Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)O.[C:8]1([CH3:19])[CH:13]=[CH:12][C:11]([S:14]([NH:17][NH2:18])(=[O:16])=[O:15])=[CH:10][CH:9]=1>CO>[C:8]1([CH3:19])[CH:9]=[CH:10][C:11]([S:14]([NH:17][N:18]=[CH:3][C:2]([Cl:7])([Cl:6])[Cl:1])(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=CC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol were dissolved 0.99 g (6 mmole) of chloral hydrate and 0.93 g (5 mmole) of p-toluenesulfonylhydrazine, and the mixture was stirred at room temperature for 30 minutes to form trichloroacetaldehyde-p-toluenesulfonylhydrazone. Then, to the reaction mixture was added under room temperature 30 ml of a 5% aqueous ammonia containing 3.44 g (17.5 mmole) of ammonium pentasulfide for 15 minutes. Thereafter, the reaction was continued for further 2 hours while maintaining the pH of the reaction system at 10.4 by using a 30% by weight aqueous potassium hydroxide solution. The analysis after completion of the reaction was carried out in the same manner as in Example 1. A yield of the obtained product to the starting p-toluenesulfonylhydrazine was as follows.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH3:3].C(OC)(OC)OC.[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:10][CH2:11][CH3:12])=[CH:32][CH:33]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: CCCN(CCC)CCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
The compound (9.25 g) obtained in Example 1-2 was dissolved in anhydrous methanol (200 ml) and then added with trimethyl orthoformate (8.81 ml) and the compound (12.6 g) obtained in Example 23-3. The whole was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Then, sodium borohydride (2.03 g) was added thereto in an ice bath and the whole was stirred at room temperature for 2 hours. After completion of the reaction, distilled water was added thereto and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (19.3 g) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]([NH2:12])=O)[CH:5]=[N:6][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([NH:26][C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30])[CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCOC(C)=O.O>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:13][C:14]1[CH:15]=[C:16]([N:26]2[C:27](=[O:32])[CH:28]=[C:29]([CH3:30])[N:12]=[C:10]2[CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NC(=O)COc1cncc(F)c1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2cncc(F)c2)n1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
To a mixture of 2-((5-fluoropyridin-3-yl)oxy)acetamide (200 mg, 1.18 mmol) and N-(3-fluoro-4-morpholinophenyl)-3-oxobutanamide (330 mg, 1.18 mmol) in xylene (10 mL) was added titanium tetraisopropanolate (2.7 mg, 9.5 mmol) and the mixture was refluxed for 50 h. The mixture was cooled to rt and 60 mL of EtOAc and 10 mL of water were added. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (130 mg, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2c[nH]c3ccccc23)c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(C2CNc3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-(3-Chlorophenyl)indole (5.30 g, 23.3 mmol) was dissolved in 50 mL of 1 M BH3 in THF. The mixture was cooled to about 0° C. To the solution was added slowly TFA (50 mL). After addition, the solution was stirred for about 10 minutes. To the solution was added slowly 1M BH3 in THF (40 mL). The mixture was stirred for about 5 minutes and then concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with EtOAc/hexane 1:6. The title compound was obtained as an oil (Yield; 3.93 g, 74%). Rf=0.20 (Silica, EtOAc/hexane 1:4) MS (ES):229.1; Calc. MW=229.7.)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:11][C:10]([CH3:12])=[CH:9][C:8]=2[Cl:13])=[N:18][CH:19]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Cc1cc(Cl)c(OCCO)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(Br)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A sol. of 2-(2,6-dichloro-4-methyl-phenoxy)-ethanol (18.6 g, 84 mmol) in THF (360 mL) was cooled to 0° C. NaH (about 55% in oil, 6.60 g, about 153 mmol) was added in portions, and the mixture was stirred at rt for 30 min. A sol. of 2,5-dibromopyridine (18.0 g, 76.3 mmol) in THF (60 mL) was added dropwise, and the mixture was heated to reflux for 90 min. The mixture was allowed to cool to rt, and ice was added carefully. The solvents were partially removed under reduced pressure, and the residue was diluted with EtOAc. This mixture was washed with aq. sat. NH4Cl. The aq. layer was extracted back with EtOAc (2×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 3:97) yielded the title compound (22.7 g, 79%). LC-MS: tR=1.13 min; ES+: 378.08.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][C@H:33]([CH3:36])[C:34]#[N:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([C@H:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:36])#[N:35]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: C[C@@H](N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 40 mg, 0.093 mmol) and (R)-2-aminopropanenitrile (Int-X, 13.00 mg, 0.185 mmol) were dissolved in DMF (1 mL). 4-Methylmorpholine (37.5 mg, 0.371 mmol) and HATU (45.8 mg, 0.121 mmol) were added. After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 2—CH3CN/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 35 min, 20 mL/min, 220 nM, product retention=28.5 min) to provide single enantiomer N-((R)-1-cyanoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (27 mg, 0.055 mmol, 59.6% yield): [M+H]+=484.0; 1H NMR (400 MHz, methanol-d4) δ ppm 8.93 (1 H, d, J=7.70 Hz), 8.13-8.24 (2 H, m), 7.50-7.80 (7 H, m), 5.17 (1 H, s), 4.86-4.91 (1 H, m), 1.56 (3 H, d, J=7.04 Hz); HPLC peak RT=9.9 min (Method A).
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37](O)[CH:38]=C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]=[CH2:38])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: C=CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 79.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-propen-1-ol (13 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.C1(C)C=CC(S([O-])(=O)=[O:21])=CC=1.[Na+].CO.O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:21]
Reactant: ClC(Cl)=COc1cccc(CBr)c1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1cccc(OC=C(Cl)Cl)c1
Temperature: 50 °C

Procedure:
A mixture of 3(2,2-dichlorovinyloxy)benzyl bromide (2.8 g), sodium p-toluene sulphonate (2.0 g) and methanol (20 ml) is warmed to 50° C for 1 hour, after which water (20 ml) and toluene (20 ml) is added with agitation. The toluene layer is separated, washed with water and concentrated by evaporation of the solvent under reduced pressure. The concentrate is then added dropwise to a 15% (w/v) aqueous solution of potassium hydroxide (100 ml) and the mixture warmed to 60° C for 1 hour, cooled to the ambient temperature and extracted with a mixture of toluene (10 ml) and methyl iso-butylketone (10 ml), the extracts dried over anhydrous magnesium sulphate and the solvents evaporated under reduced pressure to yield 3(2,2-dichlorovinyloxy)benzyl alcohol as a residual pale yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:11][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cncc(Cl)c1Br
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-3-chloro-5-nitro-pyridine (700 mg, 2.948 mmol), tert-butyl piperazine-1-carboxylate (823.6 mg, 4.422 mmol) and DIPEA (762.0 mg, 1.027 mL, 5.896 mmol) in NMP (2.5 mL) was stirred overnight at RT. The reaction mixture was partitioned between EtOAc and water. Combined organic extract was washed with brine, dried over MgSO4, concentrated under reduced pressure to yield tert-butyl 4-(3-chloro-5-nitropyridin-4-yl)piperazine-1-carboxylate which was used in next step without further purification (1 g, 99%). MS (ES+) 343.1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1N.[N:19]1C=CC=CC=1.[C:25]([C:29](Cl)=[O:30])([CH3:28])([CH3:27])[CH3:26].O>C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[CH2:26][C:25]([CH3:28])([CH3:27])[C:29]([NH2:19])=[O:30]
Reactant: CC(C)(C)C(=O)Cl
Reactant: c1ccncc1
Reactant: COc1ccc(CSc2ccc(N)c(F)c2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CSc2ccc(CC(C)(C)C(N)=O)c(F)c2)cc1
Reaction time: 2 h

Procedure:
A mixture of the product of step 2, pyridine (3.1 ml, 38.4 mmol) and (CH3)3CCOCl (3.2 ml, 25.6 mmol) in CH2Cl2 (100 ml) was stirred for 2 h, then poured into cold water. The whole was extracted with CH2Cl2 (3×100 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated to afford 2-fluoro-4-(4′-methoxybenzylmercapto)phenyl-2,2-dimethylpropanamide. MS (Cl) m/e 348 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([NH:35][C:36]4[CH:37]=[C:38]([C:42]([O:44]C)=[O:43])[N:39]([CH3:41])[CH:40]=4)=[O:34])[N:30]([CH3:32])[CH:31]=3)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([NH:35][C:36]4[CH:37]=[C:38]([C:42]([OH:44])=[O:43])[N:39]([CH3:41])[CH:40]=4)=[O:34])[N:30]([CH3:32])[CH:31]=3)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cc1C(=O)O
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Methyl 4-(4-(4-(4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylate (510 mg, 0.82 mmol) in 10 ml of DMA was added 0.8 g of LiOH in 10 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 to form precipitates. The precipitates were filtered, washed with water and dried over P2O5 under vaccum to afford 363 mg (73%) of the title product. 1H NMR (DMF-d7) 10.31 (s, 1H), 10.18 (s, 1H), 10.11 (s, 1H), 9.10 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 4.10 (s, 1H), 3.98 (s, 1H), 3.95 (s, 1H), 3.93 (s, 1H), 1.47 (s, 9H); 13C NMR 162.16, 160.05, 159.90, 157.20, 154.31, 137.88, 135.35, 124.56, 124.39, 123.51, 123.09, 121.76, 120.09, 119.83, 118.96, 115.32, 109.53, 105.58, 102.27, 79.32, 38.13, 36.02, 35.81, 34.88, 28.79; MS m/z− 606.2 (M−H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOCC>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccc(C(=O)OC)cc2)ccc(C(C)=O)c1O
Yield: 68.7 %

Procedure:
A solution of 1.0 g (5.15 mmoles) of 2,4-dihydroxy-3-propylacetophenone, see R. A. Appleton et al. in J. Med. Chem. 1977, 20, pages 371-379, and 1.77 g (7.7 mmoles) of methyl 4-bromomethylbenzoate in 20 ml of acetone was treated with 784 mg (5.66 mmoles) of K2CO3 and stirred at reflux for 15 hours. The reaction mixture was diluted with ether, washed with water and saturated aqueous NaHCO3 solution and dried with MgSO4. Evaporation of the solvent gave an oil which crystallized. This material was purified by chromatography on silica gel with 30% hexane/dichloromethane as eluent to provide 1.212 g (69% yield) of the title compound as a white powder mp 99.5°-100.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]=[O:25])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Mg]Br.C1COCC1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]([OH:25])[CH3:26])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carbaldehyde (16.7 mg) which can be prepared according to the method described in Reference example 23, etc. was dissolved in dehydrated THF (0.5 mL; manufactured by Kanto Chemical Co., Inc.). After cooling to 0° C. with the replacement with nitrogen, 0.96 mol/L-methylmagnesium bromide-THF solution (57 μL; manufactured by Kanto Chemical Co., Inc.) and the mixture was stirred overnight while warming to room temperature. To the reaction solution, dehydrated THF (1 mL; manufactured by Kanto Chemical Co., Inc.) and 0.96 mol/L-methylmagnesium bromide-THF solution (1 mL; manufactured by Kanto Chemical Co., Inc.) were added and the mixture was stirred at room temperature for 4.5 hours. To the reaction solution, 2 mol/L hydrochloric acid was added and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-F”; n-hexane:ethyl acetate 2:1) to obtain the title compound (11.4 mg).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17](N)=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21]=O.[C:23]([BH3-])#[N:24].[Na+]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:21][N:24]([CH3:23])[C:17]1[CH:18]=[CH:19][C:14]([N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[N:11]=2)[CH3:13])=[CH:15][CH:16]=1
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Reactant: [BH3-]C#N
Reactant: C=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Product: Cc1nc(N(C)c2ccc(N(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine (14 mg, mmol) in 1.5 mL of 37% aqoues formaldehyde solution and 10 uL of glacial acetic was added Sodium cyanoborohydride (15 mg, 0.24 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding 50 uL of 1N HCl. It was diluted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate, and followed by saturated sodium chloride. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (25% ethyl acetate/hexanes) on silica gel to give the title compound (12.4 mg, 0.042 mmol, 80%). 1H NMR (CDCl3): 7.71 (m, 1H), 7.50 (ddd, J=8.4, 6.9, 1.5, 1H), 7.03-7.09 (m, 3H), 6.95 (ddd, J=8.1, 6.6, 0.9, 1H), 6.70 (m, 2H), 3.57 (s, 3H), 2.99 (s, 6H), 2.71 (s, 3H).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[N:10]([C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:24])=[CH2:23])[CH:17]=1)([CH3:15])[CH3:14])=[C:11]=[O:12]>C(Cl)(Cl)Cl>[CH2:23]=[C:22]([C:18]1[CH:17]=[C:16]([C:13]([NH:10][C:11]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[O:12])([CH3:15])[CH3:14])[CH:21]=[CH:20][CH:19]=1)[CH3:24]
Reactant: C1CN2CCC(CC2)N1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Solvent: ClC(Cl)Cl
Product: C=C(C)c1cccc(C(C)(C)NC(=O)N2CCN3CCC2CC3)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
To a solution of 1,4-diazabicyclo[3.2.2]nonane (350 mg, 2.77 mmol) and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (1.09 mL, 5.55 mmol) in chloroform (2 mL) was added 3-4 pieces of molecular sieves. The reaction mixture was stirred at room temperature for 18 h and then concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding urea as an off-white solid (650 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.31-7.26 (m, 3H), 5.34 (s, 1H), 5.07 (s, 1H), 4.73 (br s, 1H), 4.03 (BR s, 1H), 3.64 (m, 2H), 3.14-3.03 (m, 6H), 2.15 (s, 3H) 2.06 (m, 2H), 1.72 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 155.7, 148.3, 143.8, 141.3, 128.5, 124.1, 123.9, 122.0, 112.5, 57.8, 55.8, 48.1, 46.4 (2×), 41.2, 30.2 (2×), 27.3 (2×), 22.1 ppm. Purity: >98% UPLCMS (210 nm); retention time 0.71 min; (M+1) 328
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([NH:14][CH2:15][CH3:16])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=O.[C:20]1(=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][C:22](=[O:30])[O:21]1.CI.[C:34](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[N:14]([CH2:15][CH3:16])[C:22](=[O:30])[C:23]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:20]([O:21][CH3:34])=[O:31])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCn1c(=O)c(-c2ccccc2C(=O)OC)c(-c2cccc(Cl)c2)c2ccc(C)nc21

Procedure:
After the reaction of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine with isochroman-1,3-dione (75%) under heating, the compound obtained by usual work-up was reacted with methyl iodide in 2-butanone in the presence of potassium carbonate. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain methyl 2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]benzoate as a yellow solid. MS: 433.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]([NH2:33])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]([NH:33][C:15]([NH:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:16])([CH3:31])[CH3:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(C(C)(C)N)c1
Reactant: NC1CN2CCC1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1cccc(C(C)(C)NC(=O)NC2CN3CCC2CC3)c1
Yield: 58.6 %

Procedure:
Using general procedure C, quinuclidin-3-amine (380 mg, 3.01 mmol), CDI (489 mg, 3.01 mmol) and 2-(3-methoxyphenyl)propan-2-amine (506 mg, 3.07 mmol) gave 1-(2-(3-methoxyphenyl)propan-2-yl)-3-(quinuclidin-3-yl)urea (560 mg, 59%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 1H), 7.14-7.07 (m, 2H), 6.87-6.81 (ddd, 1H), 4.76 (s, 1H), 4.19 (d, 1H), 3.81 (s, 3H), 3.70-3.62 (m, 1H), 3.19-3.10 (m, 1H), 2.74-2.59 (m, 3H), 2.37-2.26 (m, 1H), 2.07-1.98 (dd, 1H), 1.80 (br s, 1H), 1.69-1.63 (m, 1H), 1.63 (s, 3H), 1.62 (s, 3H), 1.58-1.44 (m, 2H), 1.28-1.14 (m, 1H), 1.02-0.90 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.0, 157.5, 148.4, 129.9, 117.7, 112.0, 111.9, 56.7, 55.3, 54.6, 47.2, 46.8, 46.4, 30.1, 25.8, 20.0 ppm. Purity: >99.4% UPLCMS (210 nm); retention time 1.73 min; (M+1) 318.