Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:3]([OH:13])=[C:2]([NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:7]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A mixture of 0.70 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.79 g of WSC, 0.39 g of isonicotinic acid and 6 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.54 g of N-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: [NH2:1][C:2](=[N:6][OH:7])[CH2:3][S:4][CH3:5].[Cl:8][CH2:9][C:10](Cl)=[O:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:1][C:2](=[N:6][O:7][C:10]([CH2:9][Cl:8])=[O:11])[CH2:3][S:4][CH3:5]
Reactant: CSCC(N)=NO
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSCC(N)=NOC(=O)CCl
Reaction time: 1 h
Yield: 61.5 %

Procedure:
1-Amino-1-hydroxyimino-2-methylthioethane (11.32 g, 94.2 mmol) was suspended in dry chloroform (60 mL) under nitrogen. A solution of chloroacetyl chloride (7.5 mL, 94.2 mmol) in chloroform (20 mL) was added dropwise. After stirring for 1 hour, a solution of triethylamine (15.8 mL, 113 mmol) in chloroform (20 mL) was added dropwise. The reaction mixture was stirred for 15 minutes, then washed with water (2×70 mL), dried over sodium sulfate, concentrated in vacuo, and dried under vacuum to yield 11.4 g (62% yield) of 1-amino-1-((chloromethyl)carbonyloxy)imino-2-methylthioethane, as a brown semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: BrCc1cccnc1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(Cc2cccnc2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 3-bromomethyl-pyridine gave the title compound.
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]1[CH:15]=[CH:14][C:9]([S:10][CH2:11][C:12]#[CH:13])=[CH:8][CH:7]=1.Br[CH2:17][C:18]#[C:19][CH2:20][C:21]#[CH:22].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[CH3:5][C:6]1[CH:15]=[CH:14][C:9]([S:10][CH2:11][C:12]#[C:13][CH2:17][C:18]#[C:19][CH2:20][C:21]#[CH:22])=[CH:8][CH:7]=1
Reactant: C#CCSc1ccc(C)cc1
Reactant: C#CCC#CCBr
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC#CCC#CCSc1ccc(C)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
27.15 ml (13.75 g, 0.103 mol) of a 3.8N solution of ethylmagnesium bromide in ether was added dropwise under argon to a cold solution of 15.3g (0.085 mol) of 3-(p-methylthiophenoxy)-1-propyne in 80 ml of anhydrous tetrahydrofuran, at such a rate to maintain the temperature at -10°C. The resulting mixture was stirred for 1 hour and then treated with 677.2mg of cuprous cyanide. After stirring 20 minutes more, a solution of 10.8 g(0.0687 mol) of 1-bromo-2,5-hexadiyne in 25 ml of anhydrous tetrahydrofuranwas added dropwise, maintaining the temperature between 0°-5°C. The reaction mixture was stirred at room temperature for 3 additional hours, and then poured into 150 ml of 1N sulfuric acid and ice. After extraction with ether (3×150 ml) the combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA and then with water, dried over sodium sulfate and evaporated. The crude material was purified by column chromatography on 200 g of silica gel, using hexane:ethyl acetate (95:5) as eluant, and the product crystallized from methylene-chloride-hexane, to yield 9-(p-methylthiophenoxy)-1,4,7-nonatriyne, as an oil. The product was stored in dry ice.
Reaction SMILES: C([N+](CCC)(CCC)CCC)CC.[CH3:14][C:15]1([CH3:22])[CH:20]2[CH:16]1[CH2:17][CH2:18][CH:19]2[OH:21]>C(Cl)Cl>[CH3:14][C:15]1([CH3:22])[CH:20]2[CH:16]1[CH2:17][CH2:18][C:19]2=[O:21]
Reactant: CC1(C)C2CCC(O)C21
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CC1(C)C2CCC(=O)C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A chilled (0° C.) solution of N-methylmorpholime N-oxide (3.11 g, 26.5 mmol) and tetrapropylammonium perrethenate (VII) (0.280 g, 0.796 mmol) in DCM (40 mL) was prepared containing 4 Å molecular sieves (ca 0.3 g). A solution of (±)-6,6-dimethyl-bicyclo[3.1.0]hexan-2-ol (1.67 g, 13.3 mmol) in DCM (10 mL) was added dropwise and the solution allowed to warm to room temperature and stirred for 1 hour under argon. The solution was filtered through a silica plug, solvent removed under reduced pressure and the resulting oil purified by column chromatography (0-100% DCM/n-hexane, silica). 6,6-Dimethyl-bicyclo[3.1.0]hexan-2-one was obtained as a brown oil. 1H NMR (CDCl3): δ 2.35-2.15 (m, 2H), 2.10-2.00 (m, 1H), 1.97-1.85 (m, 2H), 1.66 (d, 1H, J=4.7), 1.16 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:9]1=[O:18].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH2:13]2)[C:9]1=[O:18]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C1N(c2ccccc2Cl)CCC12CCCNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1N(c2ccccc2Cl)CCC12CCCN(c1ccc(C(F)(F)F)cn1)C2
Temperature: 180 °C

Procedure:
A mixture of 2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one (16.0 mg, 0.0000604 mol, which was prepared by using a procedure that was analogous to that used for the synthesis of example 92, steps 1-4), 2-chloro-5-(trifluoromethyl)pyridine (13 mg, 0.000072 mol) and N,N-diisopropylethylamine (0.032 mL, 0.00018 mol) in N-methylpyrrolidinone (0.4 mL, 0.005 mol) was irradiated with microwaves to heat the reaction mixture to 180° C. for 20 min. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 410.2/412.2 (M+H)+.
Reaction SMILES: C([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[C:11]#[N:12])(=O)C1C=CC=CC=1.FC(F)(F)C(O)=[O:21]>C(Cl)Cl>[C:11]([C:10]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:9]=1[OH:21])#[N:12]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1c(Cl)cccc1C(=O)c1ccccc1
Solvent: ClCCl
Product: N#Cc1c(O)cccc1Cl
Yield: 67 %

Procedure:
2-Benzoyl-6-chlorobenzonitrile (10.0 g, 41 mmol) was dissolved in methylene chloride(40 ml) and trifluoroacetic acid(40 ml) and stirred at room temperature for 24 hrs. The reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CHCl2) gave the desired product(4.2 g, 67%). 1H NMR (CD3COCD3): δ10.31 (s,1H), 7.51 (t, 1H), 7.11 (d, 1H) 7.05 (d, 1H).
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([CH:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[OH:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1[Mg]Br
Reactant: O=CC1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Magnesium (2.20 g) was suspended in tetrahydrofuran (4 ml) and iodine (2 mg) was added. Thereto was added dropwise a solution of 2-bromo-1-(tert-butyldimethylsilyloxymethyl)benzene (24.0 g) obtained in Step 1 in tetrahydrofuran (10 ml) over 30 min and the reaction mixture was heated under reflux for 1 hr. Thereto was added tetrahydrofuran to give 1M 2-(tert-butyldimethylsilyloxymethyl)phenylmagnesium bromide-tetrahydrofuran solution. Then cyclopropanecarboxaldehyde (2.80 g) was dissolved in tetrahydrofuran (120 ml), and 1M 2 -(tert-butyldimethylsilyloxymethyl)phenylmagnesium bromide—tetrahydrofuran solution (80 ml) was added dropwise under ice-cooling over 50 min. The reaction mixture was stirred at room temperature for 12 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution (8 ml) under ice-cooling and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5) to give the title compound (8.20 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:5]=1.[CH3:30]C(C)([O-])C.[Na+].CI>O>[CH3:30][O:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:5]=1
Reactant: CC(C)(C)[O-]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CCO)cn2COCC[Si](C)(C)C)c1=O
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCCc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To 5 ml of mixed solvent (dehydrated tetrahydrofuran:N,N-dimethylformamide=3:1 (V/V)) solution containing 1.29 g (2.93 mmol) of 3-(2-hydroxyethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(e) was added 0.56 g (5.83 mmol) of sodium tert-butoxide under room temperature, and the mixture was stirred at the same temperature for 2 hours. Then, 1.1 ml (17.7 mmol) of methyl iodide was added to the mixture, and the mixture was further stirred for 16-hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.18 g of the title compound as a slightly yellowish oil. (Yield: 89%)
Reaction SMILES: Cl.[CH2:2]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH3:14])[C:9]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:24]([OH:26])[CH3:25]>>[CH2:2]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([C:15]2[CH:16]=[C:17]([C:18](=[NH:19])[O:26][CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=2)[CH3:14])[C:9]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCO
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C#N)c1
Agent: Cl
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C(=N)OCC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Hydrogen chloride gas was bubbled through a solution of 3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzonitrile (Preparation 36, 0.55 g, 1.86 mmol) in ethanol (8 ml) at 0° C. for 1 h. The reaction vessel was then sealed and left standing in the fridge for 48 h. The mixture was allowed to warm to room temperature and the solvent was removed in vacuo (to afford the title compound as its hydrochloride salt). The residue was dissolved in dichloromethane (20 ml) and washed with 10% w/v potassium carbonate solution (2×10 ml). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude title compound (700 mg) was isolated as a colourless oil which was taken on without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[C:12](O)(=O)[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>CN1CCCC1=O.O>[F:8][C:7]1[C:2]2[N:1]=[C:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: O=C(O)CCCC(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)CCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 100 °C
Reaction time: 6 h
Yield: 43.9 %

Procedure:
2-Amino-3,4,6-trifluorothiophenol (200 mg, 1.1 mmol) was dissolved in N-methylpyrrolidone (NMP, 1 ml) under a nitrogen stream. To the resultant solution was gradually added glutaric acid (127 mg, 1.1 mmol) at room temperature and the mixture was stirred at 100° C. for 6 hours. After naturally cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate. The alkaline phase was acidified with 10% hydrochloric acid and re-extracted with ethyl acetate. The combined organic phases were dried and then evaporated to yield a residue, which was recrystallized from acetonitrile to give 4-(4,5,7-trifluorobenzothiazol-2-yl)butanoic acid (133 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](S)=[N:8][C:7]=2[CH:12]=1.S(Cl)([Cl:15])=O>CN(C=O)C.ClCCl>[Cl:15][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[N:8]=1
Reactant: COc1ccc2oc(S)nc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2oc(Cl)nc2c1
Temperature: 68 °C

Procedure:
To a mixture of 5-methoxy-benzooxazole-2-thiol (12.14 g, 0.07 mol) and thionyl chloride were added two drops of DMF. The mixture was stirred at 68° C. for forty minutes and the formation of gas had stopped. The mixture was diluted with dichloromethane, concentrated, and dried in vacuo to give the title compound as a green solid (14.31 g): 1H NMR (CDCl3, 200 MHz): δ=7.36 (m, 1H), 7.13 (m, 1H), 6.92 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Br[CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C:31]=1[CH3:39].[Cl-].[NH4+]>CCOCC.CCCCCC>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH:8]([CH:28]=[CH:29][CH:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[C:31]3[CH3:39])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=C(CCBr)c2ccccc2C1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2ccccc2C1C=CC1c2cc(C(C)(C)C)ccc2-c2ccc(C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
To a 100 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel, 2,7-di-t-butylfluorene (1.18 g, 4.22 mmol) and dehydrated ether (30 ml) were introduced. To the flask was dropwise added a hexane solution of n-butyllithium (1.67 mol/l, 2.8 ml, 4.64 mmol) at 0° C. over a period of 1 hour, followed by stirring at room temperature for 7 hours. The reaction liquid became red orange transparent. Then, the liquid was cooled to −78° C. (a yellow orange slurry), to which a solution of 3-(2-bromoethyl)-2-methylindene (1 g, 4.22 mmol) in dehydrated ether (10 ml) was dropwise added over a period of 30 minutes. Then, the temperature of the system was allowed to spontaneously rise to room temperature, followed by stirring for 15 hours. The reaction mixture gradually became a yellow slurry. The resulting yellow slurry was poured into 200 ml of a saturated ammonium chloride aqueous solution to separate an ether phase. The aqueous phase was extracted with ether (100 ml×2), and a combined organic phase was dried over anhydrous magnesium sulfate, Then, the solvent was distilled off, and the resulting white yellow powder was reslurried with hexane (100 ml) and filtrated to obtain 1.70 g (yield: 93%) of an aimed product of a white powder.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](OC)[N:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:7]1[C:2]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 59.1 %

Procedure:
A solution of 2-chloro-6-methoxy-3-nitropyridine (20 g, 125 mmol) in DMF (120 mL) was treated with 3-trifluoromethylphenol (21 g, 129 mmol) and cesium carbonate (50 g, 154 mmol). The mixture was heated at 70° C. for 14 h. The reaction was concentrated. The residue was dissolved in ethyl acetate and washed with brine, 5% lithium chloride, and aqueous HCl and brine. After concentration, purification was achieved by column chromatography on silica gel using a continuous gradient from 0% to 40% ethyl acetate in hexanes as eluent afforded 21 g (60% yield) of 3a as a white crystals. [M+H]+=285.17.
Reaction SMILES: CN1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:18]=[C:17]([C:28](=[NH:31])[NH:29][OH:30])[C:16]=2[CH3:32])=[CH:11][CH:10]=1.[CH:33]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:18]=[C:17]([C:28](=[NH:31])[NH:29][O:30][C:39]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:40])[C:16]=2[CH3:32])=[CH:13][CH:14]=1
Reactant: O=C(O)C1CCCCC1
Reactant: Cc1c(C(=N)NO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1c(C(=N)NOC(=O)C2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NMM (0.42 mL, 3.77 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-hydroxy-4-methyl-1H-pyrazole-3-carboxamid amide (0.30 g, 0.75 mmol) obtained in Step 3, cyclohexylcarboxylic acid (97 mg, 0.75 mmol), HOBt (194 mg, 1.43 mmol) and EDCI (220 mg, 1.13 mmol) dissolved in DCM (7 mL). The mixture was stirred overnight at room temperature. After adding thereto EtOAc (30 mL), the mixture was successively washed with water, saturated NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was isolated, dried over MgSO4, filtered, and concentrated under a vacuum, to obtain 5-(4-chlorophenyl)-N-(cyclohexanecarbonyloxy)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximidamide as a white solid, which was used in the next step without further purification. The crude material was dissolved in pyridine (4 mL), and was subjected to microwave irradiation at 180° C. for 20 min., to remove volatile components under a vacuum. The residue was further purified by reverse phase preparative HPLC, to obtain the title compound as white solid (67 mg, 0.137 mmol, 18% via two steps).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:36])[C:2]1[CH:7]=CC=CC=1.C1C[O:40]CC1>[C].[Pd]>[F:36][C:10]1[CH:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2](=[O:40])[CH3:7]
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [Pd]
Product: CC(=O)COc1ccc(-c2nc3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl ((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (4.26 g), 10% palladium-carbon (containing water (50%), 0.920 g) and THF (40 mL) was stirred at room temperature for 1 hr and min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the solution was subjected to silica gel chromatography (ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in DMF (40 mL) were added potassium carbonate (1.32 g) and bromoacetone (0.888 mL), and the mixture was stirred overnight at 60° C. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.67 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=2)=[CH:57][C:56]=1[CH3:68]>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:62]=2)=[CH:57][C:56]=1[CH3:68]
Reactant: COc1ccc(-c2cccc(N)c2)cc1C
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 67 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 65% yield: LCMS (ESI) m/z 470 (MH+).