Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18](O)=[O:19])=[O:8])=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:42][CH2:43][C@H:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[OH:45]>O1CCCC1.ClCCl>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18]([NH:42][CH2:43][C@@H:44]([OH:45])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:19])=[O:8])=[CH:3][CH:2]=1
Reactant: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: NC[C@@H](O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CON=C1C[C@@H](CC(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106 %

Procedure:
To a solution of [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 25 mg, 0.07 mmol) in tetrahydrofuran (1 ml) at −25° C. were added NMM (18 mg, 0.18 mmol) followed by isobutyl chloroformate (10 mg, 0.07 mmol). The reaction mixture was stirred 10 min then a solution of (S)-2-amino-1-phenylethanol (10 mg, 0.07 mmol) in tetrahydrofuran (1 ml). The reaction was allowed to warm up to room temperature and was stirred overnight. Dichloromethane was added and the organic phase was washed with NH4Cl, NaHCO3 then brine. The organic phase was dried (MgSO4) and concentrated to afford 2-[(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino) pyrrolidin-2-yl]-N-[(2S)-2-hydroxy-2-phenylethyl]acetamide (35 mg). Yield: 94%. HPLC purity: 90%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (39 mg, 36%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:37][CH2:38][Sn](CCCC)(CCCC)CCCC.[OH-].[Na+]>O1CCOCC1.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:38][OH:37])[CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(CO)cc12
Yield: 12.5 %

Procedure:
To a solution of 3-{1-(1,3-benzodioxol-5-yl)-2[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-5-bromo-1-methyl-1H-indole (from Example 79, 300 mg, 0.534 mmol) in 1,4-dioxane (1.5 ml) under a nitrogen atmosphere was added hydroxymethyltributylstannane (253 mg, 0.79 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (30 mg). The mixture was heated to reflux for 8 hours, and then cooled. Sodium hydroxide solution (1M) was added and the mixture boiled to dissolve the product. The solution was decanted clear of an insoluble tar residue, and washed with diethyl ether. After acidification with concentrated hydrochloric acid, the aqueous mixture was extracted with ethyl acetate. The organic extract was dried (magnesium sulphate) and the solvents were evaporated in vacuo. The residue was flash chromatographed using 2% methanol in dichloromethane as eluant to give the title compound (35 mg).
Reaction SMILES: [C:1]1([C:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=O)[CH2:20][CH2:21][C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[K+].C(O)COCCOCCO>>[C:1]1([C:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(CCC(=O)CCCCC(=O)CCC(CC(=O)O)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: O=C(O)CC(CCCCCCCCCCC(CC(=O)O)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C

Procedure:
0.27 g. 3,3,14,14-Tetraphenyl-6,11-diketohexadecane-1,16-dioic acid, prepared according to Example 23, and 0.23 g. 85% hydrazine hydrate were added to a solution of 0.4 g. KOH in 10 ml. triethylene glycol. The mixture was heated for 24 hours at 120° C., subsequently heated to 195° C. in order to evaporate the water and then boiled under reflux for 7 hours. The mixture was cooled, diluted with water, extracted with ether, acidified and extracted with ether. The ether extract was washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:19]#[N:20])=[CH:11][C:12]([N+:16]([O-])=O)=[C:13]([CH3:15])[CH:14]=2)=[CH:5][CH:4]=1.[CH3:21]N(C(N(C)C)N(C)C)C.Cl>C1(C)C=CC=CC=1.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]3[C:12](=[CH:11][C:10]=2[C:19]#[N:20])[NH:16][CH:21]=[CH:15]3)=[CH:5][CH:4]=1
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: COc1ccc(-c2cc(C)c([N+](=O)[O-])cc2C#N)cc1
Agent: [Fe]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2cc3cc[nH]c3cc2C#N)cc1
Yield: 32 %

Procedure:
A mixture of 4′-methoxy-5-methyl-4-nitro-biphenyl-2-carbonitrile (118.0 mg, 0.44 mmol) and tris(dimethylamino) methane (128.0 mg, 0.88 mmol) in toluene (15 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL) and water (0.10 mL), and treated with iron powder (64.0 mg, 1.15 mmol), followed by concentrated HCl (28.0 mg, 0.29 mmol). The reaction mixture was heated to reflux for an additional 16 hours, and quenched with 1N aqueous NaOH (0.288 mL). The solution was filtered through celite and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuo to give the title compound (35 mg, 49% yield). MS (ES−) 247.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.68 (d, J=2.73 Hz, 1H), 7.66 (s, 1H), 7.48 (d, J=8.59 Hz, 2H), 7.05 (d, J=8.59 Hz, 2H), 6.58 (d, J=2.73 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]3([CH3:31])[CH3:30])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3([CH3:31])[CH3:30])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3(C)C)cn2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3(C)C)cn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 120.7 %

Procedure:
To a solution of tert-butyl 4-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-3-yl)-3,3-dimethylpiperazine-1-carboxylate 190c (1.19 g, 1.9 mmol) in dichloromethane (20 mL) was added 3M HCl in diethyl ether (15 mL). The reaction mixture was stirred at room temperature for 4 h. It was then concentrated under reduced pressure to afford 190d (900 mg, 95%). LCMS: [M+H]+ 392.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]2=[O:15].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([NH:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]2=[O:15])=[O:20])[CH3:17]
Reactant: Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.08 g (20 mmol) of 6-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Pharm. Sci., 11, 1051 (1963)] 2.37 ml (30 mmol) of ethyl isocyanate, 2.8 ml (20 mmol) of triethylamine and 50 ml of dimethylformamide is stirred at room temperature overnight. The solution is evaporated to dryness and the residue is treated with 1 N hydrochloric acid. The solid is filtered to give 4.56 g of 6-[[(ethylamino)carbonyl]-amino]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp>320° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: Cc1oc(C2(C)CCCCC2)nc1CC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(C2(C)CCCCC2)nc1CC(=O)O
Temperature: 90 °C

Procedure:
Benzyl 5-methyl-2-(1-methylcyclohexyl)-4-oxazoleacetate (1.0 g) was dissolved in ethanol (3 ml), and 2N sodium hydroxide (3 ml) was added. The mixture was heated on a water bath at 90° C. for 5 minutes, diluted with water and washed with ethyl ether. The aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted with ethyl ether. The ethyl ether extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from hexane to give 5-methyl-2-(1-methylcyclohexyl)-4-oxazoleacetic acid as crystals; yield 0.41 g (56.9%). Mp 66°-67° C. The IR and NMR spectra of this product were in good agreement with those of the compound obtained in Example 15.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][NH2:11].C1[CH2:16][O:15]CC1>C(#N)C>[NH2:9][C:4]1[N:3]=[C:2]([NH:1][C:16]([NH:11][CH3:10])=[O:15])[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: C1CCOC1
Reactant: CN
Solvent: CC#N
Product: CNC(=O)Nc1cc(Br)cc(N)n1
Temperature: 25 °C

Procedure:
To a solution of 0.188 g 2.6-diamino-4-bromopyridine in 2 ml acetonitrile was added 0.164 g 1,1-carbonyldi(1,2,4-triazole) and the mixture was stirred at room temperature. After a short period of a clear solution a suspension formed. The mixture was stirred at room temperature for 1 h. To the resulting suspension was added 0.5 ml of a methylamine solution in THF (ca 3 M) and the resulting solution was stirred at room temperature for 0.5 h. The mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase evaporated to dryness. The residue was taken up in methanol whereby crystallisation occurred. The crystals were collected by filtration and dried to constant weight to yield 0.196 g of the title compound as white crystals. MS (ISP) M+H+243.3; 245.2
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: COc1ccc(OCCCCCI)c(Cl)c1
Reactant: CCOP(=O)(CC(C)=O)OCC
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 16.9 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)5, R is C2H5, R' is CH3CO] was prepared from 0.71 g of lithium hydride, 17.2 g of diethyl acetonylphosphonate and 34 g of 5-(2-chloro-4-methoxyphenoxy)pentyl iodide according to the procedure of Example 2(b). The product was chromatographed on Florisil and further purified by preparative TLC on silica gel to give 6.3 g of diethyl [1-acetyl-6-(2-chloro-4-methoxyphenoxy)hexyl]phosphonate as a light yellow oil; MIC vs. herpes simplex type 2=6 mcg/ml. The IR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].[NH2:19]OS(O)(=O)=O>C1(C)C=CC=CC=1.O.CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH2:19])[CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: Clc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Nn1cc(Cl)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
To a 12 L round bottom flask equipped with a mechanical stirrer, thermometer and a Gooch tube was added sieve-dried dimethylformamide (2.8 L), 3-chloroindole (240 g, 91.6% pure), milled potassium carbonate (200.4 g), milled potassium hydroxide (574.3 g, 85% pure) and dimethylformamide (900 mL) at -2° to 5° C. The reaction mixture was cooled to about 0° C. and hydroxylamine-O-sulfonic acid (338.2 g, 97% pure) was added portionwise via the Gooch tube over a period of about 4 hrs, maintaining the reaction temperature at about 0° C. When the reaction was >95% complete (by high performance liquid chromatography), the reaction mixture was poured into a well-stirred, cold mixture of water (18 L and 3.6 kg ice) and toluene (2.4 L). After about 5 mins, the phases were separated and the aqueous phase was extracted with toluene (1×2.4 L and 1×1 L). The organic fractions were combined and filtered through Celite. The filtrate was concentrated under reduced pressure (about 50 mm Hg) at about 60° C. to yield 245 g (86%) of product.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:4].[C:13]([O:17][C:18]([NH:20][CH:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:22]([O:24][C@@H:25]1[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[Br-:1].[C:13]([O:17][C:18]([NH:20][CH:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:22]([O:24][C@@H:25]1[CH:30]2[CH2:31][CH2:32][N+:27]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])=[O:4])([CH2:28][CH2:29]2)[CH2:26]1)=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: COc1ccccc1C(=O)CBr
Solvent: CC#N
Product: COc1ccccc1C(=O)C[N+]12CCC(CC1)[C@@H](OC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1)C2
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
2-Bromo-1-(2-methoxyphenyl)ethanone (45.8 mg, 0.20 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C1) (72.0 mg, 0.20 mmol) in acetonitrile (3 ml). The reaction was stirred at RT overnight. The product was collected by suction filtration to get (3R)-3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-1-(2-(2-methoxyphenyl)-2-oxoethyl)-1-azoniabicyclo[2.2.2]octane bromide (112 mg; 95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:17])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:30](I)[CH3:31].[CH3:33][C:34]#N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH2:33][CH3:34])[C:13]([S:17][CH2:30][CH3:31])=[N:12]3)[CH2:10][CH:9]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Reactant: CC#N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCSC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC
Yield: 69 %

Procedure:
To a mixture of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (250 mg, 0.64 mmol) and K2CO3 (356 mg, 2.6 mmol) in CH3CN (8 mL) was added EtI (402 mg, 2.6 mmol). The reaction mixture was refluxed for 2 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC to give 6-bromo-1′-ethyl-2′-(ethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (195 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[C:17]([CH2:19]O)[CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[C:17]([CH2:19][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CN1CCN(c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2CO)CC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2CN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To {5-[(7-chloroquinolin-4-yl)amino]-2-(4-methylpiperazin-1-yl)phenyl}methanol (0.300 g, 0.78 mmol) in 6 mL of DMF at 0° C. was added thionyl chloride (0.28 mL, 5 eq). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solvent was evaporated. The residue was suspended in 6 mL of DMF and morpholine (1.39 mL, 20 eq) was added at 0° C. The solution was stirred overnight at room temperature, evaporated and the residue was purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a pale yellow solid (238 mg, 67% yield). m/z (ESI) 452.2 [M+H]+;
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33](/[CH:36]=[CH:37]/[CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:25]([C@H:30]1[CH2:31][CH2:32][C@H:33](/[CH:36]=[CH:37]/[CH2:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:5][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:10]([F:11])[C:2]=3[F:1])=[CH:44][CH:45]=2)[CH2:34][CH2:35]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(O)cc2)CC1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(CC/C=C/[C@H]3CC[C@H](CCCCC)CC3)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.7 g of 2,3-difluoro-4-dodecyloxybenzoic acid, 1.5 g of 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]phenol and 0.1 g of 4-(dimethylamino)pyridine were dissolved in 250 ml of dichloromethane and the solution was treated portionwise within 10 minutes while stirring with 1/2 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight and then filtered. The filtrate was diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with 100 ml of water, dried over magnesium sulphate, filtered and then concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave 2 g of 2,3-difluoro-4-dodecyloxybenzoic acid 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]phenyl ester with m.p. (C-SC) 51° C., SC -N 115° C. and cl.p. (N-I) 133° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-])=O)[CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>[Pd].CO.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH2:18])[CH:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1ccc(-c2ccc(N)c(N)c2)cc1
Reaction time: 1 h

Procedure:
4′-Butyl-3-nitro-biphenyl-4-ylamine (117 mg, 3.70 mmol) and 10% Pd/C (10 mg) in 2:1 v/v MeOH/EtOAc (4 ml) is treated to a steady bubbling of H2 (g) for 15 minutes. The reaction is kept under 1 atm of H2 for 1 hour with stirring. The reaction is filtered through Celite and the filtrate concentrated in vacuo to afford 4′-butyl-biphenyl-3,4-diamine: ESMS m/z 241.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1)[CH3:11].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.O>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:16]=1)[CH3:11]
Reactant: Cc1ccc(CN)cc1
Reactant: CCOC(=O)Cc1cccc(C=O)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
A solution of 4-methylbenzylamine (0.097 mL, 0.76 mmol) and (3-formyl-phenyl)-acetic acid ethyl ester (138 mg, 0.72 mmol) in MeOH (2 mL) was stirred for 3 h at room temperature. The reaction was cooled to 0° C. and NaBH4 (43 mg, 1.15 mmol) was added. After stirring at room temperature for 10 minutes, a 1:1 mixture of saturated aqueous NaHCO3:H2O was added. The product was extracted into CH2Cl2 (3×) and the organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (231 mg). 1H NMR (400 MHz, CDCl3) δ 7.13-7.30 (m, 8H), 4.14 (q, 2H), 3.83 (d, 4H), 3.78 (s, 2H), 2.34 (s, 3H), 1.25 (t, 3H); MS 298 (M+1).
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[O:7])[CH:5]=[CH:4]N=C1.NC1C[CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:24][C:23]1[O:22][N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]=1[C:16]1[O:15][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]([NH:1][CH:5]3[CH2:33][CH2:34][O:35][CH2:36][CH2:4]3)=[O:7])=[CH:13][CH:12]=2)=[N:18][N:17]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)n3ccnc3)cc2)o1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)NC3CCOCC3)cc2)o1
Yield: 46 %

Procedure:
As described for example 78c, imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone (200 mg, 0.50 mmol) was converted using 4-aminotetrahydropyran instead of cyclopropylamine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 100 mg, 46%) which was obtained a white solid. MS: m/e=431.3 [M+H]+.