Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([F:11])([F:10])[C:3](=O)/[CH:4]=[CH:5]/OCC.C[N:13](C)[CH:14]=[CH:15][C:16]#[N:17].C([O-])(=O)C.[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:15]([C:16]#[N:17])=[CH:14][N:13]=1
Reactant: CCO/C=C/C(=O)C(F)(F)Cl
Reactant: CN(C)C=CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(F)(F)Cl)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
(3E)-1-Chloro-4-ethoxy-1,1-difluorobut-3-en-2-one (7.36 g, 40 mmol) was dissolved in dry toluene (40 mL) and treated with 3-dimethylaminoacrylonitrile (4.61 g, 48 mmol) at room temperature. The solution was heated at about 100° C. for 3.5 hr. The solvent was then removed under reduced pressure and the remaining mixture was re-dissolved in DMF (20 mL), treated with ammonium acetate (4.62 g, 60 mmol) and stirred at room temperature overnight. Water was added to the reaction mixture and and the resulting mixture was extracted with ether-CH2CH2 (1:2, v/v) twice. The combined organic layer was washed with brine, dried, filtered and concentrated. The residue was purified on silica gel to give 3.1 g of 6-[chloro(difluoro)methyl]nicotinonitrile (A) as light colored oil in 41% yield. GC-MS: mass calcd for C7H3ClF2N2 [M]+188. Found 188.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH:2]1[CH2:10][NH:11][C:12]([C:14]1[C:15]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([Cl:36])[CH:29]=2)=[N:16][C:17]([N:20]2[CH2:25][CH:24]3[CH:22]([CH2:23]3)[CH2:21]2)=[N:18][CH:19]=1)=[O:13].[CH2:37]=O.[BH4-].[Na+]>CO>[CH:22]12[CH2:23][CH:24]1[CH2:25][N:20]([C:17]1[N:16]=[C:15]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([Cl:36])[CH:29]=3)[C:14]([C:12]([NH:11][CH2:10][CH:2]3[CH2:3][C:4]4([CH2:5][CH2:6][N:7]([CH3:37])[CH2:8][CH2:9]4)[CH2:1]3)=[O:13])=[CH:19][N:18]=1)[CH2:21]2
Reactant: C=O
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CC3(CCNCC3)C2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CC3(CCN(C)CC3)C2)cc1Cl
Reaction time: 10 h
Yield: 27.2 %

Procedure:
In methanol (50 mL) was dissolved the above N-(7-azaspiro[3.5]nonan-2-ylmethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-formamide (357 mg, 0.7 mmol). Formalin (284 mg, 3.5 mmol) was added. Sodium borohydride (133 mg, 3.5 mmol) was added slowly. The reaction was continued for 10 h then quenched with water. The reaction mixture was extracted with ethyl acetate. The organic phase was dried and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methyl)pyrimidine-5-form amide (100 mg, 27.4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2].Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2]
Reactant: ClCc1ccc(CCc2ccccc2)cc1
Reactant: CCOC(=O)CCCCN(CCc1ccccc1O)C1CCCc2nc(C(=O)OCC)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccccc2)cc1)C1CCCc2nc(C(=O)OCC)ccc21
Reaction time: 6 h

Procedure:
Under argon, 500 mg (1.07 mmol) of ethyl 5-{(5-ethoxy-5-oxopentyl)[2-(2-hydroxyphenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate, 246 mg (1.07 mmol) of 1-(chloromethyl)-4-(2-phenylethyl)benzene and 295 mg (2.13 mmol) of potassium carbonate in 5 ml of DMF were heated to 80° C. and stirred at this temperature for 6 hours. After cooling, water and ethyl acetate were added to the reaction mixture and the phases were then separated. The organic phase was washed twice with water and once with saturated sodium chloride solution and then concentrated to dryness. This gave 760 mg (1.01 mmol, content 88%, 94% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[CH3:17][O:18][C:19](=[O:30])[N:20]([CH2:28]Cl)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>C1C=CC=CC=1>[CH3:17][O:18][C:19](=[O:30])[N:20]([CH2:28][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1
Reactant: COC(=O)N(CCl)c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)N(COc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1

Procedure:
A solution of 16.3 g (0.1 mole) of 2,4-dichlorophenol and 14 ml (0.1 mole) of triethylamine in 100 ml of benzene was added dropwise, over the course of 15 minutes, to a solution of 23.4 g (0.1 mole) of Methyl-N-chloromethyl-N-(4-chlorophenyl)-carbamate in 200 ml of dry benzene. Thereafter the triethylamine hydrochloride was filtered off, the filtrate was washed with 5% strength sodium hydroxide solution and water, and after drying over calcined sodium sulphate the benzene was distilled off under reduced pressure. 52.4 g (92% of theory) of Methyl-N-(2,4-dichlorophenoxymethyl)-N-(4-chlorophenyl)-carbamate, melting at 79°-80° C. after recrystallization from ethanol, were obtained.
Reaction SMILES: [C:1]1(=O)[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[CH2:15]([N:27]=[C:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1CCCCCCN1
Reactant: CCCCCCCCCCCCN
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCN=C1CCCCCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 28.3 g (0.223 mole) of an enantholactam in 250 ml of benzene is added 34.1 g (0.223 mole) of phosphorous oxychloride over 30 minutes. The mixture is stirred at room temperature for 4 hours after which 41.2 g (0.223 mole) of dodecylamine is added. The reaction mixture is stirred at room temperature for 1 hour and refluxed for 4 hours then allowed to stand overnight. The resulting precipitate is washed with benzene, and the benzene wash is extracted with aqueous 2 N hydrochloric acid and combined with the precipitate. The combined fractions are made alkaline with 2N sodium hydroxide, extracted into ether-methylene chloride, dried and recrystallized from isopropyl alcohol to give 2-dodecyliminooctahydroazocine.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[C:18](C)=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22]C(=O)C1C=CC(O)=CC=1OC>>[C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[C:17]([O:22][CH3:21])[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: Cc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Product: COc1cc(CCC(=O)OC(C)(C)C)ccc1C(=O)O

Procedure:
The title compound is prepared in analogy to 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid starting from 4-hydroxy-2-methoxy-benzoic acid methyl ester; LC-MS: tR=0.94 min, [M+1]+=281.23; 1H NMR (CDCl3): δ 1.34 (s, 9 H), 2.40-2.47 (m, 2 H), 2.76-2.85 (m, 2 H), 3.83 (s, 3 H), 7.21-7.28 (dd, J=7.6, 3.2 Hz, 1 H), 7.41-7.49 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([CH2:32][NH2:33])[OH:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:33][CH2:32][CH2:30][OH:31])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: Cc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1ccc(-c2cc3cc(CNCCO)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 80.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (54.0 mg, 0.138 mmol) was dissolved in acetonitrile (4.3 mL), and the solution was treated with ethanolamine (0.034 mL, 0.55 mmol), acetic acid (0.158 mL, 2.76 mmol) and sodium triacetoxyborohydride (58.0 mg, 0.276 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-methyl-7-{1-(tert-butoxycarbonyl)-5-[(2-hydroxyethylamino)methyl]indol-2-yl}isoindolinone (48.5 mg, yield 81%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[C:8]([CH:35]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[C:15]([C:17]2[S:18][CH:19]=[C:20]([Cl:22])[CH:21]=2)[N:16]=1)=[O:10].C(Cl)(Cl)Cl.[CH2:41]([OH:44])[CH2:42][OH:43]>>[ClH:3].[Cl:3][C:4]1[C:5]([O:43][CH2:42][CH2:41][OH:44])=[N:6][CH:7]=[C:8]([CH:35]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[C:15]([C:17]2[S:18][CH:19]=[C:20]([Cl:22])[CH:21]=2)[N:16]=1)=[O:10]
Reactant: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(Cl)c(Cl)c1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(OCCO)c(Cl)c1
Reaction time: 96 h

Procedure:
To a solution of 48 mg of 40% sodium hydride in 1 ml of ethyleneglycol, 100 mg of the compound of Example 5 was added at room temperature, the temperature was elevated to 50° C., and the mixture was stirred for 4 days. To the reaction solution, chloroform was added, and the organic layer was washed with saturated aqueous NaHCO3 and brine and dried over sodium sulfate. After the evaporation of the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform-MeOH=200:1˜20:1) and the obtained compound was dissolved in 5 ml of EtOAc, 0.8 ml of 0.1M HCl.EtOAc solution was added thereto, and the mixture was stirred for a while. Then, the solvent was evaporated under reduced pressure, and the residue was washed with diethylether to obtain 34 mg of 5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-(2-hydroxyethoxy)nicotinamide hydrochloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]([OH:31])([CH3:30])[CH3:29])[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>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>[NH2:25][C:22]1[O:23][CH2:24][C@:20]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]([CH3:30])([OH:31])[CH3:29])[CH:18]=3)[O:13][C:10]3[C:9]2=[CH:8][C:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:12][CH:11]=3)[N:21]=1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Reactant: OB(O)c1ccccc1
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: [K+]
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3ccccc3)ccc1O2

Procedure:
A 0.5-2 mL vial was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (72.4 mg, 0.150 mmol), phenylboronic acid (54.8 mg, 0.449 mmol), potassium carbonate (103 mg, 0.748 mmol), and tetrakis(triphenylphosphine)palladium (8.64 mg, 7.48 μmol). The vial was purged with Ar(g), then Dioxane (748 μL) and water (0.37 mL) were added in sequence. The vial was sealed and placed in a 90° C. oil bath for 1 hour. The mixture was diluted with water (15 mL), and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 40-g Redi-Sep column eluting with 0-6% MeOH/DCM to give (S)-4-(2′-amino-7-phenyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol as a slightly tan solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH3:22]>>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH2:13][C:12](=[O:15])[NH2:11])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[NH2:22]
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Reactant: N
Product: NC(=O)CCC(CCC(=O)O)(C(N)=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.30 g of racemic 3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid are placed in 20 ml of an aqueous solution of aqueous ammonia at 30% and stirred at room temperature. After 2 hours, the solution is degassed under vacuum to remove the excess aqueous ammonia and then diluted to 50 ml with water. The medium is slowly acidified to pH 2-3 with 1 N HCl. The precipitate formed is filtered, drained and then dried over KOH to give 3.13 g of the expected compound.
Reaction SMILES: [CH2:1]([N:3]1[C@H:8]([CH3:9])[CH2:7][N:6]([C:10]([N:12]2[CH2:19][C:18]3[C:17]([NH2:20])=[N:16][NH:15][C:14]=3[C:13]2([CH3:22])[CH3:21])=[O:11])[C@@H:5]([CH3:23])[CH2:4]1)[CH3:2].Cl[C:25]1[C:30]([F:31])=[CH:29][N:28]=[C:27]([O:32][CH3:33])[N:26]=1>C(O)(=O)C.O>[CH2:1]([N:3]1[C@H:8]([CH3:9])[CH2:7][N:6]([C:10]([N:12]2[CH2:19][C:18]3[C:17]([NH:20][C:25]4[C:30]([F:31])=[CH:29][N:28]=[C:27]([O:32][CH3:33])[N:26]=4)=[N:16][NH:15][C:14]=3[C:13]2([CH3:22])[CH3:21])=[O:11])[C@@H:5]([CH3:23])[CH2:4]1)[CH3:2]
Reactant: CCN1C[C@H](C)N(C(=O)N2Cc3c(N)n[nH]c3C2(C)C)C[C@H]1C
Reactant: COc1ncc(F)c(Cl)n1
Solvent: CC(=O)O
Solvent: O
Product: CCN1C[C@H](C)N(C(=O)N2Cc3c(Nc4nc(OC)ncc4F)n[nH]c3C2(C)C)C[C@H]1C

Procedure:
A solution of 5-{[(2S,5R)-4-ethyl-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine (289 mg, 0.9 mmol) and 4-chloro-5-fluoro-2-methoxypyrimidine (257 mg, 2 eq) in 5 mL of 50% acetic acid in water was heated in a microwave for 30 min at 80° C. Purification as described in Example A1 afforded the title compound AA1 as a white powder (13.1 mg, 3%). See Table 1 below for NMR data.
Reaction SMILES: C([NH:8][C:9]([CH3:15])([CH2:12][CH2:13][OH:14])[CH2:10][OH:11])C1C=CC=CC=1.[ClH:16]>CCO.[Pd]>[ClH:16].[NH2:8][C:9]([CH3:15])([CH2:12][CH2:13][OH:14])[CH2:10][OH:11]
Reactant: CC(CO)(CCO)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(N)(CO)CCO
Reaction time: 37 h
Yield: 90.2 %

Procedure:
2-Benzylamino-2-methyl-1,4-butanediol (10E, 31.08 g, 0.149 mol) was dissolved in 95% EtOH (240 mL) containing conc. HCl (21 mL, 0.25 mol) and 5% Pd/C (10.0 g) and reduced in a Parr apparatus at 40 psi over 37 h at RT. The catalyst was then removed by filtration and the solvent removed by rotary evaporation (bath at 60°) to give 20.91 g of 2-amino-2-methyl-1,4-butanediol hydrochloride (90.2%) as a clear, thick, colorless oil with acceptable NMR and mass spectra. It was used without further purification. This compound has been reported as its acetate salt (G. Cardillo et al., Chem. Commun. 1308, 1982), but no data was given. Attempts to duplicate the latter procedure were unsuccessful.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[NH3:33].O>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:33])=[N:13]2)[CH:7]=1
Reactant: N
Reactant: O=C1COC[C@](c2cc(Br)ccc2F)(C(F)F)N1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)COC1

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholin-3-one (10 g, 30.86 mmol) in CH2Cl2 (100 mL) was added P2S5 (6.86 g, 30.86 mmol) at room temperature. The resulted yellow suspension was heated to reflux for 6.5 h. The reaction mixture was filtered through a pad of silica gel (200˜300 mesh), washed with CH2Cl2 for 3 times to get a brown solution. The solvent was removed to provide the crude product as a yellow solid, which was dispersed in THF (10 mL), then 25% NH3 water solution (60 mL) was added at room temperature. 20 hours later, the reaction mixture was extracted with IPAC. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to provide the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)C(O)=COC=1CO.COC1C(OC(C(O)C2C=CC(O)=C(OC)C=2)CO)=CC=CC=1.[NH3:51]>C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[NH:51][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Agent: COc1cc(C(O)C(CO)Oc2ccccc2OC)ccc1O
Agent: O=c1cc(CO)occ1O
Solvent: CCO
Product: O=c1cc(CO)[nH]cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojic acid by the method of D. Erol, J. Med. Chem, 1994, 29, 893) (9.7 g, 40 mmol), concentrated aqueous (880) ammonia (100 mL), and ethanol (20 mL) was heated to reflux overnight. The mixture was allowed to cool to room temperature then filtered. The resultant solid was washed with ether and dried in vacuo (5.9 g); MS (APCI+) m/z 232 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([S:17]([CH2:20][CH:21]([CH:25]([CH3:27])[CH3:26])C(O)=O)(=[O:19])=[O:18])[CH2:11][CH2:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=[O:30].C[N:35](C)[CH:36]=[O:37]>ClCCl>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([S:17]([CH2:20][CH:21]([CH:25]([CH3:27])[CH3:26])[C:36]([NH:35][OH:30])=[O:37])(=[O:19])=[O:18])[CH2:11][CH2:10]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C(CS(=O)(=O)N1CCc2cc(C3CCCCC3)ccc2C1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCc2cc(C3CCCCC3)ccc2C1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
2-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyric acid (143 mg) was dissolved in dichloromethane (15 ml) under a nitrogen atmosphere and oxalyl chloride (0.15 ml) added, followed by a solution of 10% N,N-dimethylformamide in dichloromethane (7 drops). The reaction was stirred at room temperature for 2 h then evaporated under reduced pressure and azeotroped with 1:1 dichloromethane-hexane (2×10 ml). The residue was dried under vacuum then suspended in tetrahydrofuran (15 ml) and treated with 50% wt solution of aqueous hydroxylamine (0.7 ml). The mixture was left to stir at room temperature for 1 h then evaporated under reduced pressure. The residue was triturated with water (20 ml) and the resulting solid filtered off, washed with water (10 ml) and dried under vacuum at 40° C. to give the title compound (120 mg, 82%).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C([O:12][C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:24][N:23]([C:25]3[C:26]([F:33])=[C:27]([CH2:31][OH:32])[CH:28]=[CH:29][CH:30]=3)[CH2:22]2)=[CH:15][CH:14]=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.ClCCl>[F:33][C:26]1[C:27]([CH2:31][OH:32])=[CH:28][CH:29]=[CH:30][C:25]=1[N:23]1[CH2:22][CH:21]([CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13](=[O:12])[N:18]([CH3:1])[CH:17]=2)[CH2:24]1
Reactant: CC(C)(C)Oc1ccc(OCC2CN(c3cccc(CO)c3F)C2)cn1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(OCC2CN(c3cccc(CO)c3F)C2)ccc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TFA (0.5 ml) was added to a mixture of [3-(3-{[(6-tert-butoxypyridin-3-yl)oxy]methyl}azetidin-1-yl)-2-fluorophenyl]methanol (146 mg) and dichloromethane (1 ml), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (CHCl3/methanol). The purified product thus obtained was mixed with DMF (2 ml), and potassium carbonate (100 mg) and methyl iodide (68 mg) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were added to the residue. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/methanol) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}methoxy)-1-methylpyridin-2(1H)-one (82 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([C:33]3[CH2:34][CH2:35][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)nc2c(c1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CCOC(=O)c1c(C(C)C)nc2c(c1C1=CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-ethyl 5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: C(O[C:9]1[C:14](C=O)=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1C=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.C[Mg][Br:25].[Cl-].[NH4+:27]>O1CCCC1>[Br:25][C:14]1[CH:9]=[C:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:27]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: C[Mg]Br
Reactant: [NH4+]
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Brc1cccc(-c2ccccn2)c1
Reaction time: 0.67 h
Yield: 98 %

Procedure:
A solution of 2-(benzyloxy)biphenyl-3-carbaldehyde (5.55 g, 20 mmol) in anhydrous tetrahydrofuran (100 mL) was stirred under nitrogen on an water bath at room temperature and 3M methyl magnesium bromide in tetrahydrofuran (10 mL, 30 mmol, 1.5 equiv.) was added. Stirring was continued at room temperature for 40 min. The reaction mixture was poured onto saturated ammonium chloride (200 mL) and extracted with ethyl acetate (2×200 mL). The organic extract was washed with water (100 mL), dried over sodium sulfate and stripped to afford pure 1 (6 g, 98%).