Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16](Cl)=[O:17])[CH3:14].[Cl-].[NH4+]>ClCCl>[SH:2][CH2:3][CH2:4][NH:5][C:16](=[O:17])[CH:15]([CH2:13][CH3:14])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: NCCS
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(CC)C(=O)NCCS
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
22.7 g of 2-mercaptoethylamine hydrochloride (0.2 mol) and 32.4 g of triethylamine (0.32 mol) were introduced in suspension in 130 ml of dichloromethane at 0° C.-5° C. Over the course of 25 minutes, 16.8 g of 2-ethylhexanoyl chloride (0.1 mol) were added dropwise. The batch was stirred at 0° C. to 5° C. for 1 hour, at 40° C. for 1.5 hours, and then at room temperature for 12 hours. 70 ml of saturated ammonium chloride solution were added and a phase separation was carried out. This was repeated twice and the organic phases were combined, dried over sodium sulfate, and freed of their solvent under reduced pressure. The residue obtained was purified by column chromatography (97 toluene:3 methanol).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[C:13]3([CH3:22])[S:20][CH3:21])[CH2:6][S:5]1.[C:23](Cl)(=[O:25])[CH3:24].C(OC(=O)C)C>CN(C=O)C>[C:23]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([C:7]3[CH2:6][S:5][C:4](=[O:3])[NH:9][N:8]=3)=[CH:18][CH:17]=2)[C:13]([CH3:22])([S:20][CH3:21])[C:14]1=[O:19])(=[O:25])[CH3:24]
Reactant: CSC1(C)C(=O)Nc2ccc(C3=NNC(=O)SC3)cc21
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSC1(C)C(=O)N(C(C)=O)c2ccc(C3=NNC(=O)SC3)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
0.131 g sodium hydride from a 55% dispersion in mineral oil was added during 0.5 hr to a solution of 0.921 g of 1,3-dihydro-5-(3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3-methyl-3-methylthio-2H-indol-2-one (compound of Example 1) in 25 ml DMF at 5° C. The mixture was stirred for 0.5 hr at 5° C. then 0.5 hr at 20° C. and cooled at 5° C. 0.215 ml of acetyl chloride in 1 ml DMF was added dropwise under stirring. The mixture was stirred for 0.5 hr at 5° C. then 1.5 hrs at 20° C. 250 ml ethylacetate was added and the corresponding organic solution was washed with water, dried and evaporated to dryness. The residual oil was purified by chromatography on silica (methylene chloride-ethylacetate: 9/1) to yield 0.4 g of white crystalline compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.[CH3:15][N:16]([CH3:27])[C:17]1[N:22]=[CH:21][C:20]([C:23](=[N:25]O)[NH2:24])=[CH:19][CH:18]=1>>[CH3:9][O:8][CH2:6][C:5]1[CH:4]=[C:3]([C:12]2[O:13][N:25]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([N:16]([CH3:27])[CH3:15])=[N:22][CH:21]=3)[N:24]=2)[CH:2]=[CH:11][C:10]=1[C:2]1[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=1[CH3:12]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: CN(C)c1ccc(C(N)=NO)cn1
Product: COCc1cc(-c2nc(-c3ccc(N(C)C)nc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and 6-(dimethylamino)-N′-hydroxypyridine-3-carboximidamide (UkrOrgSynthesis, BBV-073023). After purification by flash chromatography (silica, EtOAc/cHex) followed by a crystallization from a hot mixture of MTBE and heptane, the title compound was obtained as a white powder. HPLC (Method A), Rt: 4.0 min (purity: 100%). UPLC/MS, M+(ESI): 401.1. Elemental analysis: [C24H24N4O2-0.1H20] calculated: C, 71.66%; H, 6.06%; N, 13.93%. found: C, 71.66%; H, 6.06%; N, 13.91%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH2:3][C:2]1=O.[OH-].[Na+].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=1
Reactant: O=C1Cc2ncccc2O1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc2ncccc2o1

Procedure:
Furopyridone (6, 3.26 g, 24.15 mmol) is treated with phosphorus oxychloride (10 ml) at refluxing temperature for 3 hours. After cooling, the dark solution is poured into ice and basified with aqueous sodium hydroxide to pH ˜9. The mixture is extracted with chloroform. After evaporation of the chloroform, the brown oil is applied to flash column chromatography on silica gel to give chlorofuropyridine as yellow crystalline solid (7).
Reaction SMILES: [CH2:1]([NH:3][C@H:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:16]1([C:19]2[O:20][C:21]3[C:22](=[C:24]([C:36]#[N:37])[C:25]([CH3:35])=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27]=3F)[N:23]=2)[CH2:18][CH2:17]1>CS(C)=O>[CH:16]1([C:19]2[O:20][C:21]3[C:22](=[C:24]([C:36]#[N:37])[C:25]([CH3:35])=[C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:27]=3[N:6]3[CH2:7][CH2:8][C@H:4]([NH:3][CH2:1][CH3:2])[CH2:5]3)[N:23]=2)[CH2:18][CH2:17]1
Reactant: CCN[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN[C@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C4CC4)oc23)C1
Temperature: 95 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
(3S)-3-(Ethylamino)pyrrolidine (85 μl, 0.684 mmol) and triethylamine (95 μl, 0.684 mmol) were added to a dimethyl sulfoxide (2 ml) solution of 2-cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (100 mg, 0.342 mmol), followed by stirring in an oil bath at 95° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with isopropyl ether to obtain the entitled compound (31.0 mg, 23%) as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.C(Br)C#C>O.CN(C)C=O>[CH2:12]([O:13][CH2:9][C:4]1[O:3][CH:7]=[CH:6][CH:5]=1)[C:11]#[CH:10]
Reactant: OCc1ccco1
Reactant: C1CCOC1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOCc1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a mixture of sodium hydride (7.7 g, 190 mmol, 60% in oil) and tetrahydrofuran (100 mL) was added dropwise furfuryl alcohol (15 mL, 170 mmol) at 0° C. The reaction mixture was warmed to room temperature, N,N-dimethylformamide (30 mL) was added at that temperature, and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was returned to 0° C., propargyl bromide (23 g, 190 mmol) was added at that temperature, and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:30) to give the title compound (7.6 g, 32% yield).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=2[F:20])[C:3]=1[CH:21]=O.O.[NH2:24][NH2:25]>COCCOC>[F:20][C:13]1[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:12]=1[NH:11][C:4]1[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[C:2]2[C:3]=1[CH:21]=[N:24][NH:25]2
Reactant: NN
Reactant: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2C=O)c(F)c1
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(Nc2c(C(=O)O)ccc3[nH]ncc23)c(F)c1
Temperature: 90 °C
Yield: 82 %

Procedure:
To a suspension of 4-fluoro-2-(2-fluoro-4-methylsulfanyl-phenylamino)-3-formyl-benzoic acid (105 mg, 0.32 mmol) in DME (5 mL) was added hydrazine hydrate (5 mL) and the reaction mixture heated at 90° C. for 18 hours. The volatile solvent was removed in vacuo and the residue acidified with concentrated HCl whilst applying cooling. The resultant precipitate was collected by filtration and washed with water to give the title compound as a tan solid (85 mg, 82%). LCMS (Method B) RT 3.12 [M+H]+ 318.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[N:30]1([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1>>[N:30]1([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40][C:2]3[N:7]=[CH:6][C:5]4[CH:8]=[C:9]([C:18]5[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH:22]=5)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:4]=4[CH:3]=3)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: Nc1ccc(Cn2cccn2)cc1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(Cn5cccn5)cc4)cc3n2C(=O)OC(C)(C)C)cn1

Procedure:
The title compound was prepared from tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (70 mg, 0.15 mmol) and 4-((1H-pyrazol-1-yl)methyl)aniline (31.3 mg, 0.181 mmol, 1.2 eq), using the method described in Preparation 35 and using silica gel column chromatography eluting with EtOAc:hexane:triethylamine 10:10:1 (12 mg, 14.3%). 1H-NMR (500 MHz, CDCl3) 1.49 (s, 9H), 1.69 (s, 9H), 5.2 (s, 2H), 6.32 (s, 1H), 6.58 (s, 1H), 6.66 (d, J=8.3 Hz, 2H), 7 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.33 (m, 1H), 7.62 (s, 1H), 7.82 (s, 1H), 8.21 (s, 1H), 8.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[C:5](I)=[CH:4][N:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[C:5]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cccs1
Reactant: CC(=O)NCCNc1nc(Cl)ncc1I
Product: CC(=O)NCCNc1nc(Cl)ncc1-c1cccs1
Yield: 79 %

Procedure:
In the reaction of N-[2-(2-chloro-5-iodopyrimidine-4-ylamino)ethyl]-acetamide (870 mg, 2.6 mmol) with thiophen-2-boronic acid (359 mg, 2.8 mmol) according to procedure 3, the desired product is obtained in 79% yield (602 mg) after chromatographic purification (silica gel, ethyl acetate/hexane (0%-90% ethyl acetate)).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:27][O-:28].[Na+]>CO>[CH3:27][O:28][CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 82 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.3 mmol) with sodium methoxide (1.6 mmol) in methanol (10 ml) at a temperature 65° C. for 6 hours and by purifying the compound by silica gel column chromatography in 82% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)=[CH:23][CH:22]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=[C:29]1[C:28]2[C:32](=[CH:33][CH:34]=[CH:35][C:27]=2[C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)[NH:31][C:30]1=[O:36]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 63.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (31 mg, 63.9%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Triethylamine (35.95 mL, 257.9 mmol) was added to a suspension of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (49.6 g, 172 mmol) in dichloromethane (500 mL). 1-Amino-2-methylpropan-2-ol (16.86 g, 189 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours and then-concentrated under reduced pressure. The residue was triturated with water and stirred for 1 hour. The precipitated solid was isolated by filtration, washed with water, and dried. This material was suspended in diethyl ether (400 mL), sonicated, isolated by filtration, and then dried in a vacuum oven at 40° C. for 16 hours to provide 58.1 g of 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid, mp 189-190° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](Cl)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)Cl
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: CCCCCC(=O)n1ccnc1

Procedure:
The method of Pfander and Laederach [H. Pfander and M. Laederach, Carbohyd. Res. 99(2), 175-79 (1982)] was used. 1-Hexanoylimidazole was prepared by stirring 2 equivalents of imidazole with 1 equivalent hexanoyl chloride in toluene solution. The mixture was filtered and concentrated to a low-melting solid. This product, 1-hexanoylimidazole, was further purified by distillation.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][NH:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CCOC(C)=O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][N:27]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)OC(C)(C)C)C4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 3) (70 mg, 0.170 mmol) and caesium carbonate (167 mg, 0.511 mmol) in dry DMF (5 ml) were treated with tert-butyl bromoacetate (0.038 ml, 0.256 mmol) and stirred at RT for 3 hours to give a single product. EtOAc (40 ml) was added and the mixture washed with water (2×50 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (85 mg) as a clear, colourless oil. MS (ES) C28H32N4O4 requires 488; found 489 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[C:34](OC(=O)C)(=[O:36])[CH3:35].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:32][C:30]1[CH:29]=[CH:28][C:27](=[O:33])[N:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:18]3[N:14]([CH2:13][C:11]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH:12]=4)[O:4][CH2:3][CH2:2][NH:1][C:34](=[O:36])[CH3:35])[CH:15]=[N:16][CH:17]=3)=[CH:25][N:24]=2)[CH:31]=1
Reactant: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCN
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Reaction time: 2 h

Procedure:
2-(2-Amino-ethoxy)-4-[5-(5-chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-imidazol-1-ylmethyl]-benzonitrile (L-824,459, 50 mg, 0.11 mmol) was dissolved in CH2Cl2 (550 tl) and treated with acetic anhydride (208 μl, 0.22 mmol). DIEA was then added until pH=7-8. The reaction mixture was stirred at room temp. for 2 hours. Saturated NaHCO3 was added (10 mL) and the solution was extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to yield the final product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][N:8]([CH3:13])[S:9]([N:4]1[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]1)(=[O:11])=[O:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cn[nH]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnn(S(=O)(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-1H-pyrazole (10.4 g, 127.2 mmol) in CH2Cl2 (200 mL). N,N-dimethylsulfamoyl chloride (17.14 mL, 167.1 mmol) and triethylamine (35 mL, 251.1 mmol) were added to the reaction. The reaction mixture was stirred for 30 min at 0° C. in a water/ice bath and then stirred overnight at room temperature. The reaction was quenched with NaHCO3 (sat.) (40 mL) and the aqueous phase was extracted with 3×200 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/hexanes (1:6) as the eluent to afford the title compound (22.2 g, 92%) as a light yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([NH:19][C:3](=[O:4])[CH2:2][Cl:1])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)CCl
Reactant: NC(Cc1ccccc1)c1cccs1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)NC(Cc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of chloroacetyl chloride (4 mL, 0.05 mol) in chloroform (40 mL) was added dropwise to a solution of α-(2-thienyl)benzeneethanamine (10 g, 0.049 mol) and triethylamine (14 mL, 0.098 mol) in chloroform (180 mL) at 0° C. The mixture was stirred to room temperature for 1 hour. Dilute HCl (300 mL of 0.75N) was added and the reaction mixture was partitioned. The chloroform layer was separated, dried (MgSO4) and concentrated to give the amide as a light brown solid (11 g).
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH:8]1[CH2:12][C:11]2[CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:16][C:10]=2[O:9]1)(=O)=O.Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH2:26][CH2:25][CH2:7][CH:8]2[CH2:12][C:11]3[CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:16][C:10]=3[O:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(COS(=O)(=O)C(F)(F)F)O2
Reactant: BrCCc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)CC(CCCc1ccccc1)O2
Yield: 75 %

Procedure:
Following the process described in example 3 (point B), starting from ethyl 2-trifluoromethanesulfonyloxymethyl-2,3-dihydrobenzofuran-5-carboxylate and 2-bromoethylbenzene, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 95:5 (75% yield).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1>COC(C)(C)C>[CH:1]1([NH:7][C:8]([NH:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(CCCN)CC1
Reactant: S=C=NC1CCCCC1
Solvent: COC(C)(C)C
Product: CN1CCN(CCCNC(=S)NC2CCCCC2)CC1
Reaction time: 18 h
Yield: 82.7 %

Procedure:
Cyclohexyl isothiocyanate (1.51 g, 10.7 mmole) in 5 mL t-butyl methyl ether was added to a solution of 1.68 g (10.7 mmole) 3-(4-methyl-1-piperazinyl)propylamine (Lancaster Synthesis, Windham N. H.) in t-butyl methyl ether (10 mL). After 18 hr at room temp., filtration gave 2.64 g (83%) 1-cyclohexyl-3-[(4-methyl-1-piperazinyl)propyl]thiourea, melting pt. 109–111° C. A solution of 2.388 g (8 mmole) of this thiourea in 12 mL ethanol containing 2.1 mL (25.2 mmole) conc. HCl was added to a warm solution of 2.755 g (16 mmole) 2-methyl-1,4-naphthoquinone in 20 mL warm ethanol with stirring. After 3 days, 1.925 g crude solid was filtered out. Of this, 1.0 g was recrystallized from 20 mL 95% methanol+80 mL acetone to give 0.927 g (40%) of the title compound, melting pt. 242–244° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([OH:16])[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].I[CH2:20]C>CN(C=O)C.CCOC(C)=O>[CH3:20][O:16][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[C:10]2[C:5]=1[NH:4][N:3]=[C:2]2[CH3:1]
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(C)c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2[nH]nc(C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a 0° C. solution of ethyl 3-methyl-7-hydroxy-1H-indazole-5-carboxylate (0.84 g, 3.8 mmol) in DMF (25 mL) was added 60% oil dispersion of NaH (152 mg, 3.81 mmol). After stirring for 1 hour at 0° C., a solution of iodoethane (595 mg, 0.31 mL, 3.81 mmol) in DMF (3 mL) was added. The mixture was kept at 0° C. for several hours before allowing the mixture to warm to room temperature while stirring overnight. Dilute with EtOAc, wash with saturated aqueous NaHCO3, water, saturated aqueous NaCl and the organic extract was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (80 g column, 0-30% EtOAc/hexanes gradient) to provide ethyl 7-methoxy-3-methyl-1H-indazole-5-carboxylate (516 mg, 55%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([Br:13])[CH:7]=[C:8]([N+]([O-])=O)[CH:9]=1)([O-:3])=[O:2].[CH3:14][O-:15].[Na+]>CO>[Br:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([O:15][CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 80 %

Procedure:
3,5-Dinitrobromobenzene (1.25 g, 5.06 mmol) was stirred in methanol (12 mL) and a solution of sodium methoxide (0.5 M in methanol, 12.6 mL) was added. The mixture was heated to 60° C. for 2 hours and cooled to RT. The mixture was quenched with hydrogen chloride solution (1 N) and extracted with dichloromethane. Evaporation and purification by silica chromatography using ethyl acetate and hexanes gave the desired compound (1.0 g, 80%). LCMS for C7H7BrNO3 (M+H)+: m/z=232.1.