Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:14]1([CH2:20][N:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH:23]2[CH2:25][O:24]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CO.C1(C)C=CC=CC=1>[C:27]1([CH2:26][N:21]([CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH:23]([OH:24])[CH2:25][N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]2=[O:1])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Reactant: Oc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1ncccn1CC(O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 55 °C
Yield: 47.5 %

Procedure:
A solution of 2-hydroxypyrimidine (0.16 mol) in methanol (300 ml) was stirred at room temperature for 30 minutes. A solution of Na2CO3 (0.16 mol) in methanol (40 ml) was added. The mixture was stirred and refluxed for 15 minutes and cooled to 55° C. A solution of N,N-bis(phenylmethyl)-2-oxiranemethanamine (0.16 mol) in toluene (320 ml) was added dropwise. The mixture was stirred at 50° C. overnight Water (150 ml) was added The mixture was stirred at 55° C. for 15 minutes. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 26.55 g of (±)-[3-[bis(phenylmethyl)amino]-2-hydroxypropyl]-2(1H)pyrimidinone (intermediate 4).
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]([O-:18])=[O:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31]>CN(C)C=O>[O:31]=[C:27]1[N:26]([CH2:25][CH2:24][O:17][C:16](=[O:18])[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH2:30][CH2:29][O:28]1
Reactant: O=C1OCCN1CCCl
Reactant: O=C([O-])c1ccccc1Nc1ccnc2cc(Cl)ccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCOC1=O)c1ccccc1Nc1ccnc2cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A mixture comprising 12.8 g of N-(7-chloro-4-quinolyl)-anthranilic acid sodium salt, 6.64 g of 90% 3-(β-chloroethyl)-oxazolidine-2-one and 80 ml of dimethylformamide was heated under stirring at 120° C. for five hours. Upon completion of the reaction, the mixture was cooled, filtered, and the solvent eliminated in vacuo. To the residue, 80 ml of ether were added and the solid thus obtained was collected on filter and purified by chromatography on a silica gel column using ethyl acetate as eluent. The desired product was crystallized from isopropanol to give 11.2 g of N-(7-chloro-4-quinolyl)-anthranilic acid β-(2-oxo-3-oxazolidinyl)-ethyl ester, melting at 122°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH2:24][C:23]1=[O:32].N1C2C(=CC=CC=2)NCC1=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]([CH3:21])[C:23](=[O:32])[CH2:24]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: CN1C(=O)CNc2ccccc21
Agent: O=C([O-])O
Agent: O=C1CNc2ccccc2N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(=O)N(C)c2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (98.8 mg) and 1-methyl-3,4-dihydro-1H-quinoxalin-2-one (prepared as the minor regioisomer following a similar procedure described for 3,4-dihydro-1H-quinoxalin-2-one; R. E. TenBrink et al., J. Med. Chem., 1994, 37, pp. 758-768) (165 mg) in dimethylformamide (0.75 mL) was heated at 140° C. for 60 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted twice with diethyl ether. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 20% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (16.2 mg), m.p. 132° C.-134° C.
Reaction SMILES: N1C=CC=CC=1C[C:8]1(CC2C=CC=CN=2)[N:12]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)[C:11](=S)[NH:10][C:9]1=[O:24].C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:13]12([N:12]3[CH2:8][C:9](=[O:24])[N:10]=[CH:11]3)[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:22]1)[CH2:14]2
Reactant: O=C1NC(=S)N(C23CC4CC(CC(C4)C2)C3)C1(Cc1ccccn1)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: O=C1CN(C23CC4CC(CC(C4)C2)C3)C=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under a N2 atmosphere in 50 ml of acetone were combined 0.432 g (1 mmol) of bispyridylmethyl N-1-adamantyl thiohydantoin, 0.138 g (1 mmol) of potassium carbonate and 0.142 g (1 mmol) of methyl iodide and the reaction mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and partitioned in 100 ml EtOAc/10 ml H2O. The organic layer was separated, washed with H2 O(4×10 ml), brine (1x), dried over NaSO4 and concentrated in vacuo. The crude product was purified via column chromatography (silica gel: 92.5/7.25 EtOAc/MeOH) and crystallized from isopropyl ether/hexane (IPE/Hex) to yield N-1-adamantylimidazolinone
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Cl.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CN(C)CCCCl
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: CN(C)CCCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[3-(dimethylamino)propyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 238) and 3-(dimethylamino)propyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cn1
Yield: 35 %

Procedure:
A mixture of 25 g of 2-methyl-5-pyridinol, 32 g of 4-chlorobenzaldehyde, 75 g of potassium carbonate and 200 ml of dimethylformamide was heated under refluxing for 6 hours with stirring. After cooling, the mixture was filtered and the filtrate was concentrated. The resulting oily substance was dissolved in diethyl ether, and the solution was washed successively with an aqueous solution of sodium hydroxide and water, and dried over magnesium sulfate. The solvent was then distilled off and the resulting oily substance was dissolved in isopropyl alcohol. To the solution was added concentrated hydrochloric acid, and the resulting hydrochloride was filtered and recrystallized from a mixture of methanol and ethyl acetate to obtain colorless needles. The crystals were added to an aqueous solution of sodium carbonate and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off to obtain an oily substance which crystallized upon standing. The crystals were recrystallized from hexane to obtain 17 g (35% yield) of 4-(2-methyl-5-pyridyloxy)benzaldehyde as colorless prisms having a melting point of 45°-46° C. and a boiling point of 133° C./2 mmHg (bath temperature).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[CH3:1][CH:2]1[NH:7][CH:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: Cc1cccc(CNC(=O)OC(C)(C)C)n1
Solvent: CO
Product: CC1CCCC(CNC(=O)OC(C)(C)C)N1

Procedure:
Nishimura catalyst (0.53 g) was added to a solution of tert-butyl (6-methylpyridin-2-yl)methylcarbamate (4.4 g, 0.02 mmol) in MeOH (60 mL) in a Parr Shaker high pressure vessel which was installed on Parr Shaker. The vessel was shaken under constant 5 bar hydrogen pressure for 30 min. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo to give desired product rac-tert-butyl (6-methylpiperidin-2-yl)methylcarbamate which was used for next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 3.20-3.17 (m, 1H), 3.01-2.96 (m, 1H), 2.72-2.64 (m, 2H), 1.82-1.77 (m, 1H), 1.63-1.54 (m, 2H), 1.49 (s, 9H), 1.39-1.35 (m, 2H), 1.12-0.99 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:26])[C:24]=1Cl>>[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:26])[C:24]=1[N:15]1[CH2:16][CH2:17][CH:12]([S:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)(=[O:11])=[O:10])[CH2:13][CH2:14]1
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 29.4 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was reacted with 3,4,5-trichloropyridine (224 mg, 1.22 mmol) to afford the title compound (66 mg), a white solid, in 55% yield.
Reaction SMILES: [N:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3].O.[BH4-].[Na+]>C1COCC1>[N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
Racemic 3-azido-4-oxochroman-7-carbonitrile Int-2-B (2.30 g, 10.8 mmol) was dissolved in THF (103 mL) and water (5.42 mL) at 0° C. To this solution was added sodium borohydride (0.53 g, 14.1 mmol). The reaction mixture was stirred at 0° C. for 45 mins. Next, the reaction was quenched by addition of 1N HCl. The resulting solution was extracted with EtOAc and washed with water and brine. The organic layers were combined, dried (MgSO4) and concentrated to give racemic (3R*,4S*)-3-azido-4-hydroxychroman-7-carbonitrile Int-2-C (2.21 g, 10.2 mmol, 94.3% yield): LCMS=217.06 [M+H]+.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Br:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[CH:10]=[CH:9][C:8]([F:30])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)ccc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Br)c32)ccc1F
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 55 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 10 minutes. After adding 0.3 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 68 mg of the title compound as-a colorless powder.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[N:21]=3)=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].C(Cl)[Cl:36].Cl.O1CCOCC1>>[ClH:36].[CH3:34][N:32]1[CH:33]=[C:29]([C:22]2[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]4)[N:16]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)[CH:30]=[N:31]1
Reactant: ClCCl
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)n3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)n3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
Tert-butyl 3-(cyanomethyl)-3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Example 129; 28.3 mg, 0.0616 mmol) was dissolved in DCM (308 μL, 0.0616 mmol) and treated with 4N HCl in dioxane (308 μL, 1.23 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuo to afford 2-(3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (14.3 mg, 53.7% yield) as a white solid. MS (apci) m/z=360.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([C:11]3[O:10][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:13][C:12]=3[C:14]([NH2:16])=[O:15])=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.029 g, 0.075 mmol) in DCM (3 mL) was added triethylamine (12 uL, 0.086 mmol) followed by acetyl chloride (6 uL, 0.084 mmol). The resulting solution was stirred at room temperature for 2 hours when further portion of triethylamine (12 uL, 0.086 mmol) and acetyl chloride (6 uL, 0.084 mmol) were added and the reaction stirred at room temperature for 1 hour. The solvent was then removed in vacuo. The residue was purified by preparative HPLC to afford 5-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.025 g, 0.059 mmol, 78%) as a white solid. 1H NMR (DMSO) 2.06 (3H, s), 3.28 (2H, m), 3.56 (2H, m, masked by water), 3.59 (4H, m), 7.08 (2H, d), 7.38 (2H, t), 7.63 (1H, br. s), 7.64 (1H, br. s), 7.72 (1H, m), 8.18 (2H, d). LCMS (2) Rt: 2.52 min; m/z (ES+) 427.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 79 %

Procedure:
The title compound is prepared in 79% yield (1.70 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (1.47 g, 6.32 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([O:13][C@@H:22]2[CH:23]3[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]3)[CH2:21]2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)C(Nc1ccc(F)cc1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.1 %

Procedure:
2-(4-Fluorophenylamino)-2-phenylacetic acid hydrochloride (I7) (2.00 g, 8.15 mmol), (R)-quinuclidin-3-ol (1.14 g, 8.97 mmol), HOBt (1.10 g, 8.15 mmol) and DCC (0.841 g, 4.08 mmol) were dissolved in THF (25 ml), and the mixture was stirred at room temperature for three days. Then a second portion of HOBt (0.55 g, 4.08 mmol), DCC (0.84 g, 4.08 mmol) and (R)-quinuclidin-3-ol (0.52 g, 4.08 mmol) were added and the mixture was stirred at room temperature overnight. THF was removed under vacuum, and the residue was treated with H2O and extracted twice with EtOAc. The organic phase was washed with saturated Na2CO3 and dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The crude was purified by flash chromatography (EtOAc/MeOH=9/1 to 75/25) to obtain (R)-quinuclidin-3-yl 2-(4-fluorophenylamino)-2-phenylacetate (1.1 g, 38.1% yield, mixture of diasteromers).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]4[N:23]([C:24](=[O:34])[C:25]5[C:30]([F:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=5[F:33])[N:22]=[C:21]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=5)[S:20]4)[C:13]=3[N:14]=2)[CH:5]=1.[Li+].[OH-].Cl>C1COCC1.CO>[F:42][C:37]1[CH:36]=[C:35]([C:21]2[S:20][CH:19]([C:15]3[C:13]4[N:14]=[C:10]([C:6]5[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=5)[C:3]([OH:43])=[O:2])[O:11][C:12]=4[CH:18]=[CH:17][CH:16]=3)[N:23]([C:24](=[O:34])[C:25]3[C:26]([F:33])=[CH:27][C:28]([F:32])=[CH:29][C:30]=3[F:31])[N:22]=2)[CH:40]=[CH:39][C:38]=1[F:41]
Reactant: COC(=O)c1cccc(-c2nc3c(C4SC(c5ccc(F)c(F)c5)=NN4C(=O)c4c(F)cc(F)cc4F)cccc3o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nc3c(C4SC(c5ccc(F)c(F)c5)=NN4C(=O)c4c(F)cc(F)cc4F)cccc3o2)c1

Procedure:
3-{4-[5-(3,4-Difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoic acid methyl ester (0.02 mmol) is dissolved in THF/MeOH (1 mL/0.5 mL) and treated with aqueous LiOH (1 M) (0.5 mL) at room temperature for 30 minutes. Aqueous HCl (3 M) is added to adjust the pH to 5-6. The solvent is removed and the residue is purified by preparative HPLC (20-100% MeCN/H2O) to yield 3-{4-[5-(3,4-difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoic acid: 1H NMR (400 MHz, CDCl3) 8.95 (s, 1H), 8.48 (d, J=7.9 Hz, 1H), 8.27 (d, J=7.8 Hz, 1H), 7.92 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.6 (dd, J1=7.7 Hz, J2=1.2 Hz, 1H), 7.46 (m, 1H), 7.29-7.42 (m, 3H), 7.19 (q, J=8.2 Hz, 1H), 6.76-6.81 (m, 2H); LC/MS (ES+): (M+1) 596.0, (M+Na) 618.0.
Reaction SMILES: C([Li])CCC.O1CCCC1.[F:11][C:12]1[CH:13]=[C:14]([C:19]2([CH2:24][CH3:25])[O:23][CH2:22][CH2:21][O:20]2)[CH:15]=[C:16]([F:18])[CH:17]=1.[Br:26]C(Cl)(Cl)C(Br)(Cl)Cl>O>[Br:26][C:17]1[C:12]([F:11])=[CH:13][C:14]([C:19]2([CH2:24][CH3:25])[O:20][CH2:21][CH2:22][O:23]2)=[CH:15][C:16]=1[F:18]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CCC1(c2cc(F)cc(F)c2)OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC1(c2cc(F)c(Br)c(F)c2)OCCO1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
Under a nitrogen atmosphere at −78° C., n-butyllithium (1.56 M hexane solution, 4.84 ml) was added to a tetrahydrofuran (20 ml) solution of 2-(3,5-difluorophenyl)-2-ethyl-1,3-dioxolane (1.01 g). The reaction liquid was stirred at −78° C. for 15 minutes, then a tetrahydrofuran (10 ml) solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (3.07 g) was added. After stirred at room temperature for 45 minutes, water was added to it, and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated off, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain the entitled compound (1.20 g) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[N:20]4[CH:26]=[C:25]([O:27][CH2:28][C:29](OCC)=[O:30])[CH:24]=[CH:23][C:21]4=[N:22][C:18]=3[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:34])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:35][NH2:36]>C(O)C>[CH3:35][NH:36][C:29](=[O:30])[CH2:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[N:20]([CH:26]=1)[C:19]1[N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:11](=[O:34])[C:12]3[C:17]([C:18]=1[N:22]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CN
Reactant: CCOC(=O)COc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Solvent: CCO
Product: CNC(=O)COc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 70 °C
Yield: 58 %

Procedure:
A mixture of compound 13 (1.0 equiv., 0.22 mmol, 0.100 g) and methylamine (40% in water, 6 ml) in ethanol (8 ml) was heated at 70° C. for 4 h. After cooling, the reaction product was filtered off and washed with isopropanol and isopropylether successively to give N-methyl-2-[[5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]imidazo-[4,5-c]isoquinolin-9-yl]oxy]-acetamide (15) (0.057 g, yield=58%, purity (LC)=98%) as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[N:26]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([C:16]#[N:26])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 3.2 g of 6-chloro-1'-methyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], Example 30, 2.0 g of cyanogen bromide and 6.0 g of potassium carbonate in 100 ml of chloroform is stirred at ambient temperature for 6 hours. Thereafter, the mixture is sequentially quenched with water, extracted with dilute sodium hydroxide and dried. The chloroform is removed under reduced pressure and the residue is passed through a silica gel column, ether eluant, providing an orange oil which crystallizes upon standing. The solid is recrystallized from an acetone-hexane mixture to provide orange prisms, mp 163°-165° C. of 6-chloro-1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine].