Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([OH:10])[C:7]([NH2:11])=[CH:6][C:4]=1[OH:5].[C:12]1([C:18](Cl)(Cl)Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[O:5][C:4]3[CH:6]=[C:7]4[N:11]=[C:18]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[O:10][C:8]4=[CH:9][C:3]=3[N:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: Nc1cc(O)c(N)cc1O
Agent: Cl
Product: c1ccc(-c2nc3cc4oc(-c5ccccc5)nc4cc3o2)cc1
Temperature: 190 °C

Procedure:
In the apparatus described in Example 13, 5.9 g of 2,5-diaminohydroquinone hydrochloride (28 m moles) were placed and at 180° C, 7.6 g of benzotrichloride (39 m moles) were added drop by drop. After 3 hours of heating at 190° C, the mixture was cooled and ground with mortar and pestle. The reaction product was extracted twice with 150 ml of xylene and passed through an aluminum oxide column heated at 125° C. The product was 4.5 g of crude XXII (74% of the theory). After two recrystallizations from xylene the melting point was 319°-323° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH:33]([F:35])[F:34])=[C:27]([F:36])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:35][CH:33]([F:34])[O:32][C:28]1[C:29]([F:31])=[CH:30][C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)=[CH:26][C:27]=1[F:36]
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OC(F)F)c(F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OC(F)F)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (45 mg, 0.251 mmol) with 2-bromo-N-{4-[4-(difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (125 mg, 0.313 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 20 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.39 (s, 3H), 5.32 (s, 2H), 6.23 (s, 1H), 7.28 (t, J=72.3 Hz, 1H), 7.35 (s, 1H), 7.79 (d, J=9.6 Hz, 2H), 7.90 (s, 1H), 12.73 (br s, 1H); ESI-MS (m/z) 498.08 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])=[C:12]([F:26])[CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]([CH3:28])[C:15]3=[O:25])=[C:12]([F:26])[CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
A stirred solution of 0.85 gram (2.1 mmole) of 3-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, 0.48 gram (3.5 mmole) of potassium carbonate, 0.91 gram (6.4 mmole) of iodomethane, and 35 mL of acetone was heated at 40° C. for 2 hours, then stirred at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was extracted with two 50 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a yellow oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 8:1 hexane:ethyl acetate. The product-containing fractions were combined and concentrated under reduce pressure, yielding 0.60 gram of 3-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 68°-70° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([NH2:44])=[O:43]>C1COCC1>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:41][C:42]([NH2:44])=[O:43])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in THF (3 mL) was added potassium carbonate (174 mg, 1.26 mmol) and 2-bromoacetamide (63 mg, 0.46 mmol) and the reaction mixture was stirred at RT for 18 hours. The volatiles were evaporated in vacuo and the residue partitioned between DCM and an aqueous saturated sodium bicarbonate solution. The organic layer was washed with water followed by brine, dried (MgSO4), concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-5% MeOH in DCM) to give 319 isolated as a cream solid after freeze drying from methanol and water (40 mg, 22%). LCMS: RT=3.03 min, [M+H]+=425. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.18 Hz), 8.05 (1H, s), 7.20 (1H, dd, J=8.24, 1.83 Hz), 7.08 (1H, s), 7.00 (2H, d, J=1.87 Hz), 5.83-5.73 (1H, m), 4.34-4.28 (2H, m), 3.69-3.62 (2H, m), 3.63-3.52 (1H, m), 3.41-3.35 (2H, m), 3.21-3.14 (2H, m), 2.99 (2H, s), 1.50 (6H, d, J=6.59 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH2:17]([N:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][NH2:23])[CH3:18]>CCOCC>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH3:25])[CH2:17][CH3:18]
Reactant: COC(=O)/C=C\C(=O)O
Reactant: CCN(CC)CCCN
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCN(CC)CCCN[C@@H](CC(=O)OC)C(=O)O
Yield: 53.3 %

Procedure:
71.5 g (0.5 mol+10% excess) of maleic acid-monomethyl ester are reacted, in the manner described in Example 1, with 100 ml of triethylamine and 65.1 g (0.5 mol) of 3-diethylaminopropylamine. The reaction product is mixed with 500 ml of ether, the mixture is filtered and the residue is washed with ether. After drying at 60° C. in vacuo, the crude product is recrystallised in acetone to yield 69.44 g (53.4% of theory) of a white crystalline aspartic acid derivative, the melting point of which is 154.5°-156.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(C(=O)O)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 90.9 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol) in methanol (4 mL) was added a solution of NaOH (40 mg, 1 mmol) in water (2 mL). The mixture was heated at 70° C. for 2 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (175 mg). m/z (M+H)+: 583
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([CH3:28])([CH3:27])[C:19](=[O:26])[C:20]=1[C:21]([O:23]CC)=O.Cl.[C:30]([O:34][C:35](=[O:38])[CH2:36][NH2:37])([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1>[OH:10][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([CH3:27])([CH3:28])[C:19](=[O:26])[C:20]=1[C:21]([NH:37][CH2:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[O:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
DIPEA (0.05 mL, 276 μmol) was added to a stirred mixture of ethyl 5-hydroxy-8,8-dimethyl-7-oxo-7,8-dihydroquinoline-6-carboxylate (24 mg, 92 μmol) and glycine tert-butyl ester hydrochloride (38 mg, 230 μmol) in 1,4-dioxane (3 mL). The reaction mixture was then stirred at 75° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by silica flash chromatography (0-75% EtOAc/hexane) to give the title compound as a crystalline white solid (15 mg, 47%). MS (m/z)=347 (M+H)+. Calculated for C18H22N2O5 346.4.
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Al](C)C.C[O:28][C:29](=O)[NH:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:39][CH3:40])[N:32]=1>C(Cl)Cl>[Cl:1][C:2]1[C:11]([S:12]([NH:15][C:29]([NH:30][C:31]2[N:32]=[C:33]([O:39][CH3:40])[N:34]=[C:35]([O:37][CH3:38])[N:36]=2)=[O:28])(=[O:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Reactant: NS(=O)(=O)c1c(Cl)ccc2cccnc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2c(Cl)ccc3cccnc23)nc(OC)n1
Reaction time: 0.75 h
Yield: 27.5 %

Procedure:
To a stirred mixture of 7-chloro-8-quinolinesulfonamide (1.5 g) in 75 ml methylene chloride is added a 2 M toluene solution of trimethyl aluminum (4.7 ml). The resulting solution is stirred under N2 for 45 min. Solid methyl(4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate (1.1 g) is added and the mixture is heated at reflux for 60 h. The reaction is quenched sequentially with acetic acid (1 ml), 6 N HCl (2.5 ml) and water (13 ml). The organic solution is retained, dried with MgSO4, and is concentrated to an oil-solid mixture. Filtration afforded 0.6 g yellow solid m.p. 169°-191° C. (dec). The infrared spectrum showed characteristic absorption bands at 3300 and 1700 cm-1.
Reaction SMILES: COC1C=CC(C[N:8]2[N:12]=[N:11][C:10]([CH2:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20][C:21]([N:23]4[CH2:32][CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([NH:33][C:34]([NH:36][C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=6[F:43])=[O:35])[CH:29]=5)[CH2:24]4)=[O:22])[CH2:16][CH2:15]3)=[N:9]2)=CC=1.[H][H]>[C].[Pd].C(O)C>[N:11]1[NH:12][N:8]=[N:9][C:10]=1[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[F:43])=[O:35])[CH:29]=3)[CH2:24]2)=[O:22])[CH2:16][CH2:15]1
Reactant: COc1ccc(Cn2nnc(C[C@H]3CC[C@H](OC(=O)N4CCc5cc(NC(=O)Nc6ccccc6F)ccc5C4)CC3)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)O[C@H]1CC[C@H](Cc3nn[nH]n3)CC1)C2)Nc1ccccc1F

Procedure:
An ethanol (6 mL) suspension of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-[2-(4-methoxy-benzyl)-2H-tetrazol-5-ylmethyl]-cyclohexyl ester (333 mg) obtained in Example (44e) and palladium carbon (55 mg) was stirred at room temperature for 3 days in a hydrogen atmosphere. The reaction mixture was filtered through Celite and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate=5:1→1:1 and then dichloromethane/methanol=25:1→5:1) to obtain the title compound (22 mg, 8%) as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:24]([N:26]([CH3:30])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([N:26]([CH3:30])[C:27]([N:13]1[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[CH2:10][CH:11]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:12]1)=[O:28])[CH3:25]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: CCN(C)C(=O)Cl
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
250 mg (0.74 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 117 mg (0.96 mmol, 1.3 eq.) of ethyl(methyl)carbamoyl chloride were reacted according to General Method 3. Yield: 215 mg (74% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)nn4-c4ccccc4)c3)c2cc1OC
Yield: 60.3 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (92 mg, 0.31 mmol), prepared as described in Example 113A, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (100 mg, 0.31 mmol) described in the previous step. The suspension was triturated with anhydrous diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea (98 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (d, J=6.9 Hz, 6H), 2.87 (m, 1H), 3.99 (s, 6H), 6.31 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.34-7.40 (m, 3H), 7.52-7.55 (m, 6H), 8.47 (s, 1H), 8.55 (s, 1H), 9.21 (s, 1H); LC-MS (ESI) m/z 525 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CCCCN1Cc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CCCCN1Cc1ccccc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
(RS)-1-Benzyl-2-bromomethylpiperidine, D31 (4.2 g) was dissolved in dry dimethylsulphoxide (15 ml) and treated with sodium cyanide (5.0 g). The solution was then stirred at 85° C. under argon for 18 h. The reaction solution was then poured into water (300 ml) and extracted with dichloromethane (2×200 ml). The organic solution was dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, diethyl ether/petroleum ether mixtures) afforded the title compound (3.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2([C:25]#[N:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:57]([C:65]1[CH:66]=[C:67]([C:71](O)=[O:72])[CH:68]=[N:69][CH:70]=1)[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2([C:25]#[N:26])[CH2:24][CH2:23][N:22]([C:71]([C:67]3[CH:68]=[N:69][CH:70]=[C:65]([CH2:57][CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH:66]=3)=[O:72])[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cncc(CCc2ccccc2)c1
Reactant: N#CC1(c2cccc(CNC(=O)OCc3ccccc3)c2)CCNCC1
Agent: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: N#CC1(c2cccc(CNC(=O)OCc3ccccc3)c2)CCN(C(=O)c2cncc(CCc3ccccc3)c2)CC1
Reaction time: 2 h
Yield: 108.5 %

Procedure:
To a solution of 0.15 g (0.33 mmole) of 4-(3-benzyloxycarbonylaminomethyl-phenyl)-piperidine-4-carbonitrile in 20 ml of acetonitrile was added 0.038 g (0.33 mmole) of N-ethylmopholine followed by 0.11 g (0.33 mmole) of TBTU. To this solution was added 0.075 g (0,33 mmole) of 5-phenethylpyridine-3-carboxylic acid in portions over 10 minutes. The mixture was stirred for 2 hours. The solution was concentrated and the residue was purified by flash chromatography using 95:5 dichloromethane:methanol to provide 0.2 g of product: 1H-NMR (300 MHz, CDCl3)δ (TMS) 1.79-2.20 (m, 4H), 2.70-2.82 (m, 4H), 2.90-3.07 (m, 2H), 3.15-3.70 (m, 2H), 4.35-4.40(d, 2H), 5.07-5.25 (d, 2H), 7.10-7.50 (m, 15H), 8.42-8.58 (m, 2H); MS (ESI) m/e 559 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].CC(O)=O.[BH3-]C#N.[Na+]>CO>[C:13]([CH:17]1[CH2:18][CH2:19][CH:20]([NH:23][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=2)[CH2:21][CH2:22]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CNC2CCC(C(C)(C)C)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl-4-formylbenzoate (73 mmol, 12 g) in 200 mL of MeOH was added 4-tert-butylcyclohexylamine (74 mmol, 13.2 mL) via syringe. The reaction mixture was heated to reflux for 0.75 h, then was cooled in an ice bath. The resulting precipitate was filtered and the filter cake was washed with 2×20 mL of cold MeOH. The solid was dried under reduced pressure, then suspended in 224 mL of MeOH. HOAc (652 mmol, 37.4 mL) was added to the solution, followed by NaBH3CN (42.7 mmol, 2.68 g) in several portions. The reaction mixture was stirred at ambient temperature for 1.5 b, then concentrated under reduced pressure to ca. 25% of the initial volume. 400 mL of EtOAc was added to the solution and the mixture was washed with 3×200 mL of 5% NaHCO3 followed by brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 1:1 EtOAc/hexanes to afford the trans isomer as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.00 (d, 2H), 7.40 (d, 2H), 3.92 (s, 3H), 3.88 (s, 2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.79 (m, 2H), 0.95-1.15 (overlapping m, 5H), 0.85 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].I[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:23]=1[CH2:33][CH2:34][CH3:35].[I-]>>[CH3:31][C:29]([CH3:30])([CH3:32])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:14][C:11]2[CH:12]=[CH:13][C:7]3[O:6][C:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=3[CH:10]=2)=[C:23]([CH2:33][CH2:34][CH3:35])[CH:24]=1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Reactant: CCCc1cc(CC(C)(C)C)ccc1OCCCI
Agent: [I-]
Product: CCCc1cc(CC(C)(C)C)ccc1OCCCOc1ccc2c(c1)CC(CC)(C(=O)O)O2

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the phenol prepared in Step 1 and the intermediate prepared in Example 2, Step 2 as the iodide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:23])[C:18](=[O:22])[NH:19]2)=[C:15]([NH:24][C:25](=[O:27])[CH3:26])[CH:14]=1.[CH:28]1[C:33]([NH:34][NH2:35])=[CH:32][CH:31]=[C:30]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:29]=1.Cl>>[OH:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:23])[C:18](=[O:22])[NH:19]2)=[C:15]([NH:24][C:25](=[O:27])[CH3:26])[CH:14]=1.[CH3:9][C:7]1[O:8][C:4]2[C:5](=[CH:10][C:11]3[C:14](=[N:35][NH:34][C:33]4[CH:28]=[CH:29][C:30]([S:36]([NH2:39])(=[O:37])=[O:38])=[CH:31][CH:32]=4)[C:13](=[O:12])[NH:1][C:2]=3[CH:3]=2)[N:6]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nc2ccc(N)cc2o1
Agent: CC(=O)Nc1cc(O)cc2c1C(=O)C(=O)N2
Agent: Cl
Product: Cc1nc2cc3c(cc2o1)NC(=O)C3=NNc1ccc(S(N)(=O)=O)cc1

Procedure:
N-(6-Hydroxy-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acetamide was prepared from 6-amino-2-methylbenzoxazole (Heleyova, et al., Collection of Czechoslovakian Chemical Communications 1996, 61, 371-80) according to Procedure A in 12% overall yield. Condensation of N-(6-hydroxy-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acetamide and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 6% yield: 1H NMR (DMSO-d6): δ 2.55 (s, 3H), 7.13 (s, 1H), 7.23 (s, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.78 (s, 1H), 11.12 (s, 1H), 12.67 (s, 1H); APCI−MS m/z 370 (M−H)−. Anal. Calcd for C16H15N5O4S: C, 51.75, H, 3.53; N, 18.86; S, 8.86. Found C, 51.50, H, 3.61; N, 18.69; S. 8.49.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[C:6]([N+:23]([O-:25])=[O:24])[N:5]=1.[CH3:26]I>CN(C=O)C>[CH3:26][C:10]([C:9]1[C:4]([CH3:3])=[N:5][C:6]([N+:23]([O-:25])=[O:24])=[CH:7][CH:8]=1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CI
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% in oil, 0.8 g, 19 mmol) in DMF (50 mL) was added tert-butyl ethyl (2-methyl-6-nitropyridin-3-yl)propanedioate (4 g, 13 mmol) at room temperature. The mixture was stirred for 1 hour and CH3I (3.7 g, 26 mmol) was added. The mixture was heated to 40° C. for 2 hours. Cooled to ambient temperature, the mixtue was poured to ice/water, extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatograph silca gel to give tert-butyl ethyl rnethyl(2-methyl-6-nitropyridin-3-yl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 4.19-4.27 (m, 2H), 2.59 (s, 3H), 1.85 (s, 3H), 1.45 (s, 9H), 1.28 (t, J=7.0 Hz, 3H).