Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([CH2:15][OH:16])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[OH:2].N1C=CC=CC=1.[C:23](=O)=[O:24].CC(C)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:14][C:3]1([C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:15][O:16][C:23](=[O:24])[O:2][CH2:1]1
Reactant: O=C=O
Reactant: CC(CO)(CO)C(=O)OCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC1(C(=O)OCc2ccccc2)COC(=O)OC1
Temperature: 25 °C
Yield: 86 %

Procedure:
Benzyl 2,2-bis(methylol)propionate (BnMPA) (11.2 g, 0.05 mol) was dissolved in CH2Cl2 (150 mL) and pyridine (25 mL, 0.3 mol) and the solution was chilled to −75° C. with dry ice/acetone under N2 atmosphere. A solution of triphosgene (7.5 g, 25 mmol) in CH2Cl2 (150 mL) was added dropwise over 1 hours, and then the reaction mixture was allowed to warm to room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous NH4Cl (75 mL), after which the organic layer was washed with 1 M aqueous HCl (3×100 mL), saturated aqueous NaHCO3 (1×100 mL), dried over MgSO4, filtered and evaporated. The resulting solid was recrystallized from ethyl acetate (15 mL) to give MTCOBn as a white solid (10.7 g, 86%). 1H NMR (400 MHz, CDCl3, 22° C.): delta 7.37 (m, 5H, PhH), 5.20 (s, 2H, —OCH2Ph), 4.69 (d, 2H, —CH2OCOO), 4.23 (d, 2H, —CH2OCOO), 1.31 (s, 3H, —CH3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH:21][CH2:22][CH2:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]([N:8]1[CH2:9][C@@H:10]([OH:11])[C@H:12]([N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23][OH:24])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: OCCNCc1ccccc1
Product: OCCN(Cc1ccccc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
3-Benzyl-6-oxa-3-azabicyclo[3.1.0]hexane is reacted with 2-(benzylamino)-ethanol, analogously to Example D a), to give trans-1-benzyl-3-[N-benzyl-N-(2-hydroxyethyl)-amino]-4-hydroxypyrrolidine which is then reacted analogously to Example F a) to give 5,8-dibenzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane which is purified by chromatography (silica gel, cyclohexane/tert.-butyl methyl ether/ethyl acetate 1:1:1).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH:14]([NH:17][CH2:18][CH:19]([OH:22])[CH2:20]Cl)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]([CH3:13])[C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH:19]([OH:22])[CH2:18][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:7][CH:6]=1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: CC(C)NCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)NCC(O)COc1ccc(NC(=O)N(C)C)cc1
Reaction time: 5 h

Procedure:
A mixture of 20 g of p-(N',N'-dimethylureido)-phenol, 15 g of 3-isopropylamino-2-hydroxy-1-chloropropane, and 20 g of finely ground potassium carbonate in 250 ml of acetone is stirred at 50° for 5 hours. The solid part of the mixture is filtered off and the acetone solution is evaporated in a vacuum. The residue is dissolved in 100 ml of 2N hydrochloric acid, the undissolved part is filtered off and the remaining mixture is extracted with methylene chloride. The aqueous phase is rendered alkaline by adding 2N sodium hydroxide solution and is extracted with methylene chloride. After the evaporation of the solvent, 1-[p-(N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylaminopropane is isolated which melts at 138°-139° after recrystallisation from benzene and has the formula ##SPC6##
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[C:24]1=[S:25])[CH:2]=[CH2:3]
Reactant: C=CCNCCCNc1c(C)cccc1Cl
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
To an ice-cold solution of the diamine of Step C (4.9 g) and triethylamine (5.8 mL) in chloroform (70 mL) under nitrogen was added thiophosgene (1.6 mL). After 20 minutes at ambient temperature, additional thiophosgene (0.5 mL) was added. After 15 minutes, the reaction was quenched with water and extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a yellow solid which was triturated with diethyl ether to give the title product (3.2 g, 55.6%) as a white solid, m.p. 82-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.O>CN(C)C=O.[I-].[K+]>[F:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:10][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]=1[NH2:9]
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
2-Chloro-4-fluoro-5-aminophenol (1.02 g, 6.28 mmol), potassium carbonate (1.72 g, 12.4 mmol), potassium iodide (4.0 mg, 0.024 mmol) and N,N-dimethylformamide (5 ml) as a solvent were placed in a two-necked round bottom flask (25 cc) and stirred at 80° C. for one hour. Then, cyclopentyl bromide (1.00 g, 6.71 mmol) was added thereto, followed by stirring at 80° C. for further 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (20 ml) was added thereto, and the mixuture was extracted with toluene (20 ml×3 portions). The organic layers were combined, washed with water (10 ml) and a saturated aqueous sodium chloride solution (10 ml) and dried over magnesium sulfate. After removing the drying agent, the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.43 g, 6.23 mmol, 99.0% yield). Boiling point: 143°-145° C./1.5 mmHg.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.C[O:16]B(OC)OC.C(OO)(=O)C>CCOCC.CCCCCC>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([OH:16])=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cn1
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(O)cn1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M hexane solution of n-butyllithium (23 mL, 58 mmol) was added over 30 minutes to a −78° C. solution of 5-bromo-2-methoxypyridine (10 g, 53 mmol) in ether (120 mL), keeping the temperature below −65° C. The slurry was stirred for 30 minutes, and then trimethylborate (6.1 mL) was added quickly to the reaction solution. Again the temperature was maintained below −65° C. The solution was stirred for 10 minutes, warmed to 15° C. and then cooled to −78° C. Peracetic acid (56 mmol) was added dropwise, while the temperature was kept at or below −65° C. After addition, the reaction was warmed briefly to −50° C., cooled back to −65° C., then stirred at approximately 25° C. overnight. The reaction was quenched with water (100 mL), and then extracted with ether (3×150 mL). The organic portions were combined and washed with aqueous NaHSO3 solution and brine. The organic portions were extracted two times with 2N aqueous NaOH solution. The pooled basic aqueous fractions were washed with Et2O and then acidified with NaHSO4. The product precipitated out as oil; the aqueous mixture was extracted three times with Et2O, the pooled ether fractions were dried with Na2SO4, and stripped of solvent in vacuo. Yielded 3.6 g of a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Si:9]([O:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Si:9]([O:16][CH:17]1[CH2:18][CH2:19][CH:20]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])[CH2:21][CH2:22]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Nc1ccccc1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 2-iodoaniline (2.5 g, 10.9 mmol) in dichloromethane (160 mL) was added 4-(tert-butyldimethylsilanyloxy)cyclohexanone (2.39 g, 10.9 mmol) and acetic acid (8 mL). After the reaction was stirred for 1 hour at room temperature, sodium triacetoxyborohydride (3.47 g, 16.4 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic solution was dried (MgSO4) and concentrated to give 4.47 g of the desired amine, which was used without further purification. LC-MS (C18H30INOSi calc'd 431) m/z 432 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:12][CH2:13][CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:16]([O-])=[O:17].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:12][CH2:13][CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][C:9]([N:16]=[O:17])=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: OCCCN(CCCO)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=Nc1ccc(N(CCCO)CCCO)cc1
Reaction time: 1 h

Procedure:
N,N-bis(3-hydroxypropyl) aniline (10.46 g) was dissolved in hydrochloric acid (20cm3) at 0-5° C. and sodium nitrite (3.45 g) in water(15cm3) was added dropwise. The mixture was stirred for 1 hr, water (10cm3) was added, made alkaline with sodium carbonate, separated in to an oil and water layer. The oil was dissolved in dichloromethane and the solvent removed to leave N,N-bis(3-hydroxypropyl)4-nitrosoaniline as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]2[C:21]([C:22]#[N:23])=[CH:20][N:19]=[C:18]3[CH:24]=[CH:25][S:26][C:17]=23)=[CH:11][N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[NH2:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]2[C:21]([C:22]#[N:23])=[CH:20][N:19]=[C:18]3[CH:24]=[CH:25][S:26][C:17]=23)=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCNc2c(C#N)cnc3ccsc23)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccsc2c1NCCc1cnc(N)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
A mixture of {5-[2-(6-cyano-thieno[3,2-b]pyridin-7-ylamino)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (36.1 mg, 0.09 mmol) and trifluoroacetic acid (1 ml) in 4 ml of dichloromethane was stirred at room temperature for 16 hr. Dichloromethane was evaporated, and the residue obtained was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over MgSO4, filtered, and concentrated in vacuum to give a yellow crude product 24 mg. (89%). 1H NMR (300 MHz, CD3OD) δ 8.85 (s, 1H), 8.46 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.7 Hz, 1H), 7.14 (s, 1H), 4.19 (t, J=7.2 Hz, 2H), 3.22 (t, J=7.2 Hz, 2H); LC-MS (ESI) m/z 302.0 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CSc1cccc(CC(=O)O)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CSc1cccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)c1

Procedure:
Following General Procedure BI above, and using 3-methylthiophenylacetic acid (CAS #18698-73-2) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3SC)[C:6]=2[CH:24]=1.O[O:26][S:27]([O-:29])=O.[K+].[CH2:31]1COCC1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[N:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:27]([CH3:31])(=[O:29])=[O:26])[C:6]=2[CH:24]=1
Reactant: CSc1ccccc1-n1c(C(C)NC(C)=O)nc2ccc(F)cc21
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CC(=O)NC(C)c1nc2ccc(F)cc2n1-c1ccccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of N-(1-(6-fluoro-1-(2-(methylthio)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide (1.1697 g, 3.41 mmol) in THF (25.5 mL) and water (8.52 mL) was added oxone (5.23 g, 8.52 mmol) and the mixture was stirred at rt. After 48 h, to the mixture was added water (50 mL), extracted with DCM (50 mL×2). The combined organic layers were dried over Na2SO4, filtered, combined with the white solid, and concentrated under reduced pressure to give N-(1-(6-fluoro-1-(2-(methylsulfonyl)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide as an orange solid: LC-MS (ESI) m/z 376.0 [M+H]+. The orange solid was carried on crude without purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[SH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[S:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: Sc1ccccn1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=S)cc1)c1ccccc1
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-mercaptopyridine. HPLC-MS: m/z=351.1 (M+1); Rt=3.95 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1cccc(C)c1B(O)O
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 47.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2,6-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.034 g (47%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[N:6]=1.[Cl-].[NH4+]>C1COCC1>[Cl:14][C:7]1[N:6]=[C:5]([O:2][CH3:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Sodium methoxide (1.40 g) was gradually added to a THF (50 mL) solution of 2,6-dichloro-3-nitropyridine (5.00 g) over 30 minutes under ice-cooling. Then, the reaction solution was agitated at 0° C. for 1 hour, and agitated at room temperature for further 12 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate 2:1), and 2.90 g (58%) of 6-chloro-2-methoxy-3-nitropyridine was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4].[Cl:14][CH2:15][C:16](Cl)=[O:17].Cl>[OH-].[Na+].CCOCC>[Cl:14][CH2:15][C:16]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[O:4])=[O:17]
Reactant: NCC(=O)NCC(=O)NCC(=O)O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CNC(=O)CNC(=O)CNC(=O)CCl
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.5 g (0.013 mol) of glycylglycylglycine in 75 ml of 1.0N NaOH in a 500 ml flask under nitrogen at 0° C., a solution of 13.0 g (0.115 mol) of chloroacetyl chloride in 100 ml of ether was added dropwise from one addition funnel while simultaneously 100 ml of 1.0N NaOH was added dropwise from another. After additions were complete, the reaction mixture was stirred for 1.5 hr. at 0° C. The mixture was then acidified with concentrated HCl while cooling. After stirring for an additional 30 min. the mixture was concentrated to one-third volume under reduced pressure at 40° C. The residue precipitated upon cooling in an ice bath. Isolation of the solid gave 2.75 g (78.5%) after two washings.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.Br[CH2:23][CH2:24][CH2:25][OH:26].[I-].[K+].Cl>O.CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1O2
Reactant: OCCCBr
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1

Procedure:
A solution of 3.5 g. (11.8 mmol) of 4-(2-chloro-9-xanthenylidene)piperidine (prepared as in Example 14), 2.0 g. (13.4 mmol) of 3-bromo-1-propanol and 50 mg. of potassium iodide in 50 ml. of dimethylformamide is stirred at 23° C. for 18 hours and 100° C. for 12 hours. The reaction mixture is poured into water, basified and extracted with a mixture of ether and ethyl acetate. The extract is washed with water, dried and the solvent evaporated. The residue is chromatographed on an alumina column using ethyl acetate-ether 1:1 as the eluent. The first fraction yields the product which is treated with ethereal hydrogen chloride to give 4-(2-chloro-9-xanthenylidene)-1-(3-hydroxypropyl)piperidine hydrochloride, m.p. 225°-258° C.
Reaction SMILES: [CH:1]1[C:10]2CCCC[C:5]=2C=C[C:2]=1[OH:11].O.Cl[C:14]1[C:15](=O)[C:16](C#N)=[C:17]([C:22]#[N:23])[C:18](=[O:21])[C:19]=1Cl>O1CCOCC1>[OH:21][C:18]1[C:17]([C:22]#[N:23])=[CH:16][C:15]2[C:2](=[O:11])[CH2:1][CH2:10][CH2:5][C:14]=2[CH:19]=1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc2c(cc1O)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
5,6,7,8-tetrahydro-2-naphthalenol prepared in method II-2 (1.5 g, 8.7 mmol) was dissolved in 1,4-dioxane (8 mL) in a 100 mL round bottom flask. To this was added water (2 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (4.1 g, 18.2 mmol, 2.1 eq) in anhydrous 1,4-dioxane (16 mL) dropwise. The reaction mixture turned to black immediately after addition and resulting mixture was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was participated between EtOAc and saturated aqueous sodium bicarbonate. The aqueous layer was acidified to about pH 3 and was extracted with EtOAc three times. The organic layers were combined and evaporated in vacuo. Purification using MPLC chromatography (Biotage) gave 0.64 g (40%) of 3-hydroxy-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile as a light brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[NH:15][C:14]([O:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])=[N:13]2.Br[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>C(OCC)(=O)C.C1CCCCC1>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][N:11]1[C:10]([O:9][CH3:8])=[N:18][C:17]2[C:12]1=[N:13][C:14]([O:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])=[N:15][C:16]=2[NH2:19]
Reactant: CC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: ClCCCCBr
Solvent: C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 18 from 8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane with purification on an aminopropyl (NH2) cartridge using a 0-100% ethyl acetate-cyclohexane gradient.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([O:9]CC)=O)=[CH:5][N:6]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:1][C:2]1[S:3][C:4]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:9])=[CH:5][N:6]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnc(C)s1
Product: Cc1ncc(C(=O)N2CCCC2)s1
Temperature: 120 °C
Reaction time: 36 h
Yield: 73 %

Procedure:
A mixture of 15.42 g (0.0901 mole) of ethyl 2-methyl-5-thiazolecarboxylate and 12 g pyrrolidine was stirred at 120° C. under a nitrogen atmosphere for 36 hours to give 12.91 g of the title compound, m.p. 71-2°C. (78.6% yield with respect to the ester).
Reaction SMILES: [CH3:1][O-].[Na+].C[C:5](C)([C:9]([O-:11])=[O:10])[C:6]([O-:8])=O.[Na].[C:14]1(=[C:20]([C:24]#[N:25])[C:21]([NH2:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>CO>[C:24]([CH:20]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]([C:9]([O:11][CH3:1])=[O:10])[C:6](=[O:8])[NH:23][C:21]1=[O:22])#[N:25]
Reactant: N#CC(C(N)=O)=C1CCCCC1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)C1C(=O)NC(=O)C(C#N)C12CCCCC2
Reaction time: 0.5 h

Procedure:
24 ml of a 5.4 M solution of sodium methylate in methanol, 17.7 g of dimethylmalonate and 100 ml of methanol are placed in a 250 ml flask equipped with a mechanical stirrer, thermometer and condenser, under nitrogen flow. After 30 minutes, when the sodium has completely dissolved, a suspension of 20 g cyclohexylidenecyanoacetamide in 50 ml of methanol is added over a period of 15 minutes. The reaction mixture is left under agitation for 1 hour at 25° C. and is subsequently acidified with 5% HCl. The solid obtained is filtered off, washed with methanol and dried under vacuum. 28 g of methyl 5-cyano-2,4-dioxo-3-azaspiro[5,5]undecane-1-carboxylate are obtained.