Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C1C(=O)N([I:18])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:18])=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: CCc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(N)nc(Cl)c1I
Temperature: 25 °C

Procedure:
25.0 g (159 mmol) 4-Chloro-6-ethyl-pyrimidin-2-ylamine in 1.0 L acetic acid is cooled to 0° C. and 36.0 g (159 mmol) NIS is added in one portion. The reaction mixture is stirred at RT until conversion of the starting material is completed (18 h). An aqueous solution of 5% Na2S2O3 and 10% NaHCO3 is added until the mixture decolorizes. The formed precipitate is filtered off, taken up with water and the suspension stirred at RT for 60 minutes. The product is filtered off, washed with diethyl ether and dried in vacuo at 40° C. Yield: 40.3 g (90%). 1H NMR (DMSO-d6) δ: 7.2 (s, 2H), 2.7 (quart., 2H), 1.1 (tripl., 3H). HPLC-MS: tR=1.62 min , (M+H)+=284.
Reaction SMILES: Cl.[Br-].[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:17]3=[C:18]([CH2:21][N+](CC)(CC)CC)[CH:19]=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[F:10].Cl.[Cl:30][CH2:31][CH2:32][NH:33][CH2:34][CH2:35][Cl:36].CCN(C(C)C)C(C)C>CC#N>[Cl:30][CH2:31][CH2:32][N:33]([CH2:21][C:18]1[CH:19]=[CH:20][N:16]2[C:17]=1[C:12]([NH:11][C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:4]([Cl:3])[CH:5]=1)=[N:13][CH:14]=[N:15]2)[CH2:34][CH2:35][Cl:36]
Reactant: ClCCNCCCl
Reactant: CC[N+](CC)(CC)Cc1ccn2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: Cl
Agent: [Br-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2ncnn3ccc(CN(CCCl)CCCl)c23)cc1Cl
Temperature: 60 °C

Procedure:
A mixture of Compound 1E (50 mg, 0.1 mmol), bis-(2-chloroethyl)amine hydrochloride (18 mg, 0.1 mmol), DIEA (36 μl, 0.2 mmol) in CH3CN (0.5 ml) was heated to 60° C. for 3 h. The mixture was cooled to rt and concentrated to give Compound 133A which was used directly in next step. 133A had an analytical HPLC retention time=2.986 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=416.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[C:32]([CH3:34])[CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:40]6[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]6)=[C:32]([CH3:34])[CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Cc1cc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cnc1F
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cnc1N1CCN(C)CC1
Temperature: 150 °C
Yield: 30.8 %

Procedure:
Compound 436 (200 mg, 0.41 mmol) was dissolved in NMP (2 mL), N-Methyl-piperazine (82 mg, 0.82 mmol) was added in it. The reaction mixture was heated by mw at 150° C. for 90 min. The reaction mixture was concentrated in vacuo, dissolved in DCM (20 mL). And the organic layer was washed by water, dried by Na2SO4, concentrated in vacuo, and separated by prep. TLC (EtOAc/Hexanes=1:3) to give 437 (72.1 mg, yield: 31%). 1H NMR (DMSO-d6, 400 MHz): δ9.759 (s, 1H), 8.58 (s, 1H), 8.47 (t, J=11.8 Hz, 1H), 8.25 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.63-7.53 (m, 2H), 7.29-7.19 (m, 2H), 7.08 (d, J=11.2 Hz, 2H), 4.36 (t, J=4.8 Hz, 2H), 4.20-4.11 (m, 2H), 3.74-3.68 (m, 2H), 3.29 (s, 6H), 2.76 (s, 3H), 2.32 (s, 3H). LC-MS (ESI): m/z=572 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].[C:16]1([CH2:22][CH2:23][C:24](Cl)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[C:16]1([CH2:22][CH2:23][CH2:24][N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[CH2:9]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(C2CCCNC2)ccc1F
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Yield: 93.1 %

Procedure:
The title compound was prepared by acylation of 209 mg (1 mmole) of the 3-(4-fluoro-3-methoxyphenyl)piperidine from Preparation 8, Part C, with 253 mg (1.5 mmole) of 3-phenylpropionyl chloride in toluene, followed by reduction with 175 mg (4.6 mmole) of lithium aluminum hydride in tetrahydrofuran, substantially according to the procedure of Preparation 3. This afforded 305 mg (93% yield) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=[O:33])[CH2:30]2.O>O1CCCC1>[OH:33][C:24]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH:23]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]1[CH2:26]3)[CH2:30]2
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)C3CC4CC(C3)CC2C4)cc1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 19.8 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred with 4.25 g of adamantanone for 1 hour at -70°, and heated to 25°. Then water is added, the mixture is extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 9 g of crude 4-(2-hydroxyadamant-2-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]CCCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C1COCC1.O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 24 h

Procedure:
Imidazole (Intermediate L1, available from Aldrich, 20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to benzene (320 mL). The reaction was stirred for 48 h at rt and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude produce (˜0.5 mmHg, 115-118° C.) afforded dimethylsulfamoyl) imidazole (Intermediate L2) 38.7 g (76%) as a clear and colorless oil. Upon cooling the product solidifies to give white crystals. 1-(Dimethylsulfamoyl) imidazole (Intermediate L2) (18.8 g, 0.11 mol) was added to THF (430 mL). The solution was cooled to −78° C. A solution of n-BuLi (70.9 mL, 1.6 M in hexane) was added dropwise to the reaction mixture. Upon completion, the solution was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (TBSCl) (17.8 g, 0.12 mol) in THF (50 mL) was added via cannula to the mixture. After the addition was completed the reaction mixture was warmed slowly to rt and stirred for 24 h. The mixture was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over Na2SO4. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography on SiO2 with 20% ethyl acetate/hexane afforded 1-dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (Formula 13) as a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: Oc1ccccc1F
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1ccccc1F
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 2-fluorophenol (1) (15 g), 3-bromopropanoic acid (20 g) and NaOH (11 g) was refluxed in 50 mL of water. The solution was cooled to room temperature and acidified to pH 2 with 3 M HCl. The resulting precipitate was isolated by filtration to yield 9.27 g of title compound as a white solid. The filtrate was extracted three times with EtOAc to yield 2.5 g of less pure compound (2).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1)[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:22]=2)=[CH:19][CH:20]=1)[CH3:13]
Reactant: CCOc1ccc(C#N)cn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 19.7 %

Procedure:
A mixture of methyl thiosalicylate (1.85 g, 11.0 mmol), 2-ethoxy-5-cyanopyridine (1.48 g, 10.0 mmol), triethylamine (1.80 ml, 12.9 mmol) and toluene (10 ml) was refluxed under nitrogen atmosphere for 18 hrs. The reaction mixture was concentrated. The residue was combined with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from chloroform-ethyl acetate to give the titled compound (0.56 g, 20%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-:3])=[O:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1[O:14][CH3:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
reacting 2-nitro-4-tertbutylanisole with an acid mixture of nitric acid and sulfuric acid to produce 2,6-dinitro-4-tertbutylanisole; and
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.[NH2:41][C@@H:42]([C:44]([NH:46][CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])=[O:49])=[O:45])[CH3:43].Cl>CN(C=O)C>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:41][C@@H:42]([C:44]([NH:46][CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53])=[O:49])=[O:45])[CH3:43])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@@H](N)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of Boc-Gly-Ala prepared as in Example 33B (10.2 g, 41.5 mmol) in anhydrous DMF (300 ml), was added HOBT.H2O (6.21 g, 46.0 mmol), EDC.HCl (8.81 g, 46.0 mmol) and DAla-Gly-Gly-OBzl.HCl (13.7 g, 41.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (40 ml). The resulting solution was extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were washed with 1N sodium bisulfate (100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and concentrated to half volume. The product crystallized out upon standing at RT for 30 min. Collection of the crystals by filtration and drying at high vacuum afforded 17.4 g (80% yield) of the pure product: 1H NMR (DMSO-d6) δ 1.21 (d, J=7.4 Hz, 3 H), 1.23 (d, J=7.3 Hz, 3 H), 1.38 (s, 9 H), 3.56 (d, J=6.3 Hz, 2 H), 3.75 (d, J=5.7 Hz, 2 H), 3.93 (d, J=6.0 Hz, 2 H), 4.24-4.34 (m, 2 H), 5.14 (s, 2 H), 6.98 (t, J=5.7 Hz, 1 H), 7.34-7.40 (m, 5 H), 7.93 (d, J=7.2 Hz, 1 H), 8.17-8.24 (m, 3 H).
Reaction SMILES: [CH:1]([Li])(CC)C.[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C@@H:26]([CH2:35][CH3:36])[CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][S:29]3(=[O:34])=[O:33])[C:16](=[O:37])[C@H:15]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1.IC.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:17]([C@@H:26]([CH2:35][CH3:36])[CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][S:29]3(=[O:34])=[O:33])[C:16](=[O:37])[C@@:15]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=3)([CH3:1])[CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: [Li]C(C)CC
Reactant: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@H](Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@](C)(Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
sec-Butyllithium (1.4 M in cyclohexane, 0.59 ml, 0.824 mmol) was added to a solution of (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one (Example 420, Step C, 0.484 g, 0.785 mmol) in THF (3.92 ml) at −78° C. After 15 minutes iodomethane (0.098 ml, 1.57 mmol) was added and the reaction was allowed to warm to room temperature. The reaction contents were poured into saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (10% step gradient elution 30 to 90% EtOAc in hexanes) afforded the title compound as the first eluting diastereomer.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].Cl.CN(C)CCCN=C=NCC.[F:22][C:23]1[C:28]2[N:29]=[C:30]([CH2:32][CH2:33][C:34](O)=[O:35])[S:31][C:27]=2[C:26]([F:37])=[CH:25][C:24]=1[F:38].C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][N:7]([C:34](=[O:35])[CH2:33][CH2:32][C:30]1[S:31][C:27]2[C:26]([F:37])=[CH:25][C:24]([F:38])=[C:23]([F:22])[C:28]=2[N:29]=1)[CH3:8])[CH3:3]
Reactant: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Reactant: CCOC(=O)CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(C)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To methylene chloride (10 ml) was added sarcosine ethyl ester hydrochloride (307 mg, 2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC.HCl; 422 mg, 2.2 mmol), 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid (522 mg, 2 mmol) and triethylamine (220 mg, 2.2 mmol), and the mixture was stirred at room temperature for 15 hours. The resulting mixture was washed with water, dried and evaporated to yield a residue, which was purified on a silica gel column to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine ethyl ester (610 mg, 85%) as an oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][CH:11]=1
Reactant: Cc1ccc(O)cc1
Reactant: OC(CCl)CCCl
Product: Cc1ccc(OCC(O)CCCl)cc1
Yield: 42 %

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-methylphenol to give white title compound, m.p. 62°-64° C. in 42% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:13]2[CH:14]=[CH:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:7][C:8]1[C:13]2[CH:14]=[CH:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc2occc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3occc23)cc1
Temperature: 2 °C
Reaction time: 0.83 h
Yield: 99 %

Procedure:
To a suspension of potassium carbonate (2.68 g, 19.4 mmol) in N,N-dimethylformamide (8 ml) was added a solution of 4-hydroxy-benzofuran (2.6 g, 19.4 mmol) in N,N-dimethylformamide (8 ml) at 2° C. under an argon atmosphere (for the preparation of 4-hydroxy-benzofuran see: G. Kneen, P. J. Maddocks, Syn. Commun. 1986, 16, 1635-1640.). After stirring for 50 min at 2° C., benzyl bromide (3.3 ml, 19.4 mmol) was added over a period of 15 min at 2° C. The suspension was stirred for additional 30 min at 2° C. and for 1.5 h at ambient temperature. After adding ice water (20 ml), the solution was extracted two times with diethyl ether. The combined extracts were washed three times with brine and dried over sodium sulfate. Evaporation of the solvent gave a yellow oil which was purified by column chromatography (silica gel, hexane) to give 4.3 g (19.2 mmol, 99%) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:12]([O-])=O)[C:4]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H][H]>[C].[Pd].C(O)C>[NH2:12][C:5]1[C:4]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: CCCCCOc1c(OC)ccc(C(=O)O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCCCOc1c(OC)ccc(C(=O)O)c1N
Yield: 94.7 %

Procedure:
4-Methoxy-2-nitro-3-pentyloxybenzoic acid (26.8 g, 94.6 mmol) and ethanol (350 ml) were mixed, and 10% palladium-carbon catalyst (2.6 g) was added to this solution. The reaction miture was stirred at room temperature for 7.5 hours in a hydrogen gas stream (3 kgf/cm2) and filtered. The filtrate was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 2-amino-4-methoxy-3-pentyloxybenzoic acid (22.7 g, 95%) as gray crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[CH2:26][CH2:25]1)=[O:23].I[CH3:39].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:39])[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[CH2:28][CH2:29]1)=[O:23]
Reactant: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)n(C)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% suspension in mineral oil, 40 mg, 1 mmol) was added to a solution of 1-{3-[5-chloro-2-(4-chlorophenyl)-1H-indol-3-yl]-1-oxopropyl}-4-(2-methoxyphenyl)piperazine (Description 33, 270 mg, 0.53 mmol) in dimethylformamide (10 mL) and the mixture was stirred at room temperature for 10 min. Iodomethane (165 μl, 376 mg, 2.65 mmol) was added and the mixture was stirred at room temperature for 1 h. Water (100 mL) was added and the mixture was extracted with ether (2×40 mL). The combined organic fractions were washed with water (3×40 mL) and brine (40 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a beige foam. 1H NMR (360 MHz, CDCl3) δ 7.60 (1H, d, J 1.7 Hz), 7.48 (2H, d, J 8.4 Hz), 7.32 (2H, d, J 8.4 Hz), 7.24 (1H, d, J 8.5 Hz), 7.20 (1H, dd, J 8.5, 1.7 Hz), 7.02 (1H, t, J 7.8 Hz), 6.94-6.82 (3H, m), 3.86 (3H, s), 3.75 (2H, t, J 5.0 Hz), 3.54 (3H, s), 3.40 (2H, t, J 5.0 Hz), 3.02 (2H, t, J 8.1 Hz), 2.95 (2H, t, J 5.0 Hz), 2.80 (2H, t, J 5.0 Hz), and 2.55 (2H, t, J 8.1 Hz). m/z (ES+) 522, 524 (M+1).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])(=O)=O>C(O)(=O)C>[CH2:1]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH2:17][Cl:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=NOCc1ccccc1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccccc1)C(=O)CCl
Yield: 85.7 %

Procedure:
A solution of ethyl 2-benzyloxyimino-3-oxobutyrate (syn isomer, 56.0 g.), sulfuryl chloride (40.5 g.) and acetic acid (80 ml.) was treated in a similar manner to that of Example A-(2) to give ethyl 2-benzyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 54.6 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.[C:14]([Cu])#[N:15].C(OCC)(=O)C>CN(C=O)C>[F:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:12][CH3:13])[C:5]=1[N+:9]([O-:11])=[O:10])[C:14]#[N:15]
Reactant: COc1cc(Br)cc(F)c1[N+](=O)[O-]
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (1.5 g, 6 mmol), and CuCN (698 mg, 7.8 mmol) in 10 mL of DMF was heated in a sealed tube at 160° C. overnight. It was then cooled down, diluted to ethyl acetate, washed by brine and water. The organic extract was dried and concentrated to a red solid (1 g, 85%) which was used for next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.01 (s, 3H) 7.14 (s, 1H) 7.17 (d, J=8 Hz, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[S:11]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=O)(=[O:14])(=[O:13])[NH2:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:18]([C:17]3[CH:16]=[C:15]([S:11]([NH2:12])(=[O:14])=[O:13])[CH:23]=[CH:22][CH:21]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: NS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-sulfamoylbenzoic acid (Oakwood). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.83 (t, J=7.9 Hz, 1 H), 8.21 (ddd, J=7.9, 1.8, 1.0 Hz, 1 H), 8.45 (dt, J=7.9, 1.4 Hz, 1 H), 8.58 (dt, J=8.0, 1.9 Hz, 1 H), 8.73-8.77 (m, 2 H), 9.31 (dd, J=2.2, 1.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:25]=[CH:24][C:8]([S:9]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][N:16]([CH:20]3[CH2:22][CH2:21]3)[C:15](=[O:23])[N:14]=2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O.S(N)(=O)(C1C=CC(N)=CC=1)=O>C(O)(=O)C>[CH:20]1([N:16]2[CH:17]=[C:18]([CH3:19])[C:13]([NH:12][S:9](=[O:10])([C:8]3[CH:24]=[CH:25][C:5]([NH2:4])=[CH:6][CH:7]=3)=[O:11])=[N:14][C:15]2=[O:23])[CH2:21][CH2:22]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(=O)n(C3CC3)cc2C)cc1
Agent: Nc1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cn(C2CC2)c(=O)nc1NS(=O)(=O)c1ccc(N)cc1

Procedure:
A mixture of 500 mg. of N4 -acetyl-N1 -(1-cyclopropyl-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)sulfanilamide and 5 ml. of 10% aqueous sodium hydroxide was heated on the steam bath for 1 hour, diluted with 10 ml. of water, cooled and acidified by gradual addition of 1ml. of acetic acid. The initial oily precipitate quickly solidified and filtration gave 332 mg. of product melting at 128°-133°. Recrystallization from 7 ml. of ethanol gave 120 mg. of N1 -cyclopropyl-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)sulfanilamide, melting at 134°-136°.