Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:17]([CH3:19])[CH3:18])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Yield: 77.7 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and isopropylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-isopropyl-2-(trifluoromethoxy)benzenesulfonamide (0.29 g, 78%) was provided after purification. MS (ESI) m/z 362. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C)C=O.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[C:13]#[N:14]>O>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[S:2][CH3:1])[C:13]#[N:14]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C#N)cc1F
Reaction time: 0.33 h

Procedure:
Sodium thiomethoxide (3.88 g, 55.3 mmol) was added to a dimethylformamide (100 mL) solution of 3,4-difluorobenzonitrile (7.00 g, 50.3 mmol) over 20 minutes under ice water cooling, and the mixture was further stirred for 20 minutes at the same temperature. Water (200 mL) was added to the reaction mixture, and the solid precipitated therefrom was collected by filtration and washed with water. Thus, a crude product of the title compound was obtained. The crude product thus obtained was dissolved in ethyl acetate, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Thus, the title compound (7.30 g, yield: 87%) was obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:14]([O:21][P:22]([O:32][CH2:33][CH2:34][OH:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:35][CH2:34][CH2:33][O:32][P:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=P(OCCO)(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-Nitrophenyl chloroformate (1.01 g; 5.04 mmol) was added at 0° C. under argon atmosphere to a solution of 2-[di (benzyloxy)phosphoryloxy]ethanol (1.62 g; 5.09 mmol) and triethylamine (0.7 ml; 5 mmol) in dichloromethane (20 ml). The mixture was stirred at ambient temperature for 30 minutes, evaporated and purified by flash chromatography, eluting with petroleum ether/ethyl acetate (40/60) to give 2-[di(benzyloxy)phosphoryloxy]ethyl 4-nitrophenyl carbonate.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=1)[CH:10]=2)=[O:5])C.[C:26]([O:30][C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][NH2:34])([CH3:29])([CH3:28])[CH3:27]>CCO>[C:26]([O:30][C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][NH:34][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=1)[CH:10]=2)=[O:5])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: CCOC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O
Yield: 59.2 %

Procedure:
A mixture of 7-(4-chloro-3-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (45 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (65 mg) in EtOH (0.5 mL) was microwaved at 145° C. for 3 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (36 mg). LC MS ESI+: 489 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][C:15]3[O:16][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:18][N:19]=3)=[CH:6][CH:7]=2)=[CH:33][CH:32]=1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2ccc(-c3onc(C)c3Nc3nnc(-c4ccccc4)o3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 4-ethoxycarbonylphenylboronic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and propionyl chloride
Reaction SMILES: C(O)=O.C(O[C:8](=[O:10])[CH3:9])(=O)C.[O:11]=[C:12]1C[NH:16][CH2:15][CH2:14][NH:13]1>C(Cl)Cl>[CH:12]([N:13]1[CH2:14][CH2:15][NH:16][C:8](=[O:10])[CH2:9]1)=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CNCCN1
Solvent: O=CO
Solvent: ClCCl
Product: O=CN1CCNC(=O)C1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To 80 ml of formic acid was added 28 ml of acetic anhydride at room temperature, and the mixture was stirred at 60° C. for 20 minutes. After stirring at room temperature for further 15 minutes, the reaction mixture was added dropwise to a solution of 4.2 g of 2-oxopiperazine in 400 ml of methylene chloride at 0° C. over a period of 1.25 hours, and the resulting mixture was stirred at 0° C. for further 30 minutes. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was recrystallized from acetone/hexane to give 3.0 g (56%) of 1-formyl-3-oxopiperazine.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[O:19][C:18](S)=[N:17][N:16]=1.C(O)CCCC>C(Cl)(Cl)Cl>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:18]1[O:19][C:15]([C:11]3[NH:10][CH:14]=[CH:13][CH:12]=3)=[N:16][N:17]=1)[CH2:3][CH2:2]2
Reactant: Sc1nnc(-c2ccc[nH]2)o1
Reactant: C1CN2CCC(CC2)N1
Solvent: CCCCCO
Solvent: ClC(Cl)Cl
Product: c1c[nH]c(-c2nnc(N3CCN4CCC3CC4)o2)c1
Reaction time: 15 h

Procedure:
A mixture of 1,4-diazabicyclo[3.2.2]nonane (3.02 g, 23.9 mmol), 5-(1H-pyrrol-2-yl)-1,3,4-oxadiazole-2-thiol (5.0 g, 20.9 mmol) and 1-pentanol (50 ml) was stirred for 15 h. The mixture was solved in chloroform and was filtered through celite. The mixture was purified three times by silica gel chromatography, using chloroform, methanol and aqueous ammonia (89:10:1). The product was dried and evaporated. Yield 382 mg (6%). LC-ESI-HRMS of [M+H]+ shows 260.15096 Da. Calc. 260.15059 Da, dev. 1.4 ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:18]=[N:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:19].[F:20][C:21]([F:27])([F:26])[S:22]([NH2:25])(=[O:24])=[O:23].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:20][C:21]([F:27])([F:26])[S:22]([NH:25][CH2:13][C:12]1[CH:15]=[CH:16][N:17]=[CH:18][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:19])[N:2]([CH3:1])[C:6]=2[CH:7]=1)(=[O:24])=[O:23]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: Cn1c(=O)oc2ccc(-c3cnccc3C=O)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)oc2ccc(-c3cnccc3CNS(=O)(=O)C(F)(F)F)cc21
Temperature: 70 °C
Reaction time: 15 h
Yield: 22.2 %

Procedure:
A mixture of 3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)isonicotinaldehyde (128 mg, 0.5 mmol), trifluoromethanesulfonamide (94 mg, 0.63 mmol), acetic acid (60.5 mg, 1 mmol) and 4° A molecular sieves in 1,2-dichloroentane (2 mL) heated at 70° C. under nitrogen for 6 h. The suspension was cooled to room temperature and sodium triacetoxyborohydride (excess amount) was added. The reaction mixture was further stirred at room temperature for an additional 15 h. The mixture was diluted with dichloromethane (20 mL) and filtered through a pad of celite. The filter cake was thoroughly washed with an additional 30 mL of dichloromethane. The combined filtrates were washed with NaHCO3 (saturated solution). The aqueous phase was extracted with dichloromethane (2×50 mL). The organic phases were combined, dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (0-100% ethyl acetate in heptane, v/v) and yielded 43 mg of 1,1,1-trifluoro-N-((3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-4-yl)methyl)methane-sulfonamide as colorless solid ESI-MS m/z; 388.0 [M+1]+, Retention time 1.19 min; 1HNMR (MeOD, 400.342 MHz): δ 3.43 (s, 3H), 4.41 (5, 2H), 7.12 (dd, J=8.2, 1.8 Hz, 1H), 7.15 (s, 1H), 7.21 (d, J=1.6 Hz, 1H), 760 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.60 (d, J=8.2 Hz, 1H); and 5-(4-(hydroxymethyl)pyridin-3-yl)-3-methylbenzo[d]oxazol-2(3H)-one 37 mg as pinkish solid ESI-MS m/z: 257.0 [M+1]+, Retention time 0.84 min; 1HNMR (MeOD, 400.342 MHz): δ 3.3 (s, 3H), 4.41 (s, 2H), 7.12 (dd, J=1.76, 8.2 Hz, 1H), 7.21 (d, J=1.56 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.60 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.60 (d. J=5.2 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:19](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([NH2:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CCc1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (1.08 g), triethylamine (1.1 ml) and tetrahydrofuran (100 ml) was added ethyl chlorocarbonate (0.6 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (20 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-(5-phenyl-4-isoxazolyl)propionamide (0.82 g, yield 78%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 151–152° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:14][OH:15]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][O:9]2)=[N:3][CH:4]=1
Reactant: OCC1CCCO1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCC2CCCO2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahydrofuran-2-methanol by the method of Example 10(b).
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][NH:8][C:7](=S)[C:6]1=[O:15].[C:24]([NH:32][NH2:33])(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C(O)CCC>[Cl:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][N:8]2[C:24]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:32][N:33]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1C(=S)NCC(C2CC2)N1Cc1cccc(C(F)(F)F)c1Cl
Reactant: NNC(=O)c1cccnc1
Solvent: CCCCO
Product: O=C1c2nnc(-c3cccnc3)n2CC(C2CC2)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of (±)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-cyclopropyl-3-thioxopiperazin-2-one (100 mg, 0.28 mmol) and nicotinohydrazide (38 mg, 0.28 mmol) in 1-butanol (3 mL) was heated at 130° C. for 16 h. After cooling to rt, the precipitate was filtered and washed with hexanes to afford the desired product as a white solid (68 mg, 55%). MS (ESI): mass calcd. for C21H17ClF3N5O, 447.1; m/z found, 448.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=1.7 Hz, 1H), 8.79 (dd, J=4.8, 1.6 Hz, 1H), 8.21-8.16 (m, 1H), 7.74-7.61 (m, 2H), 7.52 (dd, J=7.9, 4.9 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 5.47 (d, J=15.8 Hz, 1H), 4.76 (d, J=15.8 Hz, 1H), 4.52 (dd, J=12.7, 4.3 Hz, 1H), 4.41 (dd, J=12.7, 3.1 Hz, 1H), 3.18-3.11 (m, 1H), 1.08-0.90 (m, 1H), 0.84-0.69 (m, 1H), 0.59-0.47 (m, 2H), 0.20-0.14 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH3:32])=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[N:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCOc1ccc(Br)cn1
Product: CCOc1ccc(-n2c(C)c(Sc3cccc(C(=O)OC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromo-2-ethoxypyridine.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:33][C:34](=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)C>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][C:34]([OH:33])=[O:43])=[CH:41][CH:40]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)Cc1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and (4-amino-phenyl)-acetic acid ethyl ester according to the procedure of Example 66. MS m/z 541.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[N:10][OH:11])[NH2:9])=[N:6][CH:7]=1.[C:12](OC(=O)C)(=O)[CH3:13]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:12]([CH3:13])[O:11][N:10]=2)=[N:6][CH:7]=1
Reactant: NC(=NO)c1ccc(Br)cn1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(Br)cn2)no1
Temperature: 100 °C
Yield: 32.1 %

Procedure:
To a solution of 5-bromo-N′-hydroxypicolinimidamide II (0.75 g, 3.50 mmol) in acetic acid (50.0 mL) was added acetic anhydride (0.75 mL, 7.0 mmol) and the resulting reaction mixture was heated to 100° C. for 2 h. After the completion of reaction (TLC monitoring), acetic acid was distilled off, added water (25.0 mL) and extracted with EtOAc (2×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated to obtain the desired product (0.27 g, 45%). MS: 240.01 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH3:13])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:14]>C(O)(C)(C)C>[C:1]1([C@@H:7]([CH3:13])[C:8]([NH2:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: CCOC(=O)C(C)c1ccccc1
Solvent: CC(C)(C)O
Product: C[C@@H](C(N)=O)c1ccccc1
Yield: 90 %

Procedure:
A mixture of 1.6 g of ethyl 2-phenyl-propionate and 18 ml of tert-butanol is treated at 50° C. with stirring with 0.35 g of lipase from Candida antarctica (Novozym 435, activity 7000 PLU/g). Ammonia is then passed into the reaction mixture with stirring at 50° to 53° C. until it is saturated. The mixture is stirred at 50° to 53° C. for a further 8 hours and during the course of this a slow stream of ammonia is continuously passed through the apparatus. The mixture is then worked up in the manner indicated in Example 1. 0.6 g (90% of theory, conversion 46 area per cent GC) of (R)-2-phenyl-propionamide having an ee value of >98% is obtained.
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:8]=1.[N:22]1([C:28]2[N:29]=[C:30]([CH2:35][C:36]([O-])=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[Na+]>CN(C)C=O>[N:22]1([C:28]2[N:29]=[C:30]([CH2:35][C:36]([NH:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH2:13][C:9]3[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=3)=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1OCc1cccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.2 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-M′-ethylcarbodiimide hydrochloride and 366 mg of 2-(pyridin-3-ylmethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rised with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 150 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[2-(pyridin-3-ylmethoxy)phenyl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:3]=1)(=[O:27])[CH3:26]
Reactant: O=c1[nH]c(-c2cccc(O)c2)nc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 105 °C
Reaction time: 3.5 h

Procedure:
To 2-(3-hydroxyphenyl)quinazolin-4(3H)-one (11.0 g, 45.98 mmole) was added pyridine (16.06 mL, 15.71 g, 0.199 mmole) followed by addition of acetic anhydride (145 mL) and the reaction mixture was heated to 105° C. and stirred for 3.5 h. The reaction mixture was cooled to ambient temperature and then poured onto ice-water (800 mL) and stirred for 2 h. The solid was then filtered and washed with water, ethanol, ether and finally hexane and dried for several hours under high vacuum to give 3-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate. (8.4 g, mmol, 65%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)(=[O:26])[CH3:25]>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24](=[O:26])[CH3:25])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1c(C(=O)c2ccccn2)cnc2c(C(F)(F)F)cccc12

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-acetylphenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 421 ([M+H]+); 1H NMR (CDCl3) δ 9.24 (s, 1H), 8.63 (d, J=4.16 Hz, 1H), 8.13 (d, J=7.03 Hz, 1H), 7.93 (m, 2H), 7.81 (m, 1H), 7.51 (m, 5H), 7.18 (m, 1H), 2.41 (s, 3H).
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].C(O)[C@@H](O)C(O)[C@@H](O)[CH2:15][OH:16]>>[OH:10][CH2:1][C@@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:15][OH:16])[OH:9])[OH:7])[OH:5])[OH:3]
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: OC[C@@H](O)C(O)[C@@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Xylitol (for example, “Xylitol P” manufactured by Nikkne Chemical and Synthetic Industry Co., Ltd., “Xylisorb” manufactured by Roquette, and “Xylit P” manufactured by Towa Chemical Industries Co, Ltd.; etc.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[C:5]=1[C:12]([O:14][CH3:15])=[O:13].[H][H].[ClH:19]>CO.[Pd]>[ClH:19].[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH2:11])[C:5]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cccc(C#N)c1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(CN)c1C(=O)OC
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of methyl-3-cyano-2-(methoxycarbonyl)benzoate (12.3 g, 57 mmol) in methanol (250 ml) and 4N HCl (40 ml) was added 10% Pd/C (1.2 g). The mixture was hydrogenated under 50 psi of hydrogen in a Parr Type Shaker for 17 hours. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was further evaporated with ethanol (2×25 ml) and toluene (25 ml) and dried under vacuum. The resulting solid was slurried in ether (50 ml) for 1 hour. The slurry was then filtered and dried to give 13.46 g (90%) of the product as a white solid: 1H NMR (DMSO-d6) δ 8.79 (b, 2H), 7.94 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 4.03 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H); 13C NMR (DMSO-d6) δ 167.58, 166.12, 133.41, 133.18, 132.28, 130.62, 129.49, 52.99, 52.92, 39.25.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][CH3:13].[CH3:14]N(C(OC)OC)C.N1CCCC1>CN(C=O)C>[CH3:13][O:12][C:3]1[C:4]([CH3:11])=[CH:5][CH:6]=[C:7]2[C:2]=1[CH:1]=[CH:14][NH:8]2
Reactant: COC(OC)N(C)C
Reactant: COc1c(C)ccc([N+](=O)[O-])c1C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1c(C)ccc2[nH]ccc12
Temperature: 125 °C
Reaction time: 3 h
Yield: 16.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-nitroanisole (3.26 g, 18 mmol) in dry DMF (36 ml) were added DMF dimethyl acetal (2.51 g, 19.8 mmol, 2.8 ml) and pyrrolidine (1.8 ml). The reaction mixture was stirred under N2 at 125° C. for 3 h, cooled to rt and concentrated in vacuo. The oily residue was dissolved in a mixture of toluene-acetic acid (5:3, 36 ml) and added to a stirred mixture of iron powder (18 g) and silica gel (70-230 mesh, 45 g) in a mixture of toluene-acetic acid (5:3, 234 ml). The mixture was then heated at reflux under N2 for 1 h, cooled to rt, diluted with CH2Cl2 and filtered. The filter cake was washed thoroughly with CH2Cl2 and the combined filtrates were washed successively with Na2S2O5 solution, saturated aq. NaHCO3 and brine, dried and evaporated. The residue was flash chromatographed [(CH2Cl2-hexanes (3:2)] to give 27 as a colourless viscous oil (0.48 g, 16%) which was used without further purification; δH (90 MHz) 8.10 (1 H, br s, NH), 6.88-7.08 (3 H, m, 2-, 6-, and 7-H), 6.50-6.64 (1 H, m, 3-H), 3.98 (3 H, s, OMe) and 2.32 (3 H, s, Me).