: COC(=O)c1cc(C)oc1C

Procedure:
40 parts by weight of iron-III chloride and 136 parts by weight of 85 percent strength α-acetoxypropionaldehyde are added successively to a solution of 150 parts by weight of methyl acetoacetate in 120 parts by weight of methanol. The mixture, which becomes warm, is then refluxed for 2 hours. When it has cooled, the reaction solution is washed with water and distilled. 127 g of 2,5-dimethylfuran-3-carboxylic acid methyl ester are obtained.
Reaction SMILES: [C:1]([C:3]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].Br[C:23]1[N:32]=[C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][N:25]2[N:24]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][N:25]2[N:24]=[C:23]([C:2]#[C:1][C:3]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[N:4]=3)[N:32]=[C:26]2[CH:27]=1
Reactant: Clc1ccn2nc(Br)nc2c1
Reactant: C#Cc1nc(N2CCCC2)n(Cc2ccc(OC)cc2)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C#Cc3nc4cc(Cl)ccn4n3)nc2N2CCCC2)cc1
Temperature: 75 °C
Yield: 28.6 %

Procedure:
A mixture of 3-ethynyl-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (75 mg, 266 μmol, Eq: 1.00), 2-bromo-7-chloro-[1,2,4]triazolo[1,5-a]pyridine (67.9 mg, 292 μmol, Eq: 1.1) and triethylamine (40.3 mg, 55.5 μl, 398 μmol, Eq: 1.5) in tetrahydrofuran (2 ml) was purged with argon, then copper (I) iodide (1.01 mg, 5.31 μmol, Eq: 0.02), bis(triphenylphosphine) palladium(II) chloride (3.73 mg, 5.31 μmol, Eq: 0.02) and triphenylphosphine (1.39 mg, 5.31 μmol, Eq: 0.02) were added, the vessel was capped and heated for 18 hours to 75° C. Still starting material. The mixture was cooled, purged with argon and another portion of copper (I) iodide (1.01 mg, 5.31 μmol, Eq: 0.02), bis(triphenylphosphine) palladium(II) chloride (3.73 mg, 5.31 μmol, Eq: 0.02) and triphenylphosphine (1.39 mg, 5.31 μmol, Eq: 0.02) was added and the mixture was stirred again over night at 75° C. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 7-chloro-2-[1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylethynyl]-[1,2,4]triazolo[1,5-a]pyridine (33 mg 26.8%) as an orange oil. MS: m/e=434.4 (M+H+)
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1.[OH-].[Li+]>CN(C=O)C.O.C1COCC1>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC1CCCCN1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Clontech 01072, 25 g; 117.28 mmol; 1 eq.) and 2-methylpiperidine (41.54 mL; 351.84 mmol; 3 eq.) in DMF (100 mL) was heated to 50° C. for 2 hours The reaction was cooled to RT and diluted with water (100 mL), extracted with EtOAc, dried over MgSO4 and concentrated giving a yellow oil. The residue was taken up in THF (250 mL) and lithium hydroxide (14.04 g; 586.41 mmol; 5 eq.) was added followed by water (250 mL). The reaction mixture was stirred at RT for 2 days. After evaporation of THF, the solution was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 5 with AcOH, extracted with Et2O, dried over MgSO4 and concentrated affording the title compound as a yellow solid (24.81 g, 80%). 1H NMR (DMSO-d6, 300 MHz) δ 13.09 (br s, 1H), 8.23-8.22 (d, J=2.14 Hz, 1H), 8.04-8.01 (dd, J=8.72 Hz, 2.19 Hz, 1H), 7.44-7.41 (d, J=8.94 Hz, 1H), 3.63-3.61 (m, 1H), 3.22-3.18 (m, 1H), 2.89-2.85 (m, 1H), 1.78-1.44 (m, 6H), 1.06-1.04 (d, J=6.65 Hz, 3H). LC/MS (Method B): 265.2 (M+H)+; 263.2 (M+H)−. HPLC (Method A) Rt 3.96 min (Purity: 97.9%)
Reaction SMILES: ClC1C=C2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6](C(OCC)=O)=C2S(Cl)(=O)=O.[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.C[NH2:59]>>[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:59])=[O:50])=[C:33]2[S:53]([N:7]([CH:8]1[CH2:9][CH2:10]1)[CH3:6])(=[O:54])=[O:55]
Reactant: CN
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Product: CN(C1CC1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(I)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with N-cyclopropyl-N-methylammonium oxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 420.16 [M+H]+.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)CCCN=C=NCC.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:52][C@H:53]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56]>C(Cl)Cl.CCOC(C)=O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:52][C@H:53]([C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
500 mg (1.7 mmol) Z-Phe-OH was dissolved in 10 mL of CH2Cl2. Subsequently, 415 mg N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.HCl (EDCl, 2.2 mmol, 1.3 eq), 250 mg 7-aza-N-hydroxybenzatriazole (HOAt, 1.8 mmol, 1.1 eq), 478 μL triethylamine (TEA, 1.8 mmol, 1.1 eq) and 344 mg H-Leu-OtBu (1.8 mmol, 1.1 eq) were added. The reaction mixture was stirred at ambient temperature for 20 h. Subsequently, 20 mL EtOAc was added and the organic mixture was washed with 15 mL saturated aqueous Na2CO3 (2×), 15 mL saturated aqueous NaHCO3 (2×), 15 mL brine, dried (Na2SO4), concentrated in vacuo and co-evaporated with 10 mL toluene
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C@H:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].B(F)(F)F.CCOCC.C(O)(=O)[CH2:44][C:45](CC(O)=O)([C:47](O)=O)[OH:46]>O1CCCC1.CC(C)=O>[C:11]([O:15][C:16]([N:18]1[C:22](=[O:23])[CH:21]([C:45]([OH:46])([CH3:47])[CH3:44])[CH2:20][C@H:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: FB(F)F
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)C(C(C)(C)O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of lithium hexamethyldisilazide in tetrahydrofuran is cooled to −78° C. and treated with a solution of 15.95 g of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester in 100 mL of tetrahydrofuran maintaining the temperature at −78° C. The resulting mixture was stirred for 40 minutes and a mixture of 40 mL of acetone and 7 mL of boron trifluoride diethyl etherate added within 20 minutes. The reaction mixture is stirred for 2.5 hours at −78° C. and 300 mL of a 10% solution of citric acid added and the reaction mixture warmed to room temperature. The layers are separated and the aqueous layer is re-extracted with 300 mL of dichloromethane. The combined organic layers are dried, filtered and the solvent removed to give (S)-4-(1-hydroxy-1-methyl-ethyl)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzylester 1-tert-butyl ester as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17]C)=O)=[CH:8][C:9]=2[CH2:10][CH2:11][CH:12]=1)#[N:2].[NH3:19].[H][H]>CO>[NH2:2][CH2:1][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:19])=[O:17])[CH:6]=[CH:5][C:4]1=2
Reactant: COC(=O)COc1ccc2c(c1)CCC=C2C#N
Reactant: N
Reactant: [H][H]
Solvent: CO
Product: NCC1CCCc2cc(OCC(N)=O)ccc21

Procedure:
0.25 mol of the α,β-unsaturated nitrile from Example 5 is dissolved in 600 ml of methanol and 185 ml of liquid ammonia. After addition of 22 g of methanol-moist Raney nickel, the mixture is hydrogenated at 70° C. under 100 atmospheres of hydrogen for 3 hours. It is briefly heated under reflux, the catalyst is filtered off hot and the filtrate is then evaporated. The product can be further processed directly (see Example 9), or can be precipitated as the hydrochloride from diglyme.
Reaction SMILES: [C:1]([O:13]CCCC)(=[O:12])[CH:2]([CH2:4][C:5]([O:7]CCCC)=[O:6])[SH:3].[CH2:18]([Sn:22](=O)[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([C:4]([CH2:1][CH2:2][CH2:4][CH3:5])([C:5]([O-:7])=[O:6])[CH:2]([SH:3])[C:1]([O-:13])=[O:12])[CH2:19][CH2:20][CH3:21].[CH2:18]([Sn+2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CCCCOC(=O)CC(S)C(=O)OCCCC
Product: CCCCC(CCCC)(C(=O)[O-])C(S)C(=O)[O-]
Product: CCCC[Sn+2]CCCC

Procedure:
Dibutyl thiomalate 140 grams (93% assay) was warmed to 90° C and dibutyltin oxide 125 grams was added slowly with stirring and continued heating. The dibutyltin oxide had dissolved by the time the mixture reached 130° C to give dibutyltin mono (dibutyl thiomalate) a viscous liquid.
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.Cl.[NH:49]1[CH2:54][CH2:53][CH:52]([C:55]2[C:56](=[O:65])[NH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:65]=[C:56]1[C:55]([CH:52]2[CH2:53][CH2:54][N:49]([C:1]([O:2][C@H:3]([CH2:18][C:19]3[CH:27]=[C:26]([CH3:28])[C:25]4[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[N:24]=4)[CH:20]=3)[C:4](=[O:17])[N:5]3[CH2:10][CH2:9][CH:8]([N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]4)[CH2:7][CH2:6]3)=[O:37])[CH2:50][CH2:51]2)=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[NH:57]1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (89.5 mg, 1.50 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (0.16 mL, 0.90 mmol), and stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 102 mg (60%) as a colorless film. Mass spec.: 755.53 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.30 g, 1.17 mmole) in THF (10 mL) and MeOH (10 mL) was added 6N NaOH (5 mL). The reaction solution was heated to 50° C. for 2 hrs. The reaction solution was concentrated under vacuum, made acidic (pH ˜2) with 3N HCl, and extracted with DCM. The organic solution was dried (Na2SO4) and concentrated to a solid (0.22 g) which was used without further purification. LC-MS (ES) m/z=243 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH:16]([CH2:18]O)[CH2:15][C:14]2=[O:20])=[CH:9][CH:8]=1.CS(Cl)(=O)=O.[C-:29]#[N:30].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:14](=[O:20])[CH2:15][CH:16]([CH2:18][C:29]#[N:30])[CH2:17]2)=[CH:11][CH:12]=1
Reactant: O=C1CC(CO)CN1c1ccc(OCc2cccc(F)c2)cc1
Reactant: [C-]#N
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Product: N#CCC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
The title compound is prepared in analogy to Example 33b) from (RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-hydroxymethyl-pyrrolidin-2-one, methanesulfonyl chloride and sodium cyanide. Yield: 27% of a colorless solid. MS: m/e=325.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2([OH:14])[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:5][CH:6]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2([OH:14])[CH2:12][CH2:11][CH:10]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: O=C1CCC(O)(c2cc(Br)cs2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cc(Br)cs3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-(4-bromo-thiophen-2-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([CH3:17])([OH:16])[CH3:15])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:40]=[CH:41][C:32]([CH2:31][O:16][C:14]([CH3:15])([CH3:17])[CH:13]([N:12]2[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: COC(=O)c1ccc(COC(C)(C)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Yield: 12 %

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol and methyl 4-(bromomethyl)benzoate (commercially available) to give the desired compound as a white solid (12%). MS (Turbo Spray): m/z=567.3 [M+H].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:28])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([OH:25])=[O:24])=[C:20]([CH3:28])[CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1[nH]c(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution (10 mL) of ethyl 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carboxylate (200 mg) in tetrahydrofuran was added an aqueous solution (2 mL) of lithium hydroxide monohydrate (65 mg), and the mixture was stirred at 50° C. overnight. The reaction mixture was slowly warmed to room temperature and stirred overnight. After cooling to room temperature, the reaction mixture was neutralized with 1N hydrochloric acid. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4) and concentrated to give the title compound (165 mg, yield 89%) as white crystals. melting point 127° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[CH2:24][CH2:23][CH2:22][C:13]3=[N:14][N:15]([CH2:18][CH:19](O)[CH3:20])[C:16]([CH:17]=1)=[C:12]23)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>ClCCl.O>[N:37]([CH:19]([CH3:20])[CH2:18][N:15]1[C:16]2[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=[C:11]3[CH2:24][CH2:23][CH2:22][C:13]([C:12]=23)=[N:14]1)=[N+:38]=[N-:39]
Reactant: CC(O)Cn1nc2c3c(cc(OCc4ccccc4)cc31)CCC2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(Cn1nc2c3c(cc(OCc4ccccc4)cc31)CCC2)N=[N+]=[N-]
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred solution of the product from Step F (0.77 g, 2.4 mmol) in dichloromethane (10 mL) was added triethylamine (0.40 mL, 2.9 mmol) followed by methanesulfonyl chloride (0.22 mL, 2.9 mmol) at 0° C. After 30 min, dichloromethane (50 mL) was added followed by water (50 mL). The organic layer was separated and the aqueous was extracted with dichloromethane (2×50 mL). The combined extracts were washed with brine (30 mL), dried (MgSO4), and evaporated to a residue that was taken up in DMF (6 mL) and sodium azide (0.33 g, 5.0 mmol) was added. The reaction mixture was heated at 70° C. for 17 h, poured into water, and extracted with ether (3×50 mL). The combined extracts were washed with brine, dried (MgSO4), and evaporated to a residue that was purified by column chromatography (silica, hexane to 10% ethyl acetate in hexane) to give an oil (0.75 g, 90%): MS (ES) m/z 348 (M+).