Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:19][NH2:20]>CO>[CH3:19][NH:20][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN
Reactant: ClCCOc1ccccc1C=Cc1ccccn1
Solvent: CO
Product: CNCCOc1ccccc1C=Cc1ccccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
16 gm of 2-[o-(β-chloro-ethoxy)-styryl]-pyridine (m.p. 57°-59° C.) were dissolved in 50 ml of methanol, the solution was mixed at -15° C. with 120 ml of liquid methylamine freshly removed from a bomb, and the mixture was heated at 80° C. in an autoclave for 4 hours. After cooling and releasing the pressure, the contents of the autoclave were evaporated, the residue was dissolved in dilute acetic acid, and the solution was extracted twice with ether to remove weakly basic products. Then, the aqueous phase was made alkaline with 2 N sodium hydroxide solution and was extracted with ethyl acetate. After drying the ethyl acetate extract with sodium sulfate and distilling off the solvent, an oily residue was obtained which crystallized after standing overnight. 13.6 gm (88.2% of theory) of 2-[o-(β-methylaminoethoxy)-styryl]-pyridine were obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[O:41][C:42]([CH3:45])=[N:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[O:41][C:42]([CH3:45])=[N:43][N:44]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnc(C)o4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnc(C)o4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.36 g) in methylene chloride (10.8 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.12 g) in methylene chloride (7.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 238) (230 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: ClCCN1CCOCC1
Product: O=C(c1cn(CCN2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 50 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 4-(2-chloro-ethyl)-morpholine gave the title compound in 50% yield. ES-MS m/e (%): 480.5 (M+H+).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O>O1CCCC1>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (255) (2.5 g, 5.27 mmol) in tetrahydrofuran (60.0 mL) was added a aqueous solution (30.0 mL) of LiOH.H2O (2.21 g, 52.67 mmol) and the reaction mixture was refluxed for 16 h. After completion of the reaction, the organic solvent was removed on a rotary evaporator and water (10.0 mL) was added. The aqueous solution was acidified with concentrated HCl to pH=5.0 at 0° C. to give a white solid which was filtered off. The solid residue was triturated in diethyl ether and filtered. After drying, 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid (256) was obtained (1.6 g, 72.58%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:10])N)[CH:5]=[CH:6][CH:7]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2.Cl>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13]3[CH2:12][N:11]4[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]4)[C:14]=3[N:8]([CH3:10])[C:4]=2[CH:3]=1
Reactant: CN(N)c1cccc(Br)c1
Reactant: O=C1CCN2CCC1CC2
Agent: Cl
Solvent: CC(C)O
Product: Cn1c2c(c3ccc(Br)cc31)CN1CCC2CC1
Yield: 57.4 %

Procedure:
1-(3-Bromophenyl)-1-methylhydrazine (0.50 g, 2.5 mmol) and 1-azabicyclo[3.2.2]nonan-4-one (0.38 g, 2.7 mmol) were dissolved in isopropanol (4 mL), and concentrated aqueous HCl (0.8 mL) was added. The reaction mixture was heated to reflux for 18 h, concentrated and basified using 2 N NaOH. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0%-100% solvent mixture B in methylene chloride; solvent mixture B=80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give the title compound (438 mg, 58%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=2.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 4.25 (s, 2H), 3.61 (s, 3H), 3.30-3.24 (m, 3H), 3.14-3.08 (m, 2H), 2.02-1.99 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)(Cl)=O.[CH3:16][NH2:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:17][CH3:16])=[O:8]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: CN
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cc(Cl)ccc1C
Temperature: 25 °C
Yield: 89.2 %

Procedure:
5-Chloro-2-methylbenzoic acid (9.16 g, 53.7 mmol) and thionyl chloride (25.6 g, 15.7 ml, 215 mmol) were heated at reflux temperature for 1.5 h. Solvent was evaporated under reduced pressure and the residue dissolved in DCM (55 mL). Methylamine (aq.) (40%) (12.51 g, 13.90 mL, 161 mmol) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was extracted with EtOAc (50 mL), washed with brine (50 mL), dried (Na2SO4) and evaporated in vacuo to afford 5-chloro-2,N-dimethylbenzamide (8.79 g, 47.9 mmol, 89%) as a white solid. This was used directly in the next stage without purification
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[O:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([C:20]([F:21])([F:22])[F:23])[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=1[C:9]([NH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH:1][CH:30]1[CH2:31][CH2:32][O:27][CH2:28][CH2:29]1)=[O:26]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=C1CCOCC1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC1CCOCC1

Procedure:
The title compound, off-white foam, MS: m/e=469.3 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and tetrahydro-4H-pyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:25]([O-])=O)=[CH:4][C:5]([O:21][CH:22]([F:24])[F:23])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1)=[O:8]>[Pd].CO.C1COCC1>[NH2:25][C:3]1[C:2]([NH2:1])=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)=[O:8])=[C:5]([O:21][CH:22]([F:23])[F:24])[CH:4]=1
Reactant: Nc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)c(OC(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(OC(F)F)c(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1N

Procedure:
Prepared analogously to example 655d by hydrogenation of the product obtained from (702a) using palladium on charcoal in methanol and THF.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:34]1[CH:35]=[C:36]([C:41]([CH3:44])=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[C:15]([O:14][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[C:21]([C:34]2[CH:35]=[C:36]([C:41]([CH3:44])=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])[CH:22]=[CH:23][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCc1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(OCc3ccccc3)c(CNC(=O)OC(C)(C)C)c2)ccc1C

Procedure:
1.01 g of t-butyl N-[2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate, 593 mg of methyl 3-bromo-6-methylbenzoate, 130 mg of dichloro-bistriphenyl phosphinoferrocene palladium and 1 g of potassium carbonate were dissolved in 15 ml of dimethoxyethane, and the mixture was heated under reflux for 4 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column, to give methyl 3-(3-{[(t-butoxycarbonyl)amino]methyl}-4-benzyloxyphenyl)-6-methylbenzoate in the 4:1 hexane-ethyl acetate fraction. This crude product was dissolved in 100 ml of methanol, then 500 mg of 10% Pd—C was added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column, to give 521 mg of the title compound in the 5:1 hexane-ethyl acetate fraction.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([CH3:28])[O:13][N:12]=1>N1C=CC=CC=1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C:15]3[C:11]([CH3:10])=[N:12][O:13][C:14]=3[CH3:28])=[CH:23][CH:22]=2)(=[O:25])=[O:26])=[N:7][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(N)nc1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C#N)cn2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a solution of 6-amino-3-pyridinecarbonitrile (30 mg, 0.252 mmol) in pyridine (1 mL) at room temperature, was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (84 mg, 0.277 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand overnight. The solvent was evaporated in vacuo. The sample was purified by passing through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol, followed by a sulphonic acid (SCX) SPE cartridge eluting with methanol then 2M ammonia/methanol. The product-containing fractions were concentrated to give the title compound (23 mg) as an off-white solid. LCMS (2 min, formic) Rt 0.88 min, m/z (ES+) 385 (M+H)
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[S:13]1[C:17]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)=[CH:16][C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]1=2.Cl.[NH:32]1[C:36]([C:37]2[CH:38]=[C:39]3[C:49](=[CH:50][CH:51]=2)[O:48][C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][C:40]3=[O:52])=[N:35][N:34]=[N:33]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN1C(=O)CCC1>[S:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([N:45]3[CH2:46][CH2:47][C:42]4([CH2:41][C:40](=[O:52])[C:39]5[C:49](=[CH:50][CH:51]=[C:37]([C:36]6[NH:35][N:34]=[N:33][N:32]=6)[CH:38]=5)[O:48]4)[CH2:43][CH2:44]3)=[O:24])=[CH:25][CH:26]=2)=[CH:16][C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]1=2
Reactant: O=C(O)c1ccc(-c2cc3ccccc3s2)cc1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1CC2(CCN(C(=O)c3ccc(-c4cc5ccccc5s4)cc3)CC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
WSC hydrochloride (69.0 mg, 0.36 mmol) was added to a mixture of 4-(benzo[b]thiophen-2-yl)benzoic acid (76.3 mg, 0.300 mmol), 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (96.5 mg, 0.300 mmol), HOBT (45.9 mg, 0.300 mmol), triethylamine (0.042 mL, 0.300 mmol) and NMP (1.5 mL), and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile) to obtain the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.44 (1H, d J=2.2 Hz), 8.25 (11, dd, J=8.5, 2.2 z), 8.00 (1H, d, J=8.3 Hz), 7.96 (1H, s), 7.89-7.83 (3H, m), 7.54 (2H, d, J=7.8 Hz), 7.44-7.33 (3H, m), 4.37-4.18 (1H, m), 3.65-3.18 (3H, m), 3.00 (2H, s), 2.13-1.75 (4H, m). MS [M−H]−=520.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](O)=[O:11])[CH2:2]1.S(Cl)([Cl:16])=O>C(OCC)C>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([Cl:16])=[O:11])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(C(=O)O)C1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CC1CCC(C(C)C)C(C(=O)Cl)C1

Procedure:
The preparation of N-substituted-aryl-alkylcarboxamides is familiar to practitioners of the art of chemistry and, for example, is described in U.S. Pat. No. 4,193,936. Starting with the corresponding alkanoyl chloride, a single step reaction with the appropriate amine yields the desired product. For example, an alicyclic compound, p-menthane-3-carboxylic acid (synonym: 2-isopropyl-5-methylcyclohexanecarboxylic acid) is reacted with thionyl chloride in diethylether to yield the p-menth-3-oyl chloride which, when stirred with the substituted-arylamine at room temperature for about 4 hr, generates the corresponding N-substituted-aryl-p-menthane-3-carboxamide. The precipitated product is readily collected by filtration and may be recrystallized using solvents such ethyl acetate or purified on silica gel columns. The final products are solids stable at room temperature. The arylamine may, for example, be 3-methyl-4-iodo-phenylamine, or 4-fluorophenylamine, or 4-iodo-1-naphthylamine and the corresponding product after reaction with p-menth-3-oyl chloride would be N-(3′-methyl-4′-iodo-phenyl)-2-isopropyl-5-methylcyclohexane-3-carboxamide, N-(4′-fluorophenyl)-2-isopropyl-5-methylcyclohexane-3-carboxamide, and N-(4′-iodo-1′-naphthyl)-2-isopropyl-5-methylcyclohexane-3-carboxamide respectively.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]=1[CH3:23]>C1COCC1.CO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:24])=[O:4])=[C:8]2[CH3:23])=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1c(C)n(-c2ccc(Cl)cc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1-c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
1M Aqueous NaOH (0.5 mL) is added to a stirring solution of [1-(4-chloro-phenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (4 mg, 0.013 mmol) in 1:1 THF/MeOH (2 mL). After 18 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 1, and extracted with ethyl acetate. The organic layer is washed with water then brine, dried (MgSO4) then evaporated, to give [1-(4-chloro-phenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=301.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8](C)(C1C=CC=C(C(C)(C)O)C=1)O.C(OC=C)(=O)C.[OH:27][C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([CH3:42])([O:39][CH:40]=[CH2:41])[CH3:38])[CH:32]=1)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH3:38][C:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:28]([O:27][CH:7]=[CH2:8])([CH3:30])[CH3:29])[CH:32]=1)([O:39][CH:40]=[CH2:41])[CH3:42]
Reactant: C=COC(C)(C)c1cccc(C(C)(C)O)c1
Reactant: CC(C)(O)c1cccc(C(C)(C)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C=COC(C)=O
Solvent: Cc1ccccc1
Product: C=COC(C)(C)c1cccc(C(C)(C)OC=C)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene) diiridium(I) [Ir(cod)Cl]2 (67 mg, 0.1 mmol) and sodium carbonate (640 mg, 6 mmol) in toluene (5 ml) were added α,α,α′,α′-tetramethyl-1,3-benzenedimethanol (5 mmol) and vinyl acetate (2.15 g, 25 mmol), followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1-(1-hydroxy-1-methylethyl)-3-(1-methyl-1-vinyloxyethyl)benzene and 1,3-bis(1-methyl-1-vinyloxyethyl)benzene were formed in yields of 8% and 70%, respectively, with a conversion from α,α,α′,α′-tetramethyl-1,3-benzenedimethanol of 98%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH:9]=1)[CH3:6])[CH3:2].[CH:22]([C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31](N2C=CN=C2)=[O:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].Cl>C1(C)C=CC=CC=1.O>[CH:22]([C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])([CH3:20])[CH3:6])[CH:9]=3)[CH2:15]2)=[O:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C2CCCNC2)c1
Reactant: CC(C)c1ccc(COC(=O)n2ccnc2)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1cccc(C2CCCN(C(=O)OCc3ccc(C(C)C)cc3)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a solution of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid ethyl ester (Preparation 2; Method D; 7.60 g, 17.21 mmol) in 20 mL toluene was added imidazole-1-carboxylic acid-(4-isopropyl)benzyl ester (4.20 g, 17.21 mmol) and stirred for 18 h at ambient temperature. The reaction was diluted with water (300 mL), acidified with 1 N HCl and extracted with diethyl ether (2×200 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 6.23 g (77%) of 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester as a clear oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])OC(C)(C)C)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:34](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[CH3:34])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl [(1S)-2-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (438 mg) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 30 min and concentrated. Pyridine (2.5 mL) and acetic anhydride (0.186 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr. After concentration, the residue was dissolved in ethyl acetate, and the solution was washed successively with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The extract was applied to silica gel chromatography (NH, ethyl acetate) and concentrated under reduced pressure, and the obtained solid was washed with diisopropyl ether to give the title compound (295 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:38][CH:37]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1CC1(NC(=O)C1CC(O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 72.2 %

Procedure:
Compound 132 (6.13 g, 16.6 mmol), 4-nitrobenzoic acid (4.17 g, 25 mmol) and PPh3 (6.55 g, 25 mmol) was dissolved in THF (130 ml). The solution was cooled to ˜0° and diisopropyl azidocarboxylate (5.1 g, 25 mmol) was added slowly. The cooling was then removed and the mixture was left over-night at ambient condition. Aqueous sodium hydrogen carbonate (60 ml) was added and the mixture was extracted with dichloromethane. Purification by flash chromatography (pentane-ether, 2:1→pentane-ether, 1:2→2% methanol in ether) gave pure title compound (6.2 g, 72%).