Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1.[CH2:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]1[O:21][CH2:20]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:23]([O:22][CH2:18][CH:19]([OH:21])[CH2:20][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:3]2[CH:2]=[CH:1][C:6]([O:7][CH2:20][CH:19]([OH:21])[CH2:18][O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:5][CH:4]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOCC1CO1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)COc1ccc(S(=O)(=O)c2ccc(OCC(O)COCCCC)cc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
4,4'-Dihydroxydiphenyl sulphone (125.0 g; 0.5 mole), butyl glycidyl ether of epoxide content 7.45 equiv./kg (134.2 g; 1 equiv.), and benzyltrimethylammonium chloride (1.0 g) were stirred together and heated at 100° C. for 1 hour, at 120° C. for 2 hours, and then at 130° C. for 4 hours. The mixture was cooled, and was found to have an epoxide content of 0.03 equiv./kg, indicating that the reaction was substantially complete.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:25])[C:9]=3[C:8]2=[O:26])=[CH:4][CH:3]=1.[N+](=[CH2:31])=[N-]>ClCCl.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:25][CH3:31])[C:9]=3[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: C=[N+]=[N-]
Reactant: COCOc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: CCOCC
Solvent: ClCCl
Product: COCOc1c2c(c(OC)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 0.33 h

Procedure:
Methoxymethyl ether 6 (0.02 g, 0.052 mmol) was dissolved in 2 mL dry dichloromethane at 0° C. An excess of a diazomethane solution in diethylether was added. After about 20 minutes, all starting 6 was consumed. The mixture was concentrated in vacuo to give crude 7-(4-fluoro-benzyl)-5-methoxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione 8 (0.0223 g, 0.0527 mmol). 1H NMR (CDCl3) δ 9.1 (dd, 1H), 8.7 (dd, 1H), 7.6 (dd, 1H), 7.5 (t, 2H), 7.0 (t, 2H), 5.8 (s, 2 H), 4.8 (s, 2 H), 4.4 (s, 3H), 3.7 (s, (s, 3H), MS: 397 (M+1); 419 (M+23).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].CC(=CC)C.Cl([O-])=[O:27].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>O.C(O)(C)(C)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([OH:27])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C=O)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
In a 2 liter three-necked round-bottomed flask, fitted with a mechanical stirrer, dropping funnel, and ground glass stopper, were charged 4-(6'-acryloyloxyhexyloxy)benzaldehyde (from Example 12) (22 grams; 0.1 mole), tertiary-butyl alcohol (500 mL), and 2-methyl-2-butene (available from Aldrich Chemical Co., Milwaukee, Wis.) (232 grams; 3 moles). The reaction mixture was stirred at room temperature. Over two hours, a solution of sodium chlorite (available from Aldrich Chemical Co., Milwaukee, Wis.) (65 grams; 0.7 mole) and sodium phosphate, monobasic monohydrate (available from Aldrich Chemical Co., Milwaukee, Wis.) (75 grams; 0.5 mole) in water (300 mL) was added. The reaction mixture was stirred for 12 hours at ambient temperature at which time the organic solvents were concentrated by rotary evaporator. The residue was then dissolved in diethyl ether (500 mL) and the mixture was made acidic (pH~2) by addition of 4N HCl. The mixture was poured into a separatory funnel and the organic layer was processed. The residue was recrystallized from ethanol. Spectral analysis confirmed the presence of 4-(6'-acryloyloxyhexyloxy)benzoic acid. The crystals weighed 15 grams which represents a 65 percent yield based on starting material.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.CO.[OH-].[Na+]>C1COCC1>[C:19]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][C:16]([C:14]([NH:13][C@@H:5]([C:4]([OH:28])=[O:3])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC[C@@H](NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid diethyl ester (250 mg, 0.65 mmol) in THF (6 mL) was added to MeOH (6 mL), followed by the addition of 1N NaOH solution (5.2 mL, 5.2 mmol, 8 eq.). The mixture was stirred at room temperature overnight. Reaction was complete as determined by HPLC. Solvents were removed by rotavap and a small amount of water (5 mL) was added to make a homogeneous solution. 1N HCl was added dropwise until the solution reached a pH of 4. The solid precipitate was collected by filtration, washed with EtOAc, and dried in vacuum oven. Product N-(1,1′-biphenyl-4-ylcarbonyl)-D-glutamic acid (189 mg) was isolated in 89% yield. MS (ESI) m/z 326.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17]CC4C=CC(OC)=CC=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.O.[O-:28]P([O-])([O-])=O.[K+].[K+].[K+]>OS(O)(=O)=O>[NH2:17][C:9]1[C:8]2[C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[S:14][C:13]=2[C:12]([C:15]([NH2:16])=[O:28])=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Reactant: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: NC(=O)c1cnc(N)c2c1sc1cc(Br)ccc12

Procedure:
A solution of 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile in conc. H2SO4 (0.04 M) was stirred at room temperature for 2 h. The mixture was poured into H2O, neutralized with K3PO4, filtered, washed with H2O and dried. The crude product was swished with MeOH to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)=[CH:33][CH:32]=1>O1CCOCC1>[F:27][C:26]([F:29])([F:28])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)=[O:39])=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)([OH:30])[C:22]([F:23])([F:24])[F:25]
Reactant: Nc1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 100 °C
Yield: 33.6 %

Procedure:
2-(4-((4-(4-Aminophenyl)piperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (0.231 mmol, 0.1 g) and phenyl pyridin-4-ylcarbamate (0.346 mmol, 0.074 g) were combined in dioxane (1 mL) in a Reactivial and heated to 100° C. for 2 days. The reaction mixture was concentrated at reduced pressure. The resulting residue was taken up in dichloromethane, washed with water, dried over sodium sulphate and concentrated at reduced pressure. The residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (43 mg). MS (ESI) m/z 555.2 [M+H]+
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[C:4]1=[O:17])#[N:13]
Reactant: COc1ccccc1-c1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: COc1ccccc1-c1ccc(S(=O)(=O)N[C@H]2CCN(Cc3cccc(C#N)c3)C2=O)cc1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 2'-methoxybiphenyl-4-sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2 to give the title compound as a white foam.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:7])=[O:6])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45](O)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:46]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]2[N:9]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:18])=[O:19])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:7])=[O:6])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C(c1ccccc1)c1ccccc1)S(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 79.2 %

Procedure:
To a solution of N-isopropyl-1-benzenesulfonylindole-2-sulfonamide (10.0 g, 26.42 mmol), triphenylphosphine (10.4 g, 39.63 mmol), and benzhydrol (7.30 g, 39.63 mmol) in 100 ml of tetrahydrofuran was dropwise added a solution of diethyl azodicarboxylate (6.24 ml, 39.63 mmol) in 100 ml of tetrahydrofuran with stirring, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 34.5 g of a crude product. The obtained crude product was purified with silica gel column chromatography (ethyl acetate/hexane=1/9) followed by crystallization from ethanol to give 11.4 g (yield: 79%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([NH:1][C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cnc(N)s1
Solvent: CC(=O)O
Product: CC(=O)Nc1ncc(C#N)s1
Yield: 80 %

Procedure:
2.14 g 2-Amino-5-cyanothiazole was dissolved in 10 ml acetic acid, and 1.8 ml acetic anhydride was added to carry out reaction at 100° C. for 30 min. The reaction product was cooled down, and filtered to obtain 2.5 g of a clay-solid having metallic luster (yield 80%), 1H NMR (DMSO-d6) 2.22 (3H, s), 8.36 (1H, s), 12.95 (1H, s).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH3:10][CH:11]1[CH2:13][NH:12]1>>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][N:12]1[CH2:13][CH:11]1[CH3:10])[CH2:7][CH2:8][CH3:9]
Reactant: CC1CN1
Reactant: C=CC(=O)OCCCC
Product: CCCCOC(=O)CCN1CC1C
Reaction time: 20 h

Procedure:
To 25.6 g (0.20 mol) of n-butyl acrylate (Aldrich) was added 19.0 g (0.30 mol) of 2-methylaziridine (Aldrich, 90%) to cause a mildly exothermic reaction. The reaction mixture was allowed to stand at room temperature for 20 hours. At that time analysis of the reaction mixture by NMR spectroscopy indicated complete absence of vinylic protons of the starting n-butyl acrylate and formation of the title compound. The excess 2-methylaziridine was removed at reduced pressure to leave 37.1 g (100%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>CN(C=O)C>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[C:18](=[O:20])[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-Bromo-2,5-dimethyl-4-nitrobenzene (1 g, 4.34 mmol) and tributyl(1-ethoxyvinyl)tin (1.88 g, 5.2 mmol) in DMF (20 mL), was added tetrakis(triphenylphospine) palladium (0) (250 mg, 5% mmol). The reaction tube was sealed, the mixture was purged with N2 for 3 min and then heated at 90° C. under N2 for overnight. The reaction was cooled to room temperature and poured into aqueous HCl (1N, 100 mL). The mixture was stirred for 1 hour, and then extracted with ethyl acetate (3×100 mL). The organic extracts were combined, washed with brine and concentrated. The crude product was purified with silica gel chromatography (20% ethyl acetate in hexanes) to afford 1-(2,5-dimethyl-4-nitrophenyl)ethanone as a yellow solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].N.[OH:28]O>C(O)C>[OH:1][C@H:2]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][C:4]([NH2:5])=[O:28]
Reactant: N#CC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OO
Agent: N
Solvent: CCO
Product: NC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 27.5 °C

Procedure:
To a stirring solution of (S)-3-hydroxy-4-trityloxybutanenitrile (5.15 g, 15.01 mmol) in 15 mL of ethanol at room temperature was added aqueous NH3 (50 mL) and H2O2 (100 vol.) (34 mL, 300.00 mmol) was added in portions while maintaining the temperature of the reaction mixture below 25° C. After complete addition, the resultant reaction mixture was stirred vigorously at 25-30° C. and the reaction progress was monitored by TLC. On completion of the reaction (overnight) as indicated by the TLC, the reaction volume was concentrated to about 50% of the original volume under reduced pressure and the resultant mixture was extracted with dichloromethane (3×75 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was evaporated to leave a residue, which was purified by column chromatography employing EtOAc-hexane (80:20) as eluent to afford (S)-3-hydroxy-4-trityloxy butanamide in almost quantitative yield. m.p. 96-100° C.; [α]27D=−18.08 (c 1.0, MeOH); IR (KBr) 3467, 3349, 3012, 2980, 2918, 2839, 1671, 1098, 1076 cm−1; 1HNMR (300 MHz, CDCl3) δ 2.36 (d, 2H, J=6.5 Hz), 3.13-3.16 (m, 2H), 3.28 (6S, 1H), 4.11-4.15 (m, 1H), 5.44 (br, s, 1H), 7.18-7.38 (m, 9H), 7.39-7.42 (m, 6H); Mass (EI) 361, 259, 243, 165, 77.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cnc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 15 %

Procedure:
5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (2.6 mmol) is dissolved in DMF (12 ml), 4-(methylsulfonyl)phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 120° C. in the microwave for 45 min. The reaction solution is pored into water and extracted with Methyltert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-2-nitro-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 15%. HPLC (method C): 1.65 min; LC-MS (method A): 1.534 min, 369.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([N+:9]([O-:11])=[O:10])[C:6](=[O:8])[N:7]=1.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:8][C:6]2[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:3]=[C:2]([NH2:1])[N:7]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Nc1nc(=O)c([N+](=O)[O-])c(-c2ccco2)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc(-c3ccco3)c2[N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A suspension of 2-amino-6-(2-furyl)-5-nitropyrimidine-4(1H)-one (1.00 g, 4.50 mmol) in dichloromethane (50 mL) was treated with triethylamine (0.941 mL, 6.75 mmol) and p-toluenesulfonyl chloride (944 mg, 4.95 mmol), stirred for 1 h, diluted with dichloromethane (50 mL), washed with 2-M HCl (20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (2:1)] to give the title compound (410 mg, 24%) as a yellow solid; NMR δH (400 MHz, CDCl3) 7.95 (2H, d, J 8.5 Hz), 7.59–7.57 (1H, m), 7.39 (2H, d, J 8.5 Hz), 7.23–7.21 (1H, m), 6.59–6.51 (1H, m), 5.39 (2H, br s), 2.48 (3H, s); Retention time 5.68 min.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[S:10]([O:13]S(C(F)(F)F)(=O)=O)(=[O:12])=[O:11].O[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]2.C(=O)([O-])O.[Na+]>ClCCl>[F:8][C:9]([F:22])([F:21])[S:10]([O:13][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]2)(=[O:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
Firstly 0.22 ml (0.00160 mol) of triethylamine and then 0.26 ml (0.00155 mol) of trifluoromethanesulphonic anhydride were added dropwise under argon to an ice-cold solution of 0.38 g (0.00152 mol) of tert.-butyl 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate in 7.5 ml of dichloromethane. The mixture was stirred at room temperature for 1 hour, poured into saturated sodium hydrogen carbonate solution, extracted with ethyl acetate and completely freed from the solvents. 0.66 g of oily crude tert.-butyl 6-(trifluoromethanesulphonyloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylate was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH:8]([CH2:36][CH2:37][CH3:38])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccccc1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 28.3 %

Procedure:
A solution of methyl 2-(4-methyl-6-phenyl-2-(piperidin-1-yl)pyrimidin-5-yl)acetate (150 mg; 0.461 mmol) in dry DMF (2.5 mL) was cooled to −15° C. LHMDS (0.507 mL; 0.507 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.068 mL; 0.691 mmol), After stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-10%) in heptane to give 48 mg (28%) of the title compound as a yellow oil. ESI/APCI(+): 368 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.Cl.[CH3:16][NH:17][O:18][CH3:19]>C(N(CC)CC)C>[CH3:19][O:18][N:17]([CH3:16])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93459.2 %

Procedure:
A mixture of 6-chloronicotinic acid (80 g, 0.48 mmol) and thionyl chloride (400 ml) was heated under reflux for 3 hours. The cooled mixture was evaporated under reduced pressure and the residue was dissolved in dichloromethane (600 ml). N,O-dimethylhydroxylamine hydrochloride (54.6 g, 0.56 mmol) was added to the mixture which was then cooled in ice and treated with triethylamine (200 ml). The suspension was stirred for 1 hour at room temperature and was then filtered. The filtrate was washed with dilute sodium hydroxide solution (2N, 300 ml), brine (200 ml) and dried (MgSO4). The solution was evaporated under reduced pressure then distilled to give the title compound, (90 g), b.p. 106°-110° C. at 0.5 mm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.CC(C)([O-])C.[K+].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@:28]1([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@@H:30]([CH3:31])[O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@:28]([OH:29])([C@H:30]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[CH3:31])[CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1
Reactant: OC1CCN(c2ncccn2)CC1
Reactant: C[C@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](OC1CCN(c2ncccn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 1-(pyrimidin-2-yl)piperidin-4-ol (19.4 mg, 0.08 mmol) in N,N-dimethylformamide (0.5 mL) was added potassium tert-butoxide (10.7 mg, 0.01 mmol), followed by stirring at room temperature for 2 hrs. The resulting solution was mixed with 1-(((2R,3R)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (20.0 mg, 0.08 mmol) and anhydrous potassium carbonate (13.2 mg, 0.01 mmol) and stirred at room temperature for one hr. The resulting reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous ammonium chloride solution and then with saline to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and concentrated by evaporation at reduced pressure. The concentrate was purified using silica gel chromatography to afford the title compound (yield 21%).