Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=12.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[C:25]([O:1][C:2]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=12)(=[O:27])[CH3:26]
Reactant: CCOC(=O)c1c(O)c2ccccc2c2nc3ccccc3nc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1c(OC(C)=O)c2ccccc2c2nc3ccccc3nc12
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 640 mg ethyl 5-hydroxybenzo[a]phenazine-6-carboxylate, 6 ml of acetic anhydride and two drops of pyridine was stirred overnight and poured into water. The precipitated solid was collected by filtration and recrystallized from ethanol to give 600 mg (91.1% yield) of ethyl 5-acetoxybenzo[a]phenazine-6-carboxylate as orange needles, m.p. 195°-196° C., Anal. Calcd. (%) for C21H16N2O4 : C, 69.99; H, 4.48; N, 7.77; Found: C, 70.12; H, 4.45; N, 7.63
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH2:18])[N:17]=2)[CH:12]=[CH:13][N:14]=1.Cl[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=1>CN(C=O)C>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([NH:18][C:16]2[N:17]=[C:10]3[C:9]([N:4]4[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]4)=[N:14][CH:13]=[CH:12][N:11]3[N:15]=2)[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=1
Reactant: O=C1CNCCN1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: Nc1nc2c(Cl)nccn2n1
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(N4CCNC(=O)C4)nccn3n2)cc(OC)c1
Temperature: 180 °C

Procedure:
Piperazin-2-one (1.1 eq), 8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine (1 eq) are dissolved in DMF and heated to 180° C. in a microwave for 1 h following general procedure 3. The intermediate is reacted with 1-chloro-3,5-dimethoxy-benzene under amination conditions as described in general procedure 3 giving the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3C=NC=C[CH:16]=3)=[CH:10][C:5]2=[N:4][C:3]=1[NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19].ClCC(NC(NCC)=O)=[O:26].C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[C:11]([C:9]1[CH:8]=[CH:7][N:6]2[CH:2]=[C:3]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[N:4]=[C:5]2[CH:10]=1)(=[O:26])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)ccn2c1Cl
Reactant: CCNC(=O)NC(=O)CCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1cn2ccc(C(C)=O)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 156.7 %

Procedure:
A mixture of compound (2) (0.4 g, 1.27 mmol), N-(chloroacetyl)-N′-ethylurea (0.3 g, 1.8 mmol) and N-ethyldiisopropylamine (0.33 g, 2.5 mmol) in dry DMF (“dimethylformamide”) (5 mL) was stirred at room temperature overnight. The mixture was diluted with water to give 0.49 g of (3) as a solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[CH:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][CH2:25]3)[CH:23]=2)[C:15](=[O:34])[N:14]([CH3:35])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[CH:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][CH2:25]3)[CH:23]=2)[C:15](=[O:34])[N:14]([CH3:35])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cn(C4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cn(C3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A mixture of 243g (80 mg, 0.12 mmol) and lithium hydroxide (100 mg, 2.4 mmol) in i-propanol/THF/water (2:2:1, 8 mL) was stirred at 35° C. for 30 mins. The reaction mixture was then concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with dichloromethane three times. The combined organic layer was concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 243 (28.0 mg, 30%). MS-ESI: [M+H]+ 625.4. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J=6.5 Hz, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.35-7.34 (m, 2H), 7.11 (d, J=1.0 Hz, 1H), 6.58 (s, 1H), 5.14 (bs, 1H), 4.54 (t, J=7.5 Hz, 2H), 4.43-4.40 (m, 4H), 4.23-4.11 (m, 3H), 3.99-3.96 (m, 1H), 3.91-3.84 (m, 1H), 3.59 (s, 3H), 3.43-3.39 (m, 1H), 2.77-2.76 (m, 2H), 2.62-2.57 (m, 2H), 2.47-2.46 (m, 2H), 1.94-1.89 (m, 6H), 1.79-1.78 (m, 2H), 1.69-1.66 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Product: COc1ccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[C:10](C1NC=CN=1)(C1NC=CN=1)=[O:11].CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36]>C1COCC1.O>[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)=[O:11])[S:7][CH:8]=1
Reactant: Nc1nc(CCl)cs1
Reactant: NCc1cccc(F)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Reaction time: 2.5 h
Yield: 58 %

Procedure:
A stirred mixture of Intermediate 1: 4-(chloromethyl)thiazol-2-amine hydrochloride (27.8 g, 0.15 mol), carbonyl diimidazole (25.5 g, 0.157 mol), and anhydrous THF (0.2 L) was treated dropwise with a solution of DIPEA (26.2 mL, 0.15 mol) in THF (20 mL) at 20-30° C. After 2-3 hours stifling, a solution of 3-fluorobenzylamine (18.5 mL, 0.164 mol) in THF (40 mL) was added. The reaction was diluted with water (200 mL) and THF was evaporated under reduced pressure. The residue was extracted with DCM (2×200 mL). The combined extracts were dried over sodium sulfate and concentrated to leave an orange resin that was purified by silica gel chromatography (acetone/hexane) to afford Intermediate 4 as a pale yellow solid (26 g, 58% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[CH:21])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][OH:27]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([C:20]#[C:21][C:23]2[CH:24]=[C:25]([CH2:26][OH:27])[CH:28]=[CH:29][CH:30]=2)[CH:17]=[N:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Reactant: OCc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#Cc2cccc(CO)c2)c1

Procedure:
A small resealable tube with stir bar was charged with 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-ethynylpyridine (168 mg, 583 μmol), copper(I) iodide (11 mg, 58 μmol, 0.1 equiv.), and bis(triphenylphosphine)palladium(II) chloride (43 mg, 58 μmol, 0.1 equiv.). To these reactants was added a solution of m-iodobenzyl alcohol (136 mg, 581 μmol, 1 equiv.). The mixture was purged with nitrogen through a needle, then the tube was capped, and the brown suspension was stirred at room temperature for 18.5 h. Solids were removed by suction filtration over celite and were washed with three portions of EtOAc (4 mL each). The solution was evaporated. TLC analysis (silica gel, EtOAc/hexane 3:1) showed, besides some PPh3 and baseline material, a single spot (Rf 0.3). The brown crude product was purified by CC on silica gel (24×2.5 cm, EtOAc/hexane 3:1 changing to 1:0 after appearance of the product). The product-containing fractions were evaporated and dried (50° C./oil pump) to yield 189 mg (82%) of a light-amber glass. 1H NMR (CDCl3, TMS, 250 MHz) δ 8.35 (d, 1H, J=1.4 Hz), 8.28 (d, 1H, J=2.7 Hz), 7.57 (narrow m, 1H), 7.49-7.43 (m, 1H), 7.43-7.32 (m, 3H), 4.73 (s, 2H), 4.53 (m, 1H), 4.35, 4.14 (ABq, 2H, J=10.1 Hz, low-field part br d, J=4.3 Hz, high-field part d, J=2.9 Hz), 3.90 (t, 2H, J=7.6 Hz), 2.47-2.21 (m, 3H, apparently including OH), 1.43 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ 156.0, 154.4, 144.3, 141.8, 137.4, 130.3, 129.8, 128.3, 127.2, 123.0, 122.2, 120.5, 92.5, 85.4, 79.7, 68.5, 63.9, 59.8, 46.9 (br), 28.2, 18.8; MS (EI) m/z 394 (M+, 2.7%), 321 (3.8%), 294 (14%), 293 (11%), 265 (10%), 238 (22%), 100 (23%), 57 (100%), 56 (73%).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17]>CCOCC>[N:8]1([C:6]([NH2:5])=[O:7])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: CCOCC
Product: NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.5 %

Procedure:
Chlorosulfonyl isocyanate (1.20 g, 8.4 mmoles) was added to a mixture of 2-oxindole (0.94 g, 7.1 mmole) in ether (30 ml) and the reaction stirred at room temperature for 20 hours. The ether was removed under vacuum and the residue treated with water (10 ml) and 1N HCl (10 ml). Ethyl acetate (125 ml) was added and the mixture stirred for one hour. The ethyl acetate phase was separated, washed with 1N HCl (1×50 ml), brine (2×100 ml) and dried (MgSO4). Concentration afforded 0.97 g (77%) of crude product. Recrystallization from ethanol gave 0.18 g; m.p. 178°-180° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH3:11].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[C:3]([NH:15][CH:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCC(N)CC
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-Bromo-2,4-dichloropyrimidine (4.56 g, 20 mmol) in Ethanol (9 mL) is added 1-Ethylpropylamine (2.6 mL, 22 mmol) and DIEA (7 mL, 40 mmol) at ambient temperature. The reaction mixture is stirred at ambient temperature for 16 hrs, then is concentrated in vacuo and the residue is purified by flash chromatography (silica gel, ethyl acetate:hexane=3:97 to 30:70) to give (5-Bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine. MS (ESI) m/z 280 (M+H)+. 1H NMR (CDCl3, 400 MHz) δ 8.1 (s, 1H), 5.24 (d, 1H), 4.1 (m, 1H), 1.58 (m, 4H), 0.93 (t, 6H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:18](O)([CH3:20])[CH3:19])[C:14]([NH:16][CH3:17])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CCN(S(F)(F)[F:34])CC>ClCCl>[CH:1]1([C:4]2[C:5]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:18]([F:34])([CH3:20])[CH3:19])[C:14]([NH:16][CH3:17])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CNC(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)O
Solvent: ClCCl
Product: CNC(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of 5-cyclopropyl-N-[3-hydroxy-3-methyl-1-(methylamino)-1-oxobutan-2-yl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 236b, 75 mg, 193 μmol) in dry dichloromethane (2 ml) under an argon atmosphere was added DAST (38.8 mg, 31.8 μl, 241 μmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with dichloromethane and extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (25 mg, 33%). MS (ESI, m/z): 392.6 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[S:7][C:6]=2[CH:32]=1.C(=O)(O)[O-].[Na+].[CH3:38][N:39]=[C:40]=[O:41]>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:40]([NH:39][CH3:38])=[O:41])=[CH:29][CH:30]=3)[S:7][C:6]=2[CH:32]=1
Reactant: CN=C=O
Reactant: COc1cc(Cc2c(-c3ccc(N)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Temperature: 25 °C

Procedure:
6-Hydroxy-3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]-2-[4-aminophenyl]benzo[b]thiophene (80 mg) was dissolved in THF (5.0 mL), treated with sodium bicarbonate (45 mg) while stirring at ambient temperature, cooled to 0° C. in an ice bath before treated with methyl isocyanate (42 μL) under argon. The reaction mixture. was stirred at ambient temperature for 24 h and concentrated. Chromatography with Et3N:MeOH:EtOAc (5:10:85) afforded the title compound (50 mg).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[O:15][CH2:14][CH2:13][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])=[CH:6][CH:7]=1)=[O:12]
Reactant: COC(=O)C(=O)c1ccc(S(=O)CCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(S(=O)CCOc2ccc3ccccc3c2)cc1
Yield: 72.7 %

Procedure:
A mixture of rac.-4-[[2-(2-naphthalenyloxy)ethyl]sulfinyl]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in hot methanol (5 mL) and sufficient tetrahydrofuran to dissolve the solids was treated with 1N sodium hydroxide (2.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.35 g of rac.-4-[[2-(2-naphthalenyloxy) ethyl]sulfinyl]-alpha-oxobenzeneacetic acid as a yellow solid, mp 157°-158° C.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[S:9]1[CH:13]=[CH:12][C:11]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10]1
Reactant: Oc1cccnc1Br
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Oc1cccnc1-c1ccsc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
2-Bromopyridin-3-ol (100 mg, 0.58 mmol), 3-thiophenyl boronic acid (88 mg, 0.69 mmol), sodium carbonate (184 mg, 2.07 mmol) and Pd2(dppf)2Cl2 (94 mg, 0.12 mmol) were dissolved in dimethoxyethane/water of 1 mL/1 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(thiophene-3-yl)pyridin-3-ol (50 mg, 48%).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:17]=[CH:16][C:10]2[N:11]=[C:12]([S:14][CH3:15])[O:13][C:9]=2[CH:8]=1)(=O)=O.ClCC1C=CC2N=C(SC)OC=2C=1.[CH3:31][O:32][C:33]1[C:41]([O:42][CH3:43])=[CH:40][C:36]2[N:37]=[CH:38][NH:39][C:35]=2[CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:43][O:42][C:41]1[C:33]([O:32][CH3:31])=[CH:34][C:35]2[N:39]([CH2:6][C:7]3[CH:17]=[CH:16][C:10]4[N:11]=[C:12]([S:14][CH3:15])[O:13][C:9]=4[CH:8]=3)[CH:38]=[N:37][C:36]=2[CH:40]=1
Reactant: CSc1nc2ccc(COS(C)(=O)=O)cc2o1
Reactant: COc1cc2nc[nH]c2cc1OC
Agent: CSc1nc2ccc(CCl)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(Cc3ccc4nc(SC)oc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of a 9:1 mixture of (2-(methylthio)benzo[d]oxazol-6-yl)methyl methanesulfonate and 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (1.45 g) from Step 1 of this Example and 5,6-dimethoxybenzimidazole (945 mg, 5.31 mmol) in anhydrous DMF (10 mL) at rt was added solid K2CO3 (1.47 g, 10.62 mmol). The mixture was stirred at rt for 3 h. The mixture was partitioned between water and DCM. The organic layer was separated and washed with water. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (430 mg) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.66 (m, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.32 (dd, J=9.0, 3.0 Hz, 1H), 7.19 (s, 2H), 5.53 (s, 2H), 3.76 (s, 6H), 2.73 (s, 3H). LCMS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.[CH:10]1[C:11]2[C:26](=[O:27])[C:25]([C:28]([OH:30])=[O:29])=[CH:24][N:23]([CH:31]3[CH2:33][CH2:32]3)[C:12]=2[CH:13]=[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:15]=1[F:16].O>CC(C)=O>[CH:10]1[C:11]2[C:26](=[O:27])[C:25]([C:28]([OH:30])=[O:29])=[CH:24][N:23]([CH:31]3[CH2:32][CH2:33]3)[C:12]=2[CH:13]=[C:14]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[C:15]=1[F:16].[O:1]=[C:2]1[O:6][C@H:5]([C:7]([O-:9])=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Agent: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@@H](C(=O)[O-])O1
Reaction time: 0.5 h

Procedure:
0.781 G (0.006 mole) of (S)-5-oxotetrahydrofuran-2-carboxylic acid and 1.99 g (0.006 mole) of Ciprofloxacin were added to 10 mL of distilled water. The resulting mixture was stirred for 30 minutes to dissolve it completely. After adding 20 mL of anhydrous acetone, the resulting solution was further stirred for 30 minutes under ice-cooling and allowed to stand to precipitate solids. The precipitated solids were filtered under reduced pressure through a filter paper (Whatman Filter Paper No. 1), washed three times with each 30 mL of anhydrous acetone,-and dried under vacuum to give 2.27 g of the titled compound as white solids. M.P. 214°-219° C. (decomposition) [α]D25 =-3.33 (H2O)
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[O-:13].[Na+].O.[Br-].[K+]>C(Cl)(Cl)Cl>[C:9]([OH:11])(=[O:13])[CH:8]=[CH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: [O-]Cl
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C=Cc1ccccc1
Yield: 98.5 %

Procedure:
50 parts of benzalacetone are added slowly and in portions, in the course of 20 minutes at from 30° to 35° C, to a mixture of 900 parts by volume of sodium hypochlorite solution (containing 149 parts of sodium hypochlorite), 150 parts by volume of water and 1 part of potassium bromide. After a further reaction time of 1.5 hours at 40° C, the chloroform which has formed is separated off, the aqueous phase is acidified and the organic phase which forms is combined with the chloroform phase. The aqueous solution is extracted by shaking with a further 100 parts by volume of chloroform and the chloroform is distilled from the combined organic phases. 49.5 parts (98.5% of theory) of cinnamic acid melting at 122° C are obtained. ##SPC5##
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=O.[CH:5]([C:8]1[C:9](=[O:16])[N:10](C)[C:11](S)=[N:12][N:13]=1)([CH3:7])[CH3:6]>C(O)(=O)C>[ClH:3].[Cl:4][C:1]1[N:10]([CH3:11])[C:9](=[O:16])[C:8]([CH:5]([CH3:7])[CH3:6])=[N:13][N:12]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)c1nnc(S)n(C)c1=O
Solvent: CC(=O)O
Product: CC(C)c1nnc(Cl)n(C)c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 34.6 g (0.35 mole) of phosgene in 600 ml of acetic acid are added 60 g (0.35 mole) of 6-isopropyl-4-methyl-3-mercapto-1,2,4-triazin-5(4H)-one. After the slightly exothermic reaction has subsided, the reaction mixture is stirred for 1 hour at 25° C. The precipitate is isolated by filtration and washed with a small amount of ethyl acetate, affording 64.5 g (90% of theory) of 3-chloro-6-isopropyl-4-methyl-1,2,4-triazin-5(4H)-one hydrochloride with a melting point of 120° C. (dec.).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>O>[C:23]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)(=[O:25])[CH3:24]
Reactant: COc1ccc(C2CCCNC2)cc1OC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C2CCCN(C(C)=O)C2)cc1OC
Temperature: 20 °C

Procedure:
A mixture of 8 g of 3-(3',4'-dimethoxyphenyl)-piperidine, 80 ml of benzene and 3.6 ml of acetic acid anhydride was stirred at 20° C for an hour and was then diluted with 100 ml of water. 500 ml of an aqueous solution saturated with sodium bicarbonate were added thereto and the mixture was stirred for an hour and then was decanted. The aqueous phase was re-extracted with ethyl acetate and the organic phases were washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 6.75 g of N-acetyl-3-(3',4'-dimethoxyphenyl)-piperidine.