Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 78.2 %

Procedure:
To a mixture of tert-butyl N-(4-bromobenzyl)carbamate (5.00 g), 3-benzyloxyphenylboronic acid (4.38 g), sodium carbonate (3.70 g), water (14 mL) and N,N-dimethylformamide (70 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.01 g), and the resulting mixture was stirred at 80° C. for 14 hours. The reaction mixture was cooled to room temperature and the insoluble material was filtered out. The filtrate was partitioned between ethyl acetate (110 mL) and water (50 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=6/1) to give the title compound (5.32 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:13]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(I)nn2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of 3-iodo-5-methoxy-1H-indazole (442 mg, 1.61 mmol) in THF (10.0 mL) at 0° C. was added KOtBu 1M in THF (2.26 mL, 2.26 mmol) and the mixture stirred at 0° C. for 30 min where it became a pale brown reddish solution then added MeI (320 mg, 141 μL, 2.26 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Then dissolved in toluene and purified by chromatography (80 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min to afford 3-iodo-5-methoxy-1-methyl-1H-indazole (355 mg, 1.23 mmol, 76.4%) as an off-white solid. MS (M+H)+=288.9 (>90% purity); 1H NMR (CDCl3) δ: 7.24 (d, J=9.1 Hz, 1H), 7.10 (dd, J=9.1, 2.6 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.06 (s, 3H), 3.88 (s, 3H). The regioisomer 3-iodo-5-methoxy-2-methyl-2H-indazole (89 mg, 309 μmol, 19.2%) was also obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=O)=[C:4]2[CH2:3]1.[Cl-].[NH4+:23].N>CO>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH2:23])=[O:19])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CN1Cc2c(C(N)=O)ncn2-c2ccccc2C1=O
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of 10.0 g of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 200 ml of methanol, 0.5 g of ammonium chloride and 30 g of ammonia (100%) is stirred in an autoclave under nitrogen (40 bar) at a temperature of 120° C. for 12 hours. After cooling and discharging the over-pressure, the mixture is evaporated to dryness. After partition of the residue between methylene chloride and water, the organic phase is dried and evaporated. The residue is recrystallised from ethyl acetate, there being obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide in the form of white crystals of melting point 274°-275° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([CH3:45])[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:42]1[CH2:41][CH2:40][N:39]([C:36]2[CH:35]=[CH:34][C:33]([CH3:45])=[CH:38][CH:37]=2)[CH2:44][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: Cc1ccc(N2CCNCC2)cc1
Product: Cc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 2.6 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-p-tolyl-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (1.8 mg, 2.6%) as light yellow oil. MS m/e=505.4 [M+H]+.
Reaction SMILES: C(O[CH:5]1[O:18][C@@H:17]([C:19]([F:22])([F:21])[F:20])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:7]([O:8][C:9](=[O:11])[CH3:10])[CH2:6]1)(=O)C.[BrH:23].C(O)(=O)C>>[C:9]([O:8][C@@H:7]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:17]([C:19]([F:22])([F:21])[F:20])[O:18][C@@H:5]([Br:23])[CH2:6]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC1C[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C(F)(F)F)O1
Reactant: Br
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)C[C@H](Br)O[C@H]1C(F)(F)F

Procedure:
Step (12'): Compound 77 (the mixture of the aforesaid anomers) is brominated in its solution in hydrogen bromide-acetic acid by a conventional method, whereby there is obtained 3,4-di-O-acetyl-2,6-dideoxy-6,6,6-trifluoro-α-L-lyxo-hexopyranosyl bromide [Compound 78 of the formula ##STR118## as a 1-bromo sugar. While, when Compound 77 is reacted with iodotrimethylsilane in anhydrous toluene, there is produced a corresponding 1-iodo sugar.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:29][OH:30]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14]([NH:29][OH:30])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 76.8 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropanoic acid (1.00 g, 2.71 mmol), N,N′-carbonyldiimidazole (461 mg, 2.84 mmol) and hydroxylamine hydrochloride (208 mg, 2.99 mmol) in tetrahydrofuran (6 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide as a white solid (800 mg, 77% yield): mp, 163.0-165.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 3.11 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.67 (t, J=7.8 Hz, 1H, NCH), 6.90 (br s, 2H, Ar), 7.02 (br s, 1H, Ar), 7.86 (br s, 4H, Ar), 8.79 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.67, 34.22, 50.18, 55.44, 63.71, 111.73, 112.36, 119.65, 123.11, 131.18, 131.21, 134.56, 147.67, 148.53, 165.97, 167.61. Anal. Calcd for C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.43; H, 5.04; N, 7.20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](#[N:11])[CH:9]=[CH2:10]>>[C:2]1([NH:1][CH2:10][CH2:9][C:8]#[N:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C=CC#N
Product: N#CCCNc1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 78.3 %

Procedure:
Silica was activated by heating it above 100° C. in vacuum and was then allowed to cool to room temperature under nitrogen. To the activated silica (10 g) was absorbed aniline (1.86 g, 20 mmol) and acrylonitrile (2.65 g, 50 mmol) and the flask was capped tightly. The contents were then stirred with a magnetic stirrer for 6 days at 60° C. After this time the mixture was cooled to room temperature and extracted with MeOH. The extracts were evaporated to dryness and the residue was Kugelrohr-distilled under high vacuum to give the product 3-(phenylamino)propanenitrile (2.29 g, 78.4%) as an oil which crystallised on standing; bp 120-150° C./1-2 Torr (lit bp 120° C./1 Torr), mp 50.5-52.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:17](=[O:18])[CH2:16][CH2:15][CH:14]3[C:19]([OH:21])=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:58][C:59]1[CH:60]=[C:61]([NH2:71])[CH:62]=[C:63]([C:65]2[N:69]([CH3:70])[N:68]=[N:67][N:66]=2)[CH:64]=1>CN(C=O)C>[Br:58][C:59]1[CH:60]=[C:61]([NH:71][C:19]([CH:14]2[CH2:15][CH2:16][C:17](=[O:18])[N:13]2[CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=3)[CH2:8][CH2:9]2)=[O:21])[CH:62]=[C:63]([C:65]2[N:69]([CH3:70])[N:68]=[N:67][N:66]=2)[CH:64]=1
Reactant: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)O)CC2)ccc1Cl
Reactant: Cn1nnnc1-c1cc(N)cc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)Nc3cc(Br)cc(-c4nnnn4C)c3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carboxylic acid as DIPEA salt (2.6 g) in DMF (100 ml) was added DIPEA (2.1 g), and HATU (4 g). 3-Bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenylamine (1.4 g) was added and the reaction stirred overnight at rt. The reaction mixture was filtered and the filtrate partitioned between water and EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (DCM:MeOH 100:0 to 95:5 gradient) to give the title compound (400 mg). Rf=0.19 (95:5 DCM:MeOH).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:7]=1[O:16][CH3:17])[CH2:3][CH:4]=[CH2:5].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.CCOCC>[CH3:17][O:16][C:7]1[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[CH:2]=[CH:3][CH:4]=[CH2:5]
Reactant: C=CCC(O)c1ccc(OC)c(OC)c1OC
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC=Cc1ccc(OC)c(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
A solution of 10.30 g (43.3 mmol) of 4-hydroxy-4-(2,3,4-trimethoxyphenyl)-butene and 15 mL (107 mmol) of triethylamine in 100 mL of dichloromethane was cooled in an ice bath and 3.7 mL (47.6 mmol) of methanesulfonyl chloride was added dropwise over 5 min. The ice bath was allowed to expire and the mixture was stirred overnight. The mixture was diluted with 300 mL of ether, washed with two 100 mL portions of 5% aqueous HCl and 100 mL of saturated aqueous NaHCO3, dried over MgSO4 and the solvent removed in vacuo to leave 8.14 g of crude 1-(2,3,4-trimethoxyphenyl)-1,3-butadiene as an orange oil.
Reaction SMILES: C1(N=C=N)CCCCC1.[CH3:10][CH:11]([CH3:30])[CH2:12][S:13]([CH2:16][CH:17]([CH2:21][C:22]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[C:18]([OH:20])=O)(=[O:15])=[O:14].[NH2:31][CH:32]([CH2:46][CH3:47])[C@@H:33]([C:35]1[N:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][N:36]=1)[OH:34]>C(Cl)Cl>[OH:34][CH:33]([C:35]1[N:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][N:36]=1)[C@@H:32]([NH:31][C:18](=[O:20])[CH:17]([CH2:16][S:13]([CH2:12][CH:11]([CH3:10])[CH3:30])(=[O:14])=[O:15])[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[CH2:46][CH3:47]
Reactant: CC(C)CS(=O)(=O)CC(CC(=O)N1CCOCC1)C(=O)O
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)CC(C)C)C(O)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of PS-bound N-cyclohexylcarbodiimide (HL 200–400 mesh cross linked with 2% DVB) from Novabiochem (436 mg, 0.841 mmol, 1.93 mmol/g loading) in methylene chloride (6 mL) was treated with 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid (154 mg, 0.480 mmol) in methylene chloride (3 mL) and stirred at room temperature for 10 minutes. A solution of (S)-2-Amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-butan-1-ol (96 mg, 0.412 mmol) in methylene chloride (3 mL) was added and the reaction mixture was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was evaporated under reduced pressure. Crude purified by flash chromatography eluting with a mixture of ethyl acetate and heptane to give N-{(S)-1-[Hydroxy-(5-phenyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide as an off white solid (41 mg) (mixture of diastereoisomers).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15](C(O)=O)=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12>C(OCC)(=O)C>[CH:15]1[N:14]=[CH:13][N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[N:3]3[CH2:20][CH2:19][C@H:4]3[C:5]=12
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2-n2cncc2[C@@H]2CCN12

Procedure:
1.3 g (4.8 mmol) of (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid are heated to 240° until the gas evolution ceases. After recrysallization from ethyl acetate, there is obtained (S)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of melting point 195°-197°.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:26]=[CH:25][C:15]([CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:14][CH:13]=2)[N:11]=1)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]1[CH2:3][CH:2]1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:25][CH:26]=2)[N:11]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2csc(NC(=O)C3CC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2csc(NC(=O)C3CC3)n2)cc1
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 4-[(2-cyclopropanecarbonyl-amino)-thiazol-4-yl]-N-(tert-butoxycarbonyl)-benzylamine (2.381 g, 6.376 mmol) in anhydrous DCM (53 mL), add trifluoroacetic acid (45 mL) at room temperature and stir overnight. Concentrate the reaction mixture in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, add silica gel (14 g) and concentrate to a powder. Load the powder on to a dry column attached to an Analogix® column (150 g) and purify by preparative liquid chromatography (0:1 to 1:4 2M ammonia in methanol/DCM over 33 min, 1:4 2M ammonia in methanol/DCM over 33 min; 35 mL/min) to afford the title compound (1.668 g, 96%) as an off-white solid. MS (ES+) m/z: 274.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].[I-].[K+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:19][O:18][C:16](=[O:17])[CH:15]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C)c(C)c1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
A mixture of 2.70 g of 3,4-dimethylphenol and 0.89 g of 60% sodium hydride-oil dispersion in 40 ml of tetrahydrofuran is stirred at room temperature for 1 hour. To the mixture is added 3.7 g of potassium iodide, 1 ml of hexamethylphosphoramide and dropwise a solution of 8.55 g of methyl bromo{p-[(p-chlorophenoxy)methoxy]phenyl}acetate in 30 ml of tetrahydrofuran. The mixture is refluxed for 18 hours and worked-up as described in Example 5 to give 10.4 g of a gum. Chromatography over silica gel with dichloromethane as eluent gives the product as a gum.
Reaction SMILES: C([O-])(O)=O.[Na+].O.[C:7]1([OH:15])[CH:14]=[C:12]([CH3:13])[CH:11]=[C:9]([OH:10])[CH:8]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:27][CH3:28])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1>C(OCCCC)CCC.O1CCCC1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:27][CH3:28])=[C:21]([S:23]([O:10][C:9]2[CH:8]=[C:7]([OH:15])[CH:14]=[C:12]([CH3:13])[CH:11]=2)(=[O:24])=[O:25])[CH:22]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Yield: 295.3 %

Procedure:
Saturated aqueous NaHCO3 (70 mL) was added to a solution of 5-chloro-2-methoxynenzensulfonyl chloride (3.83 g, (15.9 mmol and orcinol monohydrate (3.39 g, 23.9 mmol) in di-n-butyl ether (53 mL) and tetrahydrofuran (17 mL). The biphasic solution was mixed vigorously at 50° C. for 7 h then at ambient temperature overnight. The reaction mixture was combined with that from a previous reaction (which used 4.53 g 18.8 mmol of 5-chloro-2-methoxybenzenesulfonyl chloride), the layers were separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered, and evaporated to give 18.25 g of a clear brown oil. The product was purified by flash column chromatography (1% to 4% ethyl acetate in dichloromethane) to give the title compound (9.86 g, 86%) as a pale yellow oil which crystallized upon standing. 1H-NMR (300 MHz, CDCl3) (7.81 (d, 1H, J=2.6 Hz), 7.55 (dd, 1H, J=8.9, 2.6 Hz), 7.02 (d, 1H, J=8.9 Hz), 6.53 (m, 2H), 6.41 (t, 1H, J=2.2 Hz), 3.99 (s, 3H), 2.24 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C14H13ClO5S: 351.0 (M+Na). Found: 351.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-:15].[Na+].Cl>CS(C)=O.O>[CH3:14][O:13][C:6]1[C:7]([C:8]([OH:10])=[O:9])=[CH:12][C:3]([C:1]([NH2:2])=[O:15])=[CH:4][CH:5]=1
Reactant: [OH-]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(N)=O)cc1C(=O)O
Temperature: 80 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
Methyl 5-cyano-2-methoxybenzoate (2 g) prepared in step A was dissolved in 24 mL of dimethyl sulfoxide, and 12 mL of a 1 M aqueous solution of sodium hydroxide was added. After stirring for 4 hours and a half at 80° C., the mixture was cooled in an ice bath, and adjusted to pH of about 4 with the use of 10 mL of 1 M hydrochloric acid. The resulting solution was diluted with 200 mL of water, and cooled for several hours in a refrigerator. The precipitate formed was separated by filtration, washed with cold water, and then dried over diphosphorus pentoxide under reduced pressure to obtain 1.3 g (63%) of 6-methoxyisophthalamic acid.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:6]=1)=[O:4].[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[F:26][C:27]([F:31])([F:30])[CH2:28][NH:29][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:6]=1)=[O:4]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Product: O=C(NCC(F)(F)F)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Yield: 21 %

Procedure:
As described for example 43 g, 3-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (25 mg, 21%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=414.0 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].Br[CH2:22][CH3:23]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([CH2:22][CH3:23])[CH:18]=[C:13]1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CCBr
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc2c(n1)-c1c(nc3ccccc3c1N)CC2
Temperature: 25 °C

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (3.0 g) in dry DMF (90 ml) was added NaH (60%)(0.63 g) slowly. The reaction was stirred at room temperature for a half hour, bromoethane (1.2 ml) was added and the reaction was stirred at room temperature overnight.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[C:32]([CH:33]=O)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:32]3[C:23](=[O:22])[NH:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1CNC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A mixture of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 130 mg, 0.448 mmol), 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (65 mg, 0.448 mmol) and 3 Å molecular sieves (100 mg) in methanol (6.0 mL) was heated at reflux for 2.5 hours under nitrogen atmosphere. It was cooled to 0° C. and sodium triacetoxy borohydride (189.5 mg, 0.996 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and purified through silica gel plug (eluting with 15% methanol in methylene chloride) to give title compound (71 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[C:13](NC(=NC(OC)=O)SC)(OC)=[O:14]>CN(C=O)C>[O:14]=[C:13]1[NH:12][C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1]1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
20 g (0.12 mol) of methyl 3,4-diaminobenzoate and 24.8 g (0.12 mol) of N,N'-dicarbomethoxy-S-methylisothiourea in 180 ml of DMF are heated under reflux for 4 hours. The DMF is then removed by distillation, the residue is vigorously stirred with water, and the crystals which have separated out are filtered off with suction and washed with water. After drying of the substance at 40° C. in vacuo, the product is suspended in acetone and then filtered off with suction.