Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([NH:9][C:10](=[O:31])[C@@H:11]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[CH:15][CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Na+].CO>C1COCC1.O>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:11]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:10]([NH:9][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:32])=[O:2])=[O:31])=[CH:14][CH:15]=1)[CH:21]=[CH2:22]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 1 (8.45 g, 18.8 mmol) was dissolved in THF (35 mL) and sodium hydroxide (1.13 g, 28.2 mmol) pre-dissolved in water (10 mL) was added. A further 15 mL of THF and 20 mL of methanol were added to obtain a homogenous solution. The reaction mixture was stirred at rt for 18 h before being concentrated in vacuo. The residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white foam, 7.25 g, 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:6][NH:7][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([C:13]3=[O:20])[CH2:11]1)[CH2:17]2)=[O:9].[BH4-].[Na+]>CO>[CH3:25][O:24][C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:23]=1)[CH2:6][NH:7][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH:13]3[OH:20])[CH2:11]1)[CH2:17]2)=[O:9]
Reactant: COc1cc(CNC(=O)C23CC4CC(C2)C(=O)C(C4)C3)cc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNC(=O)C23CC4CC(C2)C(O)C(C4)C3)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of N-(3,5-dimethoxybenzyl)-4-oxoadamantane-1-carboxamide (230 mg, 0.670 mol) in anhydrous CH3OH was added NaBH4 (100 mg, 2.7 mmol) at 0° C. The reaction mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure, diluted with CH2Cl2 and washed with water. The organic layer was separated, dried, and concentrated to give N-(3,5-dimethoxybenzyl)-4-hydroxyadamantane-1-carboxamide (230 mg, 100%). 1H NMR: (400 MHz, CDCl3): δ=1.40 (d, 1H), 1.46-1.62 (m, 6H), 1.70-1.82 (m, 5H), 1.84-1.95 (m, 3H) 2.01-2.14 (m, 2H), 3.75 (s, 3H), 3.80 (s, 3H), 3.82 (s, 1H), 4.29 (d, 2H), 5.98 (s, 1H), 6.40 (m, 0.2H), 7.08 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.Cl.[NH2:21][OH:22].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8](=[N:21][OH:22])[NH2:9])[CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1Nc1ncc(C#N)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCC[C@@H]1Nc1ncc(C(N)=NO)cc1Cl
Yield: 100 %

Procedure:
A solution of cis-methyl 2-(3-chloro-5-cyanopyridin-2-ylamino)cyclopentanecarboxylate (0.154 g; 0.55 mmol), hydroxylamine hydrochloride (0.057 g; 0.82 mmol) and DIEA (0.143 mL; 0.82 mmol) in EtOH (2 mL) was stirred at ambient temperature for 42 hours. The solvent was evaporated in vacuo and the residue dissolved in DCM/water. The mixture was passed through a hydrophobic frit and the solvent evaporated in vacuo to afford the title product (0.172 g; quantitative). 1H NMR (CDCl3, 400 MHz) δ 8.25 (1H, d, J=2 Hz), 7.74 (1H, d, J=2 Hz), 5.74 (1H, d, J=8.4 Hz), 4.77-4.70 (3H, m), 3.61 (3H, s), 3.19-3.14 (1H, m), 2.14-1.70 (6H, m).
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCOc1ccccc1
Solvent: CO
Product: COC(=O)CCOc1ccccc1
Temperature: 25 °C
Yield: 1589.1 %

Procedure:
To demonstrate the methyl ester, as well as the ethyl ester, may be used to make members of composition 7, we illustrate the preparation of the corresponding methyl ester of composition 7 in which the Et group is replaced by Me and X is O. A solution of 3-phenoxypropionic acid (10.0 g, 0.060 mol) and p-toluenesulfonic acid (0.6 g, 0.0033 mol) in methanol (250 mL) was heated at reflux through 3 Å molecular sieve for 36 hours under N2 in a flask equipped with a Soxhlet extractor and a condenser. The solution was allowed to cool to room temperature and then was concentrated to a volume of 50 mL, diluted with water (50 mL), and extracted with ether (2×75 mL). The combined organic layers were washed with 5% aqeuous NaHCO3 (75 mL), H2O (75 mL), and brine (75 mL). After drying (Na2SO4) the solution, the solvent was removed (vacuum). Vacuum distillation gave 9.45 grams (87.1%) of the title ester as a colorless liquid: by 85°-87° C./0.1 mm (literature reports 85° C./0.4 mm; see C. E. Rehberg and M. D. Dixon [J. Am. Chem. Soc. 72, 2205 [1972]): IR (neat) 1740-1750 cm-1 (C=O); 1H NMR (DCCl3) δ 2.78 [s, 2H, CH2CO2CH3 ], 3.70 [s, 3H, OCH3 ], 4.23 [2H, OCH], 6.84-7.02 and 7.18-7.35 [m, 5H, ArH]; 13C NMR (DCCl3) ppm 34.3 [H2CCO2 ], 51.7 [CH3 ], 63.2 [Ar--OCH2 ]; Ar--C [114.5, 120.8, 129.2, 158.3, 171.1].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:11]1=[S:12])[CH3:14]
Reactant: Cc1cc(C)c(N=C=S)cc1C
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(C)c(C)cc2C)C1=S
Yield: 58.4 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 17.7 g of 2,4,5-trimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (15.3g) as an off-white solid, m.p. 162°-164° C. Anal. Calcd. for. C14H18N2O S: C,64.09; H, 6.92; N, 10.68. Found: C, 64.21; H, 6.93; N, 10.80. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: Cl.C[O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[C:23](Cl)(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([NH:6][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:4]([OH:3])=[O:15])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
To a solution of L-Tyrosine methyl ester hydrochloride (1 g, 4.3 mmol) in CH2Cl2 was added triethylamine (1.49 mL, 8.6 mmol) at room temperature. Palmitoyl chloride (1.53 g, 5.6 mmol) was then added to the reaction mixture at 0° C. After the reaction was completed, as judged by TLC, the reaction mixture was quenched and extracted with 1 N HCl (3×5 mL) then saturated sodium bicarbonate (1×5 mL). The combined organic layers were dried with Na2SO4 and evaporated under vacuum to a white solid (1.86 g, 4.3 mmol). The product was carried on without further purification. 1H NMR (300 MHz, CDCl3, 23° C., 6): 6.94 (d, 1H, J=8.5), 6.73 (d, 1H, J=8.5), 5.92 (d, 1, H, J=8.0), 4.90 (d, 1H, J=5.8), 4.85 (d, 1H, J=5.8), 3.73 (s, 3H), 3.04 (ddd, 1H, J=5.8, 14.0, 27.7), 2.26-2.12 (m, 1H), 1.58 (m, 2H), 1.25 (m, 24H), 0.90 (t, 3H, J=6.67).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:32])([CH3:31])[C:4]#[C:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:13][CH:14]=3)[C@@:9]3([CH2:29][O:28][C:27]([NH2:30])=[N:26]3)[C:8]=2[CH:7]=1>CO.[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH3:32])([CH3:31])[CH2:4][CH2:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)=[CH:13][CH:14]=3)[C@@:9]3([CH2:29][O:28][C:27]([NH2:30])=[N:26]3)[C:8]=2[CH:7]=1
Reactant: COC(C)(C)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(C)(C)CCc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 25 °C

Procedure:
To a solution of (R)-2′-(3-methoxy-3-methylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (23 mg, 0.054 mmol) in MeOH (1 mL) suspension of palladium on carbon (28.7 mg, 0.027 mmol) in ethyl acetate (0.5 mL) was added and the mixture was hydrogenated (1 atm) overnight at 40° C. The mixture was cooled to room temperature, filtered through plug of Celite and concentrated to give (R)-2′-(3-methoxy-3-methylbutyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1.ClCCC1C=CC(S(C)=[O:23])=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH3:12])=[O:23])=[CH:9][CH:10]=1
Reactant: CS(=O)c1ccc(CCCl)cc1
Reactant: CSc1ccc(CCCCl)cc1
Product: CS(=O)c1ccc(CCCCl)cc1

Procedure:
12b was prepared from 11b (2.0 g; 10.0 mmol) using the method described in the synthesis of 12a. M.p.: 46° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6]C=1.[NH2:19]C1C=CN=CC=1.N1C=CC=CC=1C=O>>[N:19]1[CH:6]=[CH:5][C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:3][CH:2]=1
Reactant: Nc1ccncc1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: c1ccc(-c2nnn(-c3ccncc3)n2)nc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-aminopyridine (56.5 mg, 0.6 mmol) and 2-pyridinecarboxaldehyde (64.2 mg, 0.6 mmol) were employed to obtain 2-[2-(4-pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[N:4]=1.[CH3:42][C:43]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH2:45][CH2:44]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:49][S:46]([C:43]5([CH3:42])[CH2:45][CH2:44]5)(=[O:48])=[O:47])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[N:4]=1
Reactant: COc1cccc(-c2cc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)c1
Reactant: CC1(S(N)(=O)=O)CC1
Product: COc1cccc(-c2cc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)c1
Yield: 50.8 %

Procedure:
The acid 25 (150 mg, 0.26 mmol) was reacted with methylcyclopropane sulphonamide (72 mg, 0.53 mmol) according to the procedure described in Example 16 step g, which gave the title compound (90 mg, 50%), MS [M+1] 682.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C(O)C>[CH:9]1([NH:12][C:3]([NH:4][N+:5]([O-:7])=[O:6])=[NH:8])[CH2:11][CH2:10]1
Reactant: NC1CC1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CCO
Product: N=C(NC1CC1)N[N+](=O)[O-]
Temperature: -5 °C

Procedure:
27 g of S-methyl-N-nitroisothiourea are heated under reflux for 3.5 hours in admixture with 12.6 g of cyclopropylamine and 15 ml of ethanol. The reaction mixture is then cooled to -5° C. and the product is filtered off and washed with a small amount of cold ethanol and diethyl ether, yielding N-cyclopropyl-N'-nitroguanidine (m.p.: 127°-130° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(Cl)c(Cl)cc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cc(Cl)c(Cl)cc2C1=O
Yield: 8.4 %

Procedure:
Using an analogous reaction conditions as described in example 1, 6,7-dichloro-3,4-dihydro-2H-isoquinolin-1-one (I-41d: 0.15 g, 0.6944 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.152 g, 0.6944 mmol), 1,4-dioxane (20 mL), copper iodide (0.013 g, 0.0494 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.032 mL, 0.2083 mmol) and potassium phosphate (0.368 g, 1.736 mmol) to afford the crude product. Purification by preparative HPLC afforded 18 mg of the product (8.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17](Br)=[CH:18][C:19]=1[N:20]([CH:30]([CH3:32])[CH3:31])[C:21]([CH:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])=[O:14].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:18][C:19]=1[N:20]([CH:30]([CH3:32])[CH3:31])[C:21]([CH:23]1[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]1)=[O:22])=[O:14]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)C1CCC(C)CC1)C(C)C
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1)C(C)C
Temperature: 70 °C
Yield: 99.8 %

Procedure:
To the mixture of 3-fluorobenzeneboronic acid (25.0 mg, 0.180 mmol) and 5-Bromo-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg, 0.060 mmol) in 5:1 mixture of toluene/MeOH (1.0 mL) was added a solution of Pd(PPh3)4 (7.0 mg, 0.006 mmol, 10 mol %) in toluene (0.5 mL) followed by aqueous 2M Na2CO3 solution (0.06 mL, 0.120 mmol). The resultant reaction mixture was heated at 70° C. for 18 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC using ethyl acetate/hexane (20:80) as an eluent furnished (25.0 mg, 99% yield) of 5-(3-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N:27]([O-:29])=[O:28].[Na+].[N+]([O-])(O)=O>C(O)(=O)C>[CH3:17][C:14]1[CH:15]=[CH:16][C:4]2[O:3][C:2]([N+:27]([O-:29])=[O:28])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=1
Reactant: Cc1ccc2oc(Br)c(-c3ccccc3)c2c1
Reactant: O=N[O-]
Agent: O=C(O)C1CC=CCC1
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a solution of 25 g (0.0875 mole) of 2-bromo-5-methyl-3-phenylbenzofuran and 16.5 g of cyclohexene-4-carboxylic acid in 150 ml of acetic acid is added 17.5 g of sodium nitrite, then 17.5 ml of nitric acid is added dropwise with stirring. The mixture is stirred at about 25° C. for about three hours, then poured onto ice. The mixture is then extracted with diethyl ether. The ether solution is washed with 10% sodium bicarbonate solution, saturated sodium carbonate solution and dried. The dried solution is evaporated under vacuum to provide a yellow residue. The residue is recrystallized from carbon tetrachloride, then cyclohexane to provide yellow crystals of 5-methyl-2-nitro-3-phenylbenzofuran, m.p. 144.5°-146° C.
Reaction SMILES: [O-]CC.[Na+].[Br-].[CH3:6][N:7]([CH3:37])[C:8]1[C:9]([N+:34]([O-:36])=[O:35])=[C:10]([CH:31]=[CH:32][CH:33]=1)[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:38]1([C:44]2[N:45]=[CH:46][N:47]([CH2:49][CH2:50][CH:51]=O)[CH:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([C:44]2[N:45]=[CH:46][N:47]([CH2:49][CH2:50]/[CH:51]=[CH:11]\[C:10]3[C:9]([N+:34]([O-:36])=[O:35])=[C:8]([CH:33]=[CH:32][CH:31]=3)[N:7]([CH3:6])[CH3:37])[CH:48]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=CCCn1cnc(-c2ccccc2)c1
Reactant: CN(C)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Product: CN(C)c1cccc(/C=C\CCn2cnc(-c3ccccc3)c2)c1[N+](=O)[O-]
Yield: 48.7 %

Procedure:
An ethanolic solution of 90 mg of sodium ethoxide was dropped into an ethanolic solution containing 650 mg of 3-dimethylamino-2-nitrobenzyltriphenylphosphonium bromide and 320 mg of 3-(4-phenyl-1H-imidazol-1-yl)propionaldehyde. The obtained solution was heated under reflux for 2 hours to conduct a reaction. After the completion of the reaction, the mixture was distilled to remove the solvent. The residue was extracted with 2N NaOH and the obtained aqueous layer was made acidic again with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. The obtained oily substance which is a mixture of cis- and trans-isomers was purified by silica gel chromatography to give 220 mg of 3-[4-(4-phenyl-1H-imidazol-1-yl)-1-cis-butenyl]-2-nitro-N,N-dimethylaniline. 430 mg of zinc was added to a solution of this product in acetic acid to give 2-dimethylamino-6-[4-(4-phenyl-1H-imidazol-1-yl)-1-Cis-butenyl]aniline as an oily substance. This oily substance was dissolved in chloroform, followed by the dropwise addition of 50 mg of butyl isocyanate. The obtained mixture was heated under reflux for 2 hours to conduct a reaction. After the completion of the reaction, the obtained reaction mixture was concentrated to precipitate a crystal. This crystal was recrystallized from an ethyl acetate/hexane mixture to give 190 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([F:23])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([F:23])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1F
Temperature: 70 °C
Yield: 76.8 %

Procedure:
Add manganese dioxide (1.132 g, 13 mmol) to a solution of N-(tert-butoxycarbonyl)-3-fluoro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine (283 mg, 0.87 mmol) in anhydrous 1,4-dioxane (11.5 mL) at room temperature. Heat the reaction mixture at 70° C. overnight. Filter the reaction mixture over Celite® and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as an oil (216 mg, 77%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH:16]=[C:15]2[OH:23].ClC1C2C(=CC=C(C(C3N(C)C(C)=NC=3)O)C=2)N=C(OC)C=1CC1C=NC(C(F)(F)F)=CC=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([OH:22])[C:16]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[C:15]2[OH:23]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: CSc1ccc(C=O)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Solvent: c1ccncc1
Product: CSc1ccc(Cc2c(O)nc3ccc(Br)cc3c2O)cc1

Procedure:
A mixture of 4-(methylthio)benzaldehyde (3.00 g, 19.7 mmol), 6-bromo-4-hydroxyquinolin-2(1H)-one (4.72 g, 19.7 mmol, Intermediate 45: step a), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.23 g, 20.7 mmol), and pyridine (100 mL) was stirred at 80° C. for 4 hours and then at room temperature overnight. The reaction was cooled and the formed precipitate was filtered, washed with Et2O (100 mL), and dried to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.CCO.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(F)ccc1N
Reaction time: 96 h
Yield: 97.7 %

Procedure:
A round-bottom flask was charged with 4-fluoro-2-isopropoxy-1-nitrobenzene (49.3 g, 248 mmol), EtOH (600 mL), and 10% Pd/C (50% in water, Degussa type E101; 10 g, 20 wt % by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (×3) from a balloon filled with H2. The reaction was stirred for 4 d using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness to provide 4-fluoro-2-isopropoxybenzenamine (41.0 g, 98%) as a brown liquid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 6.67-6.72 (dd, 1H, J=2.7 Hz, 11 Hz), 6.55-6.60 (dd, 1H, J=6.0 Hz, 8.7 Hz), 6.43-6.49 (td, 1H, J=2.7 Hz, 8.4 Hz), 4.47-4.55 (m, 3H), 1.23-1.25 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −127.4 (sextet); m/z=170 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[N:7][O:8][C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[CH:10]1([C:9]2[O:8][N:7]=[C:6]([C:13]3[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:19])[C:5]=2[CH2:3][OH:2])[CH2:12][CH2:11]1
Reactant: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole-4-carboxylic acid methyl ester (0.80 g, 2.6 mmol) is dissolved in 8 mL of THF and is cooled in an ice bath. To the solution is added 1M DIBAL solution in toluene (5.66 mL) and the reaction is stirred one hour. Additional 1M DIBAL solution in toluene (5.66 mL) is added and the reaction is stirred for an additional hour. Upon completion, the reaction is quenched with methanol and acidified with aqueous HCl solution (1M). The reaction mixture is extracted with ethyl acetate and washed with brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (0.68 g, 93%). MS m/z: 284.0 (M++1)