Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:28])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:28][C:13]1[N:12]2[N:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCOCC3)nn12
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: Clc1ccc(-c2cc3nc(CN4CCOCC4)nn3c(Cl)n2)c(Cl)c1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
1250 mg (3.3 mmol) of 7-(2,4-dichlorophenyl)-2-(morpholin-4-ylmethyl)[1,2,4]triazolo-[1,5-c]pyrimidin-5-ol (Example 134A) are introduced into phosphoryl chloride (20 ml), 2.25 g (9.9 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 12 h. The reaction mixture is slowly poured, while stirring vigorously, into saturated sodium bicarbonate solution (150 ml) and ice, and solid sodium bicarbonate (approx. 10 g) is added until a pH of 8 is reached. The solid is filtered off with suction and dried. 508 mg (39% of theory) of the product are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]1=[O:10].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:3]1=[O:10]
Reactant: Cn1ccc(C=O)cc1=O
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccn(C)c(=O)c1

Procedure:
N-Methyl-4-formyl-2-pyridone* (30.17 g), monoethyl malonate (38.15 g), pyridine (150 ml) and piperidine (3 ml) were stirred under reflux for 61/2 hours. The reaction mixture was evaporated under reduced pressure to afford a residue which was crystallised from aqueous isopropanol to give ethyl β-(N-methyl-2-oxo-4-pyridyl)acrylate as a pale yellow solid (18.44 g), m.p. 126°-7° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]3[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]3[N:15]=[C:16]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(Sc3ccc(Br)cc3)c2n1
Reactant: C1CNCCN1
Product: Brc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 8-(4-bromophenyl-thio)-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 205°-207° C.) and piperazine.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].CN(C)C=[N:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)(=[O:13])=[O:12]>CN(C=O)C>[OH:4][CH2:3][CH2:2][S:1][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH2:10])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccc(Br)cc1
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(SCCO)cc1

Procedure:
A solution of 2-mercaptoethanol (58.6 g, 0.75 mol) in freshly degassed DMF (100 mL) was added dropwise under N2 to a stirred mixture of NaH (34.5 g, 50% oil suspension, 0.75 mol) and DMF (400 mL). When gas evolution was complete, N,N-dimethyl-N'-(4-bromobenzenesulfonyl)formamidine (146 g, 0.50 mol) was added and the mixture was heated on the steam bath for one hour. The DMF was removed in vacuo and methanol (500 mL) and 10% (w/v) aqueous NaOH solution (500 mL) was added to the residue. This solution was warmed on the steam bath for one hour and the methanol removed. The residue was diluted with water (2500 mL) and washed with petroleum ether. The separated aqueous layer was acidified with concentrated HCl. The white solid that separated was filtered, washed with water and dried. Extraction of the aqueous filtrate with ethyl acetate produced an additional quantity of product; total yield, 112.4 g; mp 103°-108° C. Recrystallization of a sample from water followed by recrystallization from dichloroethane gave material with mp 111°-112° C.
Reaction SMILES: C(OC([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[OH:21])=O)C.N(O[CH2:25]CC(C)C)=O>C(O)(C(F)(F)F)=O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:8]2[C:7]([O:21][CH3:25])=[CH:6][S:20][C:9]=2[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1sc2c(c1O)CCN(C(=O)OCC)CC2
Reactant: CC(C)CCON=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCc2scc(OC)c2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step b) (256 mg, 0.69 mmol) was stirred in TFA (2 mL) for 30 minutes. The reaction was concentrated and dissolved in EtOH (5 mL). Isoamyl nitrite (140 μL, 1.04 mmol) and Cu(OAc)2 (188 mg, 1.04 mmol) were added to the solution and the reaction was stirred at room temperature overnight. The reaction was filtered through a silica plug and purified by silica gel chromatography (EtOAc/Hex-gradient) to give 17 mg of the subtitle compound. MS: ESI (positive): 271 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:6]=2[C:5](=[O:23])[NH:4][C:3]1=[O:24].[CH3:25][CH:26]([CH2:29][CH3:30])[CH2:27]Cl>>[CH3:25][CH:26]([CH3:27])[CH2:29][CH2:30][N:4]1[C:5](=[O:23])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:24]
Reactant: CCC(C)CCl
Reactant: CCOP(=O)(CCCCn1cnc2c1c(=O)[nH]c(=O)n2C)OCC
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(CCC(C)C)c(=O)n2C)OCC

Procedure:
The title substance was prepared from diethyl [4-(3-methylxanthin-7-yl)-butyl]phosphonate and 2-methylbutyl chloride analogously to Example 1 and chromatographed on silica gel (eluent: dichloromethane/methanol 10:1)
Reaction SMILES: [O-][CH2:2]C.[Na+].[NH:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:26])[C:15]4[C:20]([S:21](=[O:25])(=[O:24])[C:22]=3[CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][N:7]=[N:6]1.CI>C(O)C>[CH3:2][N:7]1[N:6]=[N:5][C:9]([C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:26])[C:15]4[C:20]([S:21](=[O:24])(=[O:25])[C:22]=3[CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8]1
Reactant: CC[O-]
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: Cn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1

Procedure:
To a solution of sodium ethoxide in ethanol (20 ml) (prepared from 0.46 g sodium) was added 3-(5-tetrazolyl) thioxanthone-10,10-dioxide (6.24g). Methyl iodide (2.84 g) was added and the mixture boiled under reflux for 2 hrs. During the reflux period a yellow product was deposited. On cooling it was filtered off, washed with water and recrystallised twice from acetic acid to give 3-(2-methyl-5-tetrazolyl)thioxanthone-10,10-dioxide as yellow needles, m.p. 204°-205° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]O.Cl>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Yield: 96 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid (5.00 g, 27.0 mmol), Methanol (40 mL), and 2 N HCl in Et2O was heated at reflux for 16 hr. Volatile material was removed under vacuum. The residue was diluted with AcOEt (150 mL), washed successively with saturated NaHCO3 solution and brine, and dried over anhydrous MgSO4. Evaporation of solvent under vacuum gave the title compound (5.18 g, 96% yield) as a pale yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[C:37](CO)[CH:36]=[CH:35][N:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C>C(Cl)Cl>[Br:24][CH2:20][C:37]1[CH:36]=[CH:35][N:34]=[C:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:38]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Triphenylphosphine (970 mg, 3.7 mmol) and carbon tetrabromide (1.5 g, 4.6 mmol) were added to a solution of (2-tert-butoxycarbonylaminopyridin-4-yl)methanol (Reference compound No. 4-1, 690 mg, 3.1 mmol) in methylene chloride (20 mL) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. Ethyl acetate (30 mL) was added to the reaction mixture, the whole was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL) and brine (20 mL), and then dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting solid was filtered off with ethyl acetate to give 550 mg of the title reference compound as a colorless solid. (Yield 62%)
Reaction SMILES: [F:1][C:2]1([CH3:19])[C@@:6]([OH:8])([CH3:7])[CH:5]([CH2:9][OH:10])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].O>ClCCl>[C:20]([O:10][CH2:9][C@@H:5]1[C:6]([OH:8])([CH3:7])[C@:2]([F:1])([CH3:19])[CH:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(=O)Cl
Reactant: CC1(F)[C@H](n2ccc(=O)[nH]c2=O)OC(CO)[C@@]1(C)O
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)OC[C@H]1OC(n2ccc(=O)[nH]c2=O)[C@](C)(F)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 1-((2R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3,4-dimethyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (about 0.30 g, 1.09 mmol) in dichloromethane (about 5 ml) was added solution of butyroylchloride (about 0.28 ml, 2.70 mmol) in dichloromethane (about 5 ml) at about 0° C. and stirred at room temperature for overnight. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and extracted with dichloromethane and the combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 2% methanol in dichloromethane to elude title compound (0.15 g) as a colorless solid. Yield: 40%; 1H NMR (300 MHz, CDCl3): δ 8.42 (bs, 1H), 7.39-7.35 (dd, 1H, J1=8.4 Hz, J2=8.1 Hz), 6.37 (d, 1H, J=22.8 Hz), 5.76-5.73 (dd, 1H, J1=8.4 Hz, J2=8.1 Hz), 4.58-4.52 (m, 1H), 4.39-4.37 (m, 1H), 4.26-4.20 (m, 1H), 2.68 (s, 1H), 2.38-2.33 (t, 2H), 1.69-1.61 (m, 2H), 1.48-1.25 (m, 6H), 0.99-0.94 (t, 3H); ES Mass: [M+Na]+: 367 (100%), [M+1]+ 345 (30%); IR cm−: 3504, 3147, 1725, 1677, 1560, 1180, 1086, 1062, 994; HPLC: 99%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[Na].Cl[CH2:8][C:9]1([CH2:13]Cl)[CH2:12][O:11][CH2:10]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:8][C:9]1([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:12][O:11][CH2:10]1
Reactant: ClCC1(CCl)COC1
Reactant: COCCO
Agent: [Na]
Product: COCCOCC1(COCCOC)COC1
Temperature: 25 °C

Procedure:
To a 5 liter, three-neck flask, fitted with a reflux condenser, a stirrer, and a thermometer, were added 1824 g (24 mole) of 2-methoxyethanol followed by 139 g (6 mole) of sodium metal. The flask temperature was then raised to mild reflux and thus maintained until all the sodium had dissolved. At this time, 465 g (3 mole) of 3,3-bis(chloromethyl)oxetane was added and heating maintained for a further 24 hr. The mixture was then cooled to room temperature and the precipitated sodium chloride removed by filtration. The filtrate was dissolved in an excess of water, extracted with four portions of 500 ml methylene chloride, and then the combined organic layers were dried over magnesium sulfate. The solvent was then removed by evaporation and the required monomer isolated by fractional distillation, the fraction boiling at 85° C. and 0.1-mm pressure being collected. Redistillation from calcium hydride yielded 487 g of polymerizable grade monomer.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.N1C=CC=CC=1>ClCCl>[C:1]([N:14]1[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A solution of 73.1 g (520 mmol) of benzoyl chloride in 70 ml of dichloromethane was added dropwise to a solution of 50.0 g (495 mmol) of 4-hydroxypiperidine and 260 ml of pyridine in 260 ml of dichloromethane at 0° to 15° C. The mixture was stirred at room temperature for 3 h and white crystals (pyridine hydrochloride) thus precipitated were filtered out. The filtrate was concentrated and a remaining oil was purified by silica gel column chromatography (CHCl3 :CH3OH=95:5) to give 79.8 g (yield: 79%) of the intended compound:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[OH:23][CH2:24][CH2:25][CH:26]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:26][CH2:25][CH2:24][OH:23]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: O=CCCO
Product: CC1=C(CCON=CCCO)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-hydroxypropanal by the method of Example 1.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[CH2:11][NH:12][C:13]([C:15]1[C:16]([OH:30])=[N:17][C:18]2[C:23]([C:24]=1[CH3:25])=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=2)=[O:14].Br[CH2:35][CH2:36][O:37][CH3:38].CCOC(C)=O.CCCCCC>CS(C)=O.O.CCOC(C)=O>[F:7][C:8]1[CH:9]=[C:10]([CH2:11][NH:12][C:13]([C:15]2[C:16]([O:30][CH2:35][CH2:36][O:37][CH3:38])=[N:17][C:18]3[C:23]([C:24]=2[CH3:25])=[CH:22][CH:21]=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=3)=[O:14])[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1c(C(=O)NCc2cccc(F)c2)c(O)nc2cc(C(F)(F)F)ccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CS(C)=O
Product: COCCOc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
120 mg (0.9 mmol) K2CO3 was added to a solution of 300 mg (0.8 mmol) N-(3-fluorobenzyl)-2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid amide in DMSO (10 ml) and the solution was stirred for 60 min at RT. 121 mg (0.9 mmol) 1-bromo-2-methoxy-ethane was then added and the RS was stirred for 16 h at RT and thereafter for 72 h at 50° C. It was then diluted with water and EtOAc. The organic phase was separated, washed with brine, dried over MgSO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:3) of the residue, 72 mg (0.2 mmol, 21%) N-[(3-fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4-methyl-7-(trifluoro-methyl)-quinoline-3-carboxylic acid amide (example 7) was obtained. MS: m/z 437.1 [M+H]+.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][O:13][CH3:14])=[CH:4][N+:5]([O-:7])=[O:6].[CH:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:24])[CH2:22][NH2:23])=[CH:17][CH:16]=1>C(O)C>[OH:24][CH:21]([C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)[CH2:22][NH:23][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][O:13][CH3:14])=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: NCC(O)c1ccccc1
Reactant: COCSCCNC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: COCSCCNC(=C[N+](=O)[O-])NCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
With 15 ml of ethanol were mixed 7.5 g of the 1-methylthio-1-[2-(methoxymethylthio)ethylamino]-2-nitroethene and 5.6 g of DL-β-hydroxyphenethylamine, and the resulting mixture was stirred at room temperature for 8 hours, and then allowed to stand overnight at room temperature. The solvent was removed by distillation under reduced pressure, and the crystals thus obtained were washed with 15 ml of isopropanol and then dried to obtain 7.3 g (yield 71%) of N-(β-hydroxyphenethyl)-N'-[2-(methoxymethylthio)ethyl]-2-nitro-1,1-ethenediamine having a melting point of 107°-109.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.C1C(=O)N([Br:43])C(=O)C1>C(#N)C>[Br:43][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[C:11]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc21
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(Br)cc21
Temperature: 80 °C
Yield: 88.2 %

Procedure:
To a solution of (S)-2-(1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (1 g, 1.917 mmol) in acetonitrile (20 mL) was added NBS (0.341 g, 1.917 mmol) and the solution heated to 80° C. overnight to afford (S)-2-(1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (1.2 g, 1.69 mmol, 88% crude yield) as brown solid. The material was carried forward without further purification. LC/MS (ESI) m/e 548.0 [(M+H)+, calcd for C28H27BrN3O4 548.1; LC/MS retention time (method D): tR=0.76 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C@H:10]([CH2:14][O:15][CH3:16])[C:11]([OH:13])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([NH:39][C:11](=[O:13])[C@H:10]([N:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH2:14][O:15][CH3:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC[C@H](C(=O)O)N1Cc2ccccc2C1
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC[C@H](C(=O)NCc1ccccc1)N1Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To the crude acid (R)-2-(Isoindolin-2-yl)-3-methoxypropanoic acid (FIG. 2, No. 5)(1.25 g, 5 mmol) in dry THF was added N-methylmorpholine (0.66 mL, 6.0 mmol) at −78° C. under an argon atmosphere. After 5 min, isobutyl chloroformate (0.78 mL, 6.0 mmol) was added and stirred for another 5 min. To this reaction mixture benzylamine (0.65 mL, 6.0 mmol) was added at −78° C. after which the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was filtered through a celite pad, washed with ethyl acetate, and dried over anhydrous MgSO4. The solvent was removed in vacuo and the crude product was subjected to silica gel column chromatography (Ethyl acetate/Hexane, 4:6) to yield 1.48 g, 88% yield of (R)—N—Benzyl-2-(isoindolin-2-yl)-3-methoxypropanamide (FIG. 2, No. 6) as a crystalline solid. [Rf=0.26, ethyl acetate/hexane (4:6)]; [α]D25 +81.8 (c 1, CH2Cl2); IR (CH2Cl2) v: 1718, 1685, 1535, and 1387 cm−1; 1H NMR (400 MHz, CDCl3) δ:3.38 (bs, 3H), 3.75 (m, 1H), 4.34 (t, J=9.64 Hz, 1H), 4.46 (m, 2H), 5.0 (m, 1H), 7.1 (bs, 1H), 7.21-7.33 (m, 5H), 7.7 (dd, J=3.2, 5.48 Hz, 2H), 7.83 (dd, J=3.2, 5.48 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 29.6, 43.5, 51.7, 58.9, 70.1, 123.5, 127.1, 127.3, 127.4, 128.4, 128.6, 131.8, 134.1, 137.9, 167.3, 167.9; HRMS (ESI-TOF) m/z calcd for C19H18N2O4Na [M+Na+] 361.120. Found 361.116.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.OO.NC(N)=[O:14].CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2CO1.O>ClCCl.O1CCCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:7][O:14]2)=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: C=Cc1ccc(O)cc1
Agent: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Agent: OO
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1ccc(C2CO2)cc1
Yield: 66 %

Procedure:
Fifth recycle 4-Hydroxy styrene: 1 g, 8.3 mmol, urea hydrogen peroxide: 3 g, 32 mmol, Immobilized lipase: 87 mg, 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate: 0.3 g, 1.03 mmol, dry dichloromethane:tetrahydrofuran (4:1): 15 mL. Same procedure was followed as described in example ‘1’. Reaction time: 20 hours, Yield: 66%.
Reaction SMILES: Br.Br.[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:16].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cc(N2CCNCC2)ccc1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)ccc1O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A mixture of 123.8 parts of 2-methyl-4-(1-piperazinyl)phenol dihydrobromide, 49.4 parts of 1-fluoro-4-nitrobenzene, 58.2 parts of sodium carbonate and 300 parts of dimethyl sulfoxide was stirred over weedend at room temperature. The reaction mixture was poured into water. The product was filtered of, washed with 2-propanol and dried, yielding 101.2 parts (92.3%) of 2-methyl-4-[4-(4-nitrophenyl)-1-piperazinyl]phenol as a solid residue (compound 1.12).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]([CH3:31])([CH2:18][N:19]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:30])=[C:23]([Cl:29])[CH:24]=[C:25]2[Cl:28])=[N:20]1)[C:16]#[N:17]>C1COCC1>[C:16]([C:15]([NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)([CH3:31])[CH2:18][N:19]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:30])=[C:23]([Cl:29])[CH:24]=[C:25]2[Cl:28])=[N:20]1)#[N:17]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=475, RT=0.75 min.