Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[K+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)#[N:4].CC1C=CC(S(NCl)(=O)=O)=CC=1.Cl>CN(C=O)C.O>[C:3]([C:5]1[CH:10]=[C:9]([I:1])[C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)#[N:4]
Reactant: [I-]
Reactant: N#Cc1ccc(O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(O)c(I)c1
Yield: 47 %

Procedure:
Potassium iodide (7.97 g, 48 mmol) was dissolved in 125 ml of DMF with stirring, and 4-cyano-2-fluorophenol (16a; 5.56 g 48 mmol) and chloramine-T in 75 ml of DMF were added dropwise with stirring. The reaction mixture was poured into 650 ml of water, acidified with 6N HCl, and extracted with ethyl acetate. The organic layer was washed with 10% NaHSO3, water and brine and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the yellow solid residue was treated with 200 ml of 1N NaOH solution, filtered through supercel, and the filtrate was acidified with conc. HCl solution. The solid product was filtered, dried, dissolved in ether, and the organic layer was dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was recrystallized from ethylene chloride to afford 5.93 g (55.6%) of the title compounds.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-])=O)[C:15]=2[OH:24])(=[O:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[OH:24])(=[O:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-[3-(4-morpholinyl)propyl]-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.01 g) was reduced with hydrogen and 10% Pd/C (250 mg). The crude product (890 mg) was carried onto the next step without purification. 1H NMR (MeOD-d4): δ 6.86 (m, 2H), 3.87 (m, 4H), 3.15 (m, 6H), 2.98 (t, 2H), 1.92 (m, 2H).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:29]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)C.Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([CH:4]=[O:3])[N:29]([CH:30]([CH2:31][CH3:32])[CH2:33][CH3:34])[C:8]=4[N:9]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: CCOC(OCC)c1cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc2n1C(CC)CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(CC)n1c(C=O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
To a solution 1-(4-{4-[6-diethoxymethyl-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone (0.178 g, 0.35 mmol) in 1,4 dioxane (2.8 mL) is added 0.8 mL of concentrated HCl at ambient temperature. The reaction mixture is stirred at ambient temperature for 30 min. The mixture is neutralized with 1 N NaOH aqueous solution and saturated NaHCO3 aqueous solution, extracted with CH2Cl2. The extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 160 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde as a yellow solid.
Reaction SMILES: Cl.NC1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC(F)=CC=3F)=O)=CC=2F)C=CN=1.[C:35]([C:38]1[CH:43]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[N:68]=[CH:67][CH:66]=[CH:65][C:53]=3[C:54]([NH:56][C:57]3[CH:62]=[CH:61][C:60](F)=[CH:59][C:58]=3F)=[O:55])=[CH:47][C:46]=2[F:69])[CH:41]=[CH:40][N:39]=1)(=[O:37])[NH2:36].[Cl:70]C1N=CC=CC=1C(NC1C=CC(Cl)=CC=1)=O>>[C:35]([C:38]1[CH:43]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[N:68]=[CH:67][CH:66]=[CH:65][C:53]=3[C:54]([NH:56][C:57]3[CH:62]=[CH:61][C:60]([Cl:70])=[CH:59][CH:58]=3)=[O:55])=[CH:47][C:46]=2[F:69])[CH:41]=[CH:40][N:39]=1)(=[O:37])[NH2:36]
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Reactant: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Agent: Cl
Agent: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Product: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(Cl)cc3)cc2F)ccn1
Yield: 47 %

Procedure:
4-(4-Amino-2-fluorophenoxy)picolinamide (0.12 g, 0.50 mmol, Compound C of Example 3) was converted to the desired compound (0.090 g, 47%) in a manner similar to the preparation of 2-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-nicotinamide (Step D of Example 3), except that 2-chloro-N-(4-chlorophenyl)nicotinamide (Maybridge, 0.11 g, 0.40 mmol) was used instead of 2-chloro-N-(2,4-difluorophenyl)nicotinamide. HRMS(ESI+), 478.1082 (M+H)+ calc, 478.1059 (M+H)+ found.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1.CCN(S(F)(F)[F:27])CC>ClCCl>[F:27][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CF
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.158 g, 0.574 mmol) (Example 6d) in dichloromethane (7 mL) at 0° C. under nitrogen is added DAST (0.487 g, 2.872 mmol) dropwise. The mixture is stirred at 0° C. overnight. After dilution with dichloromethane, the organic phase is washed twice with saturated aqueous sodium bicarbonate, water and brine. The combined aqueous phase is back-extracted once with dichloromethane. The combined organic phase is dried over magnesium sulfate and filtered through a cotton plug. The residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 99:1 to 49:1) to afford 4-(5-fluoromethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a white solid; MS (ESI) m/z 275.0 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (s, 3 H), 1.57 (s, 3 H), 5.27 (s, 1 H), 5.45 (dd, J=22.7, 12.4 Hz, 1 H), 5.58 (dd, J=21.2, 12.4 Hz, 1 H), 7.21 (d, J=5.3 Hz, 1 H), 7.29 (d, J=7.3 Hz, 1 H), 7.38 (d, J=2.8 Hz, 1 H), 7.55-7.61 (m, 1 H), 7.65 (dd, J=7.6, 1.5 Hz, 1 H), 8.27 (dd, J=7.7, 1.4 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:11][C:12]1([C:25]([O:27]CC)=[O:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[OH-].[Na+]>CO>[Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:11][C:12]1([C:25]([OH:27])=[O:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1(Cc2cnn(C(C)(C)C)c2Br)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2cnn(C(C)(C)C)c2Br)(C(=O)O)CC1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 4-((5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (256 mg, 0.54 mmol) in methanol (15 mL) was added aqueous 2.5 M NaOH (5 mL), and the resultant mixture was heated at reflux for 18 hours. The mixture was cooled to room temperature and methanol was removed under reduced pressure. The resultant slurry was taken up in 25 mL water, acidified with aqueous 1 N HCl, and then extracted with ethyl acetate (2×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to yield 241 mg of 4-((5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid as a colorless solid. +APCI (M+H) 444.2, (M+2+H) 446.2; 1H NMR (400 MHz, CDCl3, δ): 7.35 (s, 1H), 3.95 (br. s., 2H), 2.92 (br. s., 2H), 2.71 (s, 2H), 2.08 (d, J=12.9 Hz, 2H), 1.73 (s, 9H), 1.50 (m, 11H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][C:6]1=[O:16])=[O:4].[P:17]([O:22]C)([O:20][CH3:21])[O:18][CH3:19]>C1(C)C=CC=CC=1>[O:4]=[C:3]([N:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][C:6]1=[O:16])[CH2:2][P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19]
Reactant: COP(OC)OC
Reactant: O=C(CBr)N1C(=O)OC[C@H]1c1ccccc1
Solvent: Cc1ccccc1
Product: COP(=O)(CC(=O)N1C(=O)OC[C@H]1c1ccccc1)OC
Temperature: 25 °C
Yield: 51.2 %

Procedure:
A solution of (R)-3-(2-bromoacetyl)-4-phenyloxazolidin-2-one (175 g, 616 mmol) and trimethyl phosphite (83.3 g, 671 mmol) in toluene (870 mL) was heated to reflux for 16 h. The reaction mixture was cooled to ambient temperature and the solvent was concentrated under reduced pressure to give a brown colored gum, which was triturated with 1:1 CH2Cl2 and hexanes (250 mL) to provide a brown solid. The solid was collected by filtration under reduced pressure and washed with CH2Cl2 (50 mL) to provide the product (98.8 g) as light brown solid.
Reaction SMILES: [H-].[Na+].[C@@H:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][C@@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:3]2[OH:10])[N:15]=[CH:14][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O[C@@H]1CCCC[C@@H]1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.2 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.39 g of cis-1,2-cyclohexanediol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes and then cooled to 0° C., to which 2 ml of a tetrahydrofuran solution containing 0.5 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.42 g of 4-chloro-6-(cis-2-hydroxycyclohexyloxy)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22](=[O:35])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.[Cl:52][C:53]1[N:54]=[N:55][C:56](Cl)=[CH:57][CH:58]=1>>[Cl:52][C:53]1[N:54]=[N:55][C:56]([C:40]2[CH:41]=[CH:42][C:37]([CH2:36][C:11]3[N:12]([C:14]4[CH:19]=[CH:18][C:17]([N:20]5[S:24](=[O:25])(=[O:26])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[C:22](=[O:35])[CH2:21]5)=[CH:16][CH:15]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:38][CH:39]=2)=[CH:57][CH:58]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC1(C)OB(c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)N(COCC[Si](C)(C)C)S4(=O)=O)cc3)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)cc2)S1(=O)=O

Procedure:
5-(4-{4-(2,4-Dichloro-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (385 mg, 0.5 mmol) was treated as described in general procedure G using 3,6-dichloropyridazine (149 mg, 1 mmol) to give 5-{4-[2-[4-(6-chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([CH3:35])([CH3:34])[C:31](=N)[NH2:32].C[O-].[Na+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:32][C:31]([C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[F:23])([CH3:35])[CH3:34])=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(C(=N)N)c1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(c1nnc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)[nH]1)c1ccccc1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
60 mg (0.20 mmol) of the compound from Example 21A were dissolved in 1 ml of DMF, and 63 mg (0.29 mmol) of 2-(2-fluorophenyl)-2-methylpropaneimidamide hydrochloride and 17 mg (0.31 mmol) of sodium methoxide were added. The suspension was stirred at 150° C. for 8 h. The reaction was then brought to completion by 45 min of stirring in a microwave reactor at 200° C. The suspension was diluted with about 1 ml of methanol and filtered, and the filtrate was purified by preparative HPLC [Method 19]. This gave 13 mg (15% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[N+](=[CH2:17])=[N-]>C(Cl)Cl>[CH3:17][O:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc2ccccc2c1O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)c1sc2ccccc2c1OC

Procedure:
A stirred, ice-bath cooled mixture of methyl 3-hydroxybenzo[b]thiophene-2-carboxylate (J. Org. Chem. 32, 2678 (1967) (2.1 g, 0.01 m) and dry methylene chloride (25 ml) was treated with ethereal diazomethane in portions until the yellow color of the diazomethane persists, and nitrogen was no longer evolved. Concentration in vacuo yielded methyl 3-methoxybenzo[b]-thiophene-2-carboxylate as a pale tan solid; m/z 324 (M+.). The material was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[Li]CCCC.CN([CH:21]=[O:22])C.Cl>CCOCC>[Br:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)c1cc(Br)cc(C=O)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
1,3-Dibromo-5-tert-butylbenzene (50 g, 0.17 mol) was dissolved in anhydrous ether (200 mL) in a dried flask under nitrogen. The reaction mixture was cooled to −78° C. and stirred under nitrogen atmosphere. A 2.46 M solution of n-BuLi in hexanes (171.2 mL, 0.171 mol) was added dropwise to the above solution and the reaction mixture was stirred at −78° C. for 30 minute after complete addition of n-BuLi. After 30 minute of stirring at −78° C., the reaction mixture was warmed to −30° C. DMF (16 mL, 0.2 mol) was added to the above reaction mixture dropwise, keeping the reaction mixture below −20° C. After addition of DMF, the reaction mixture was warmed slowly to 0° C. (30 minute) and then stirring was continued overnight to obtain a yellow-orange solution. The reaction mixture was poured into 400 mL of chilled 10% aqueous HCl and the mixture was stirred for 15 minutes. The ether layer was separated, washed with water (2×250 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the product as a pale yellow viscous liquid. The crude product was dissolved in dichloromethane (250 mL) and passed through a small pad of silica gel (250 g). Evaporation of the solvent in vacuo gave the product as a pale yellow viscous liquid (41.2 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCCNc1ccccn1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCCCNc1ccccn1)c1ccccc1

Procedure:
A mixture of 2-(3-aminopropylamino)pyridine (6 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) is heated under reflux for one hour and concentrated to give N-benzoyl-N'-[3-(2-pyridylamino)propyl]thiourea. The benzoyl thiourea is added to a solution of potassium carbonate (1.4 g.) in water (80 ml.) at 60°. The solution is maintained at this temperature for 1 hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid is removed by filtration and the filtrate is basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohol and concentration, the title product is obtained.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]#[CH:8].B(F)(F)F.CCOCC.[O:28]1[CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+]>C1COCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][O:9][CH2:6][C:7]#[C:8][CH2:31][CH2:30][CH2:29][OH:28]
Reactant: C1COC1
Reactant: C#CCOCCCc1ccccn1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCCC#CCOCCCc1ccccn1
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.57M in hexane, 35 ml) was added to a stirred solution of 2-[3-[(2-propynyl)oxy]propyl]pyridine (9.0 g) in dry THF (60 ml) at -78° under nitrogen. Boron trifluoride etherate (6.8 ml) was added and the mixture was stirred at -78° for 30 min. Oxetane (10 ml) was added and after 2 h at -78°, the mixture was treated with more oxetane (10 ml). The dark mixture was allowed to warm to 0°, saturated ammonium chloride (100 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic layer was washed with brine, dried and concentrated to a dark oil which was purified by FCC eluting with ether to give the title compound as an orange oil (5.1 g), t.l.c. (ethyl acetate-triethylamine 99:1) Rf 0.35.
Reaction SMILES: [CH3:1][N:2]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[C@@H:3]([C:24]([OH:26])=[O:25])[CH2:4][NH:5][C:6](=[O:23])[CH2:7][CH:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH2:22])=[N:20][OH:21])=[CH:15][CH:14]=2)[CH2:9]1.[C:34](OC(=O)C)(=O)[CH3:35]>C(O)(=O)C>[CH3:1][N:2]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[C@@H:3]([C:24]([OH:26])=[O:25])[CH2:4][NH:5][C:6](=[O:23])[CH2:7][CH:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:22]=[C:34]([CH3:35])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:9]1
Reactant: CCCCOC(=O)N(C)[C@H](CNC(=O)CC1CC(c2ccc(C(N)=NO)cc2)=NO1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCOC(=O)N(C)[C@H](CNC(=O)CC1CC(c2ccc(-c3noc(C)n3)cc2)=NO1)C(=O)O
Yield: 95.1 %

Procedure:
To a suspension of (R)-Methyl-3-[[[3-[4-[amino (hydroxyimino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl] acetyl]amino]-N-(butoxycarbonyl)-L-alanine (1.05 g) in acetic acid (7 mL) was added acetic anhydride (0.35 g) dropwise. After the completion of addition, the reaction mixture was refluxed for 3 h. The solvent was distilled under vacuum and the solid was dried to give (R)-methyl-N-(butoxycarbonyl)-3-[[[4,5-dihydro-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-5-isoxazolyl]acetyl]amino]-L-alanine (1.05 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(F)cc2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2,5-difluoronitrobenzene and dimethyl sulfoxide, ethyl 2-(4-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][O:5][CH:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH2:3]1
Reactant: [H][H]
Reactant: O=C1C=COC(CN2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Yield: 87 %

Procedure:
2-(4-Oxo-3,4-dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione (13 g, 0.051 mol) was dissolved in ethyl acetate (250 ml) and placed in a Parr bottle. 10% Pd/C (1.5 g) was carefully added and the mixture was shaken under a pressure of 30 psi of hydrogen for 6.5 h (Parr apparatus). Filtration followed by evaporation of the ethyl acetate in vacuo afforded a crude 11.5 g of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione pure enough for the next step. Analytical pure compound could be obtained by purification of a small sample (250 mg) by column chromatography on silica gel, utilising a mixture of hexane/ethyl acetate as a gradient (from 100/0 to 50/50). Pure fractions were collected and the solvent evaporated in vacuo affording 142 mg (55%) of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[C:14]([C:18]1[O:22][C:21]([CH3:23])=[C:20]([C:24](=O)[CH2:25]Br)[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[O:22][C:21]([CH3:23])=[C:20]([C:24]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:25]=2)[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)CBr
Product: COC(=S)c1cc(-c2nc(-c3cc(C(C)(C)C)oc3C)cs2)c(C)s1
Yield: 66.1 %

Procedure:
A solution of 955 mg (3.86 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 1 g (3.86 mmol) of 1-[5-(tert-butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one (1 g) in a manner similar to Example 8, step (a) to give methyl 4-{4-[5-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (999 mg, 64%) as a red-brown solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.14 (s, 1H), 7.74 (s, 1H), 6.46 (s, 1H), 3.86 (s, 3H), 2.74 (s, 3H), 2.66 (s, 3H), 1.27 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C19H21NO3S3, 408.1 (M+H), found 408.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a 0° C. solution of 4-(6-fluorobenzo[b]thien-3-yl)-1-piperazine-butanamine (4.04 g, 13.1 mmol), triethylamine (1.89 g, 18.6 mmol), and dichloromethane (50 mL) under a nitrogen atmosphere was added isobutyryl chloride (1.63 g, 15.3 mmol) over 6 minutes. The reaction was stirred at 0° C. for 4 hours and then was diluted with dichloromethane (140 mL). The mixture was washed successively with 5% aqueous NaOH (100 mL) and water (100 mL), dried (K2CO3), and concentrated in vacuo to give an off-white solid. The crude product was chromatographed on silica gel with 10% methanol/dichloromethane as eluent to afford an off-white solid. Recrystallization from ethyl acetate/heptane gave 2.17 g (43%) of the title compound as beige needles: m.p. 130°-131° C. TLC (silica gel, 10% methanol/dichloromethane) Rf =0.37. The IR(CHCl3), 1H NMR (CDCl3, 200 MHz), and MS (M+ 377, EI, 70 eV) were consistent for the assigned structure.