Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:6][CH:4]([CH2:5]1)[CH2:3][N:2]2[C:7]1[N:12]=[C:11]([C:13]2[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:16]([NH2:19])=[N:17][CH:18]=2)[CH:10]=[C:9]([N:24]2[CH2:29][C@@H:28]3[CH2:30][C@H:25]2[CH2:26][NH:27]3)[N:8]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(C(C)C)C(C)C)C>CS(C)=O>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([C:11]2[N:12]=[C:7]([N:2]3[CH2:3][CH:4]4[CH2:5][CH:1]3[CH2:6]4)[N:8]=[C:9]([N:24]3[CH2:29][C@@H:28]4[CH2:30][C@H:25]3[CH2:26][N:27]4[C:31](=[O:33])[CH3:32])[CH:10]=2)=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CN4)nc(N3CC4CC3C4)n2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(N2CC3CC2C3)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 45.8 %

Procedure:
To a solution of 5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-3-(trifluoromethyl)pyridin-2-amine (80 mg, 0.22 mmol) in DMSO (2 mL) was added acetic anhydride (46 mg, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.1 mL). The mixture was stirred at room temperature for 25 min. The mixture was concentrated in vacuum and the residue was purified by Prep-HPLC (BASE) to provide 1-((1S,4S)-5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethanone (46.34 mg, 40.0% yield). LCMS (ESI): [MH]+=459.9; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.36 (s, 1H), 6.79 (s, 2H), 6.53-6.21 (m, 1H), 5.10-4.89 (m, 1H), 4.80-4.78 (m, 1H), 4.74-4.63 (m, 1H), 3.55-3.51 (m, 1H), 3.44-3.35 (m, 2H), 3.23-2.84 (m, 4H), 2.82 (s, 1H), 2.00 (s, 1H), 1.91 (s, 3H), 1.83-1.81 (m, 2H), 1.29 (d, J=2.0 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1)[CH2:6][CH2:5]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)N1CCc2cc(O)ccc2C1
Reaction time: 8 h

Procedure:
1.2 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline are suspended in 50 ml of methylene chloride, 1.2 ml of triethylamine are added, and a solution of 1.4 g of 4-chlorobenzoyl chloride in 10 ml of methylene chloride is added dropwise with stirring and cooling. After standing overnight, the mixture is extracted by shaking with 2N hydrochloric acid and water, and the organic phase is dried and evaporated in a rotary evaporator. A colorless oil remains, and this crystallizes on trituration with ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14]1[NH:15][S:16](=[O:21])(=[O:20])[CH2:17][CH2:18][N:19]=1>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]1[NH:15][S:16](=[O:21])(=[O:20])[CH2:17][CH2:18][N:19]=1
Reactant: CSC1=NCCS(=O)(=O)N1
Reactant: Cc1nc[nH]c1CSCCN
Product: Cc1nc[nH]c1CSCCNC1=NCCS(=O)(=O)N1
Yield: 31.1 %

Procedure:
A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (4.0 g.) and 3-methylthio-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (4.2 g.) was heated in an oil bath at 140° for 4 hours. The product was chromatographed on a column of silica gel with ethyl acetate-ethanol (3:2) as eluant and finally recrystallised from ethanol-ether to give 3-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (2.2 g.) m.p. 146°-147°.
Reaction SMILES: CN(OC)[C:3](=[O:13])[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:16]([Mg]Cl)([CH3:18])[CH3:17].Cl>O1CCCC1.C(OCC)C>[C:9]([O:8][C:6]([NH:5][CH2:4][C:3](=[O:13])[CH:16]([CH3:18])[CH3:17])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)[Mg]Cl
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
A solution of 10.9 g of N-tert.-butoxycarbonylglycine N-methyl-N-methoxyamide in 300 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous diethyl ether was cooled at 0-5° C. while 100 ml of a 2M solution of isopropyl magnesium chloride in tetrahydrofuran was added slowly. The mixture was stirred at 0-5° C. for 4 h then poured into 1.5 liter of 1M hydrochloric acid. The product was extracted with three portions of 500 ml diethyl ether. Combined extracts were washed with 500 ml brine then dried over anhydrous magnesium sulphate, filtered and evaporated to give 8.38 g of 4-tert.-butoxycarbonylamino-2-methyl-3-butanone as a colourless oil which was used without further purification.
Reaction SMILES: [CH2:1]([S:13](Cl)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:17][C:18]1[C:35]([Cl:36])=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([NH2:31])[CH:30]=3)=[N:24][C:20]=2[CH:19]=1.O.Cl>N1C=CC=CC=1>[Cl:36][C:35]1[C:18]([Cl:17])=[CH:19][C:20]2[NH:24][C:23]([C:25]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([NH:31][S:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH:30]=3)=[N:22][C:21]=2[CH:34]=1
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCS(=O)(=O)Nc1cc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)ccc1OC
Temperature: 80 °C
Yield: 4 %

Procedure:
1-Dodecanesulfonyl chloride (0.38 g, 1.4 mmol) was added to a stirred suspension of 5-(5,6-dichloro-1H-benzoimidazol-2-yl)-2-methoxy-phenylamine from Step B (0.6 g, 1.4 mmol) in pyridine (6 mL) under an inert atmosphere, warmed briefly to 80° C. then stirred at room temperature. After approximately 20 hours the mixture was poured into water (60 mL), stirred, and acidified with aqueous HCl. After several hours the mixture was extracted with dichloromethane (60 mL, 30 mL) and the combined extracts were washed with water then 0.5 M sodium bicarbonate solution. A little saturated brine was added to assist with stratification. The organic phase was washed with saturated brine, dried over MgSO4, and stripped of solvent to leave the crude product as a crystalline residue. Recrystallization from acetonitrile followed by chromatography on silicagel in CHCl3/EtOAc (9:1) afforded the product (0.03 g), mp 203-204° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccccn2)CC1
Reaction time: 6 h
Yield: 36.1 %

Procedure:
A mixture of pyridine-2-carboxylic acid (2.7 g) and 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (5.0 g) in dry xylene (50 ml) was heated under reflux under a Dean and Stark water separator for six hours. The cooled solution was diluted with ethyl acetate (150 ml), washed with aqueous oxalic acid solution (2M; 2×100 ml) then aqueous sodium hydrogen carbonate soultion (5M; 2×100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-2-carboxamide (2.53 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:25])[CH2:14][N:15]3[C:19]([CH3:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]3)[CH2:9][CH2:8]2)[S:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(N(C)C)=O>[CH3:20][C:19]1[N:15]([CH2:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:4]3[S:5][CH:6]=[C:2]([NH:1][S:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:43])=[O:42])[N:3]=3)[CH2:8][CH2:9]2)=[O:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(NS(=O)(=O)c3ccccc3)cs2)CC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (100 mg, 0.04 mmol) in dimethylacetamide (0.8 mL) is added diisopropylethylamine (8.6 μL, 0.28 mmol), followed by benzenesulfonyl chloride (8.8 mg, 0.05 mmol) at RT. After stirring 15 min at 60° C., the reaction mixture is purified directly by preparative HPLC to give N-(2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-benzenesulfonamide (Compound No. I.g.025). MS: m/z=514 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([Mg]Br)=[CH2:22]>C1COCC1>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:20])[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1nc2ccccn2c(=O)c1Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
A mixture of 2.5 g (9.5 mmol) of the product from Step 6 (16) in 35 mL THF was cooled to −78° C. To the resulting solution was added dropwise 11.4 mL (11.4 mmol) of vinyl magnesium bromide and stirred at −78° C. for 3 hours. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (4×). The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo yielding 2.95 g of 3-benzyl-2-(1-hydroxyprop-2-enyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (23) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][S:5][C:6]=1[C:7]([OH:9])=[O:8].[C:11](Cl)(=O)[CH2:12][CH2:13][CH3:14].Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:10][C:3]1[C:2]2[N:1]=[C:11]([CH2:12][CH2:13][CH3:14])[O:8][C:7](=[O:9])[C:6]=2[S:5][N:4]=1
Reactant: Cc1nsc(C(=O)O)c1N
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(C)nsc2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-methyl-isothiazole-5-carboxylic acid (method 57) (2.91 g, 15 mmol) in pyridine (20 mL) at 0° C., was added dropwise a solution of butyryl chloride (3.18 g, 30 mmol) in chloroform (30 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. Chloroform (200 mL) was added to the reaction mixture followed by 2M HCl (200 mL) and the mixture was stirred. The chloroform layer was further washed with 2M HCl (100 mL), water (100 mL), brine (100 mL) and concentrated. Column purification of the thus obtained crude product provided the pure product as light brown solid. Yield 2 g (64%). 1H NMR (300 MHz) δ 1.03 (t, 3H), 1.80-1.92 (m, 2H), 2.65 (s, 3H), 2.76 (t, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[S:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Cl[CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>CN(C)C=O.O>[CH3:27][N:26]([CH3:28])[C:24]([CH2:23][S:17][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:25]
Reactant: CN(C)C(=O)CCl
Reactant: [H][H]
Reactant: S=c1[nH]c2ccccc2cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CSc1nc2ccccc2cc1-c1ccccc1
Reaction time: 2 h

Procedure:
3-Phenylquinolin-2-thione (4.74 g.; see Example 6) was added in portions to a well-stirred suspension of sodium hydride (1.06 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (25 ml.) at 0°-5°. After all the hydrogen gas had evolved, 2-chloro-N,N-dimethylacetamide (2.19 g.) was added and the mixture was heated at 80°. for 2 hr. The reaction mixture was then poured into water (300 ml.) and extracted with ethyl acetate (4×50 ml.). The ethyl acetate extract was washed with water (50 ml.) and then dried (MgSO4). The solvent was evaporated and the residual oil was chromatographed on basic alumina (70 g. of Brockmann Grade III), eluted with increasing concentrations of chloroform in petroleum ether. The eluate obtained with 20% v/v chloroform in petroleum ether was evaporated. The residual solid was crystallised from ethyl acetate-petroleum ether to give 2-(dimethylcarbamoylmethylthio)-3-phenylquinoline, m.p. 86°-9°.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]([N+:22]([O-])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=S)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>C(OCC)(=O)C.C(O)C.[Pd].O1CCCC1>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]2[N:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:25](=[O:27])[CH3:26])=[CH:29][CH:30]=3)=[N:22][C:9]2=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)n1
Reactant: CC(=O)c1ccc(N=C=S)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCNc1ccc2nc(Nc3ccc(C(C)=O)cc3)n(CCCN3CCCCC3)c2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
N6-butyl-3-nitro-N2-(3-piperidin-1-ylpropyl)pyridine-2,6-diamine (500 mg) in solution in a mixture of ethyl acetate/ethanol 3:1 (10 ml), and 10% palladium on carbon (50 mg) are introduced into an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the mixture is filtered on celite in a flask containing a solution of 4-acetylphenyl-isothiocyanate (270 mg, 1 eq) in tetrahydrofuran (10 ml). N-cyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; load 1.9 mmol/g; 2.63 g, 3 eq) is added to the filtrate thus obtained. The mixture is heated to reflux for 15 hours, cooled down to ambient temperature then filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound (230 mg; 34% yield).
Reaction SMILES: CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:17]([NH:21][C:22]([C:24]1[S:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=1[C:32]([OH:34])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([N:21]1[C:22](=[O:23])[C:24]2[S:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=2[C:32]1=[O:34])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1nsc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)c1nsc2c1C(=O)N(C(C)(C)C)C2=O
Yield: 95.1 %

Procedure:
7.5 g (74.1 mmol) of methylmorpholine, 2.4 g (20 mmol) of dimethylaminopyridine and 17.4 g of a 50% strength solution of propanephosphonic anhydride (27.3 mmol) in dichloromethane were added dropwise in succession to 5.4 g (20 mmol) of 5-tert-butylaminocarbonyl-3-isopropylisothiazole-4-carboxylic acid in 200 ml of dichloromethane at -5° C. and the mixture was then refluxed for 6 hours. Working up was carried out as described above for Example No. 1.003. 4.8 g (95%) of N-tert-butyl-3-isopropylisothiazole-4,5-dicarboximide were obtained as a solid of melting point 52°-53° C. (Example No. 3.001).
Reaction SMILES: Cl[C@H:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:5][CH2:4][C@H:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[N:32]([C@@H:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:5][CH2:4][C@H:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@@H](Cl)c2cccnc21)(C(C)C)C(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](N=[N+]=[N-])c2cccnc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 100 mL round-bottom flask was dissolved (5R,6S,9R)-5-chloro-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (566 mg, 1.214 mmol) in dimethylformamide (5 mL) to give a colorless solution. Sodium azide (474 mg, 7.29 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 2.5 h. LCMS indicated only partial reaction. The mixture was heated at 50° C. overnight. After 15 h, LCMS indicated complete conversion with some elimination product. The mixture was diluted with water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried, and concentrated to give a colorless oil. The crude product was carried onto the next reaction without further purification and characterization. Smaller scale purification afforded an analytical sample: MS(ESI)[M+H+]=473.27; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52-8.63 (m, 1H) 7.75 (d, J=7.81 Hz, 1H) 7.23-7.36 (m, 1H) 6.95-7.17 (m, 2H) 6.89 (br. s., 1H) 5.28 (d, J=4.03 Hz, 1H) 4.90 (d, J=9.07 Hz, 1H) 3.79 (t, J=9.44 Hz, 1H) 1.86-2.23 (m, 4H) 1.16-1.30 (m, 3H) 0.98-1.15 (m, 18H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −137.68-−137.36 (m, 1F) −141.78-−141.54 (m, 1F).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[C:8](I)[C:9]([F:11])=[CH:10][C:4]=2[O:3]1.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C>O1CCCC1>[CH3:25][C:20]1([CH3:26])[C:21]([CH3:24])([CH3:23])[O:22][B:18]([C:8]2[C:9]([F:11])=[CH:10][C:4]3[O:3][C:2]([F:13])([F:1])[O:6][C:5]=3[CH:7]=2)[O:19]1
Reactant: Fc1cc2c(cc1I)OC(F)(F)O2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc3c(cc2F)OC(F)(F)O3)OC1(C)C
Temperature: 5 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
2,2,5-Trifluoro-6-iodobenzo[d][1,3]dioxole (1.0 g, 3.3 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to 5° C. and treated with isopropylmagnesiumchloride-lithium chloride complex solution (1.3 M; 2.7 mL, 3.5 mmol). The mixture was stirred for 1 h at 5-15° C., treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (720 μL, 660 mg, 3.5 mmol) and stirred for 20 min. The reaction was quenched by addition of saturated ammonium chloride (NH4Cl; 5 mL) and mixed with ethyl acetate (20 mL) and saturated NaCl (10 mL). The separated organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (1.0 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=4.3 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 1.35 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.96 (s), −104.21 (s)); EIMS m/z 302.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[NH3:12].CO>O>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:12]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: N
Solvent: CO
Solvent: O
Product: Nc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 51 %

Procedure:
To a pressure tube was added 1,3-difluoro-2-nitrobenzene (2.8 mL, 26.4 mmol) and 7 N NH3 in CH3OH (10 mL, 70 mmol). The tube was sealed and the mixture was stirred at room temperature for 5 days. The solution was diluted with H2O, extracted with CH2Cl2, and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give an oil. The oil was triturated with hexane and the resulting orange solid was collected by filtration to give the title compound (2.1 g, 51%).
Reaction SMILES: C1O[C:5]([OH:9])([CH2:7][OH:8])[CH2:4][O:3][C:2]1([OH:12])CO.[CH:13](N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH3:22][O:23][CH2:24][O:8][CH2:7][C:5](=[O:9])[CH2:4][O:3][CH2:2][O:12][CH3:13]
Reactant: OCC1(O)COC(O)(CO)CO1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCl
Solvent: ClCCl
Product: COCOCC(=O)COCOC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a cold (0° C.), stirred mixture of 3.60 g of dihydroxyacetone dimer and 16 mL of diisopropylethylamine in 40 mL of dichloromethane is added 6.1 mL of chloromethyl methyl ether. The mixture is stirred and allowed to warm slowly to room temperature. After 18 h, the clear solution is partitioned between ether and dilute HCl. The aqueous phase is placed in a continuous extractor and extracted overnight with ether. The combined organic phase is then dried (MgSO4) and concentrated under reduced pressure. Kugelrohr distillation of the residue at ˜0.5 mmHg and 150° C. oven temperature affords 2.79 g of 2,4,8,10-tetraoxaundecan-6-one as a pale yellow oil.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>O>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH3:42])[CH3:39])([CH3:10])([CH3:11])[CH3:9]
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Reactant: CC(C)(C)CN
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
25 mg of 2-hydroxypyridine (0.26 mmol) was added to a solution of 250 mg of {(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (101b) (0.52 mmol) in 1.22 ml of (2,2-dimethylpropyl)amine (10.4 mmol), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride/acetone=2/1) to obtain 228 mg of the title compound (yield: 78%).
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])=[CH:18][C:17]=1[O:23][CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C@H:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[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:36]([NH:53][C@@H:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)cc3OC)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (44 mg, yield 97%).