Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[NH3:40]>C(Cl)(Cl)Cl>[NH2:40][CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: N
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN)cc2)c1

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and a saturated ammonia solution in chloroform (0.1 ml) according to an analogous synthetic method to Example 806, the title compound (0.7 mg) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[C:10]([OH:24])[C:11]([OH:23])=[CH:12][C:13]=1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].C([O:27][C:28](=[O:32])[CH:29](Cl)Cl)C.Cl>COCCOC.O>[CH3:7][C:8]1[C:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:12][C:11]2[O:23][CH:29]([C:28]([OH:32])=[O:27])[O:24][C:10]=2[CH:9]=1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2c(cc1S(=O)(=O)c1ccccc1)OC(C(=O)O)O2

Procedure:
27.7 g (200 mmol) of anhydrous potassium carbonate are added to a suspension of 10.6 g (40 mmol) of 4-methyl-5-phenylsulphonyl-1,2-benzenediol in 65 ml of cold 1,2-dimethoxyethane. While stirring vigorously, a solution of 7.85 g (50 mmol) of dichloroacetic acid ethyl ester in 5 ml of 1,2-dimethoxyethane is added dropwise thereto in the course of 30 minutes. The mixture is stirred for a further hour at room temperature and is then boiled under reflux for 3 hours while stirring. It is then cooled to 30°, water is added, and the whole is stirred for 30 minutes and adjusted to pH 1-2 with hydrochloric acid. Some of the 1,2-dimethoxyethane is removed in a rotary evaporator and the solution remaining is extracted three times with ethyl acetate. The combined ethyl acetate solutions are washed with water, and then with saturated sodium chloride solution, dried over sodium sulphate, treated with activated carbon and concentrated by evaporation. The resulting yellow-green oil is crystallised from ethyl acetate/hexane. The sand-coloured crystals are dissolved in ethyl acetate and treated again with activated carbon. The solvent is removed in a rotary evaporator. The yellow oil remaining is crystallised from methylene chloride at 0°, yielding 5-methyl-6-phenylsulphonyl-1,3-benzodioxole-2-carboxylic acid having a melting point of 169°-171°.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[CH3:22][N:23]([CH2:25][CH:26]([OH:28])[CH3:27])[CH3:24]>C(Cl)(Cl)Cl>[C:1]([O:28][CH:26]([CH3:27])[CH2:25][N:23]([CH3:24])[CH3:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(O)CN(C)C
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OC(C)CN(C)C

Procedure:
The (N,N-disubstituted amino)-alkanol alkanoates are readily prepared by reacting the corresponding aminoalkinol with lauroyl chloride in the presence of triethylamine. A solvent such as chloroform is optional but preferred. For example, 1-(N,N-dimethylamino)-2-propanol can be reacted with lauroyl chloride in chloroform and in the presence of triethylamine to form 1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[NH:10].Br[CH:23]([CH3:31])[C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])(O)=O.[Na+]>CC(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[C:23]([CH3:31])=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:10]=1
Reactant: N=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 52.4 %

Procedure:
Part C: 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzenecarboxamidine (15.0 g, 0.0450 mol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate (20.8 g, 2 molar equivalent) and NaHCO3 are successively added. The resulting mixture is heated at reflux temperature for 40 hours and allowed to attain room temperature. The 2-propanol is removed in vacuo, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO3 (5% aqueous solution). The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) and further purified by crystallisation from cyclohexane to give ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylate (10.45 g, 52% yield) as a yellow solid. Melting point: 160-162° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl.O>[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:22](=[O:23])[CH2:21][Cl:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 993.1 %

Procedure:
To a suspension of glycine benzylester hydrochloride (25.2 g, 12.5 mmol, Aldrich) in CH2Cl2 (200 ml) was added a solution of K2CO3 (77 g, 55.8 mmol) in H2O (200 ml). The mixture was cooled to 0° C. and chloroacetylchloride (21.0 g, 18.6 mol, Aldrich) was added dropwise in 15 min. The mixture was warmed to room temperature and stirred for 2 h. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (100 ml). The organic layers were combined and washed with H2O (100 ml), brine (100 ml), dried (MgSO4). Evaporation of solvent afforded a light yellowish glassy solid. This was triturated with 250 ml of hexane. The colorless solid was collected and dried to give 30.0 g of the material 1.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1C=CC(B(O)O)=C1>>[F:49][C:45]1[CH:44]=[C:43]([S:40]([CH2:39][C:36]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([O:50][CH3:51])[C:29]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(F)c2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(F)c2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(3-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 99) and furan-3-yl boronic acid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[N:29][CH:30]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1ccc(CBr)cn1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (6.1 g, 3.44 mmol) and benzoyl peroxide (218 mg, 0.09 mmol) were added successively to a solution of 2-chloro-5-methyl-pyridine (4.0 g, 3.13 mmol) in carbon tetrachloride (20 mL) and refluxed for 90 min. The reaction mixture was cooled to room temperature, water added and the organic layer separated. The organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and filtered. The resultant solution of 5-bromomethyl-2-chloro-pyridine was used as such for the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O.Cl.[CH3:17][NH:18][O:19][CH3:20].[Li]CCCC>>[CH3:17][N:18]([O:19][CH3:20])[C:8](=[O:10])[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[C:5]#[C:4][CH2:3][O:2][CH3:1]
Reactant: COCC#Cc1ccccc1C(=O)OC
Reactant: CNOC
Agent: Cl
Agent: [Li]CCCC
Product: COCC#Cc1ccccc1C(=O)N(C)OC
Yield: 48 %

Procedure:
Treatment of methyl 2-[3-(methyloxy)-1-propyn-1-yl]benzoate (142) (0.64 g, 3.13 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.35 g (48%) of the title compound (143) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.32 (br s, 3H), 3.43 (s, 3H), 3.50 (br s, 3H), 4.30 (s, 2H), 7.25-7.40 (m, 3H), 7.45-7.55 (m, 1H). LCMS (ESI): m/z 234 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[Si:12]([O:19][C@H:20]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])/[CH:21]=[N:22]/[S@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CCOCC>[Si:12]([O:19][C@H:20]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[C@@H:21]([NH:22][S@:23]([C:25]([CH3:26])([CH3:27])[CH3:28])=[O:24])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[S@](=O)N[C@@H](c1nccs1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 2-bromothiazole (7.9 ml, 89 mmol) in 200 mL ether was cooled to −78° C. and treated with a solution of n-butyllithium (36 ml, 89 mmol) (2.5N in hexanes). After stirring for 30 minutes the reaction mixture was slowly added to a cooled (−78° C.) suspension of (S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (25.000 g, 59 mmol) in 100 mL ether. The reaction mixture was allowed to stir at −78° C. for one hour. The reaction mixture was quenched with MeOH and saturated NH4Cl solution. The organic solution was washed with water, brine, dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography gave (S)—N-((1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide (24.81 g, 83% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:23])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCC(C)CCOc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)CCCC(C)CCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 4-(3,7-dimethyl-1-octyloxy)benzoic acid was dissolved in anhydrous chloroform (25 ml), and after ice-cooling, thionyl chloride (6.72 ml, 92.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to give the title compound as an oil. The present compound was directly used for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[N:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)([O-:3])=[O:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:46](=[O:50])[CH:47]([CH3:49])[CH3:48].O>O1CCCC1>[OH:50][CH:46]1[C:16]2[C:9](=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[CH:15]=2)[NH:8][CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:47]1([CH3:49])[CH3:48]
Reactant: CC(C)C=O
Reactant: N#Cc1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(O)c2cc(C#N)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a mixture of 4-[(3-nitro-benzylidene)-amino]-benzonitrile (21 g, 84 mmol) and ytterbium(III) triflate hydrate (5.21 g, 8.4 mmol) in dry tetrahydrofuran (150 mL) at 25° C. was added isobutyraldehyde (8.4 mL, 92 mmol) and water (1.5 mL, 84 mmol) dropwise. The reaction mixture was stirred at 25° C. for 15 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (25 g, 92%) as a light yellow oil: LC/MS m/e calcd for C18H17N3O3 (M+H)+: 324.35, observed: 324.1.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH:19]([C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[CH:22]2[CH2:23][NH:24][CH2:25][CH2:26][NH:21]2)[CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: C1CNCCN1
Reactant: O=Cc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Product: O=Cc1cccc(-n2c(C3CNCCN3)c(C=O)c3ccccc32)c1
Yield: 59 %

Procedure:
2-Chloro-1-(3-formylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-formylphenyl)-2-(piperazin-2-yl)-1H-indole-3-carboxaldehyde (59% yield) as a cream solid. ESI/MS 334 (M+H); RT 2.29 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1.N(C)C.Cl>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)=[C:16]([OH:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(OC(C)C)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.3 g, 0.79 mmol) and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.17 g, 0.95 mmol, described in Step 3 of example B(75)) were dissolved in 3:1 MeOH/CH2Cl2 (4 mL). To this suspension, Me2NH.BH3 (0.07 g, 1.19 mmol) was added as a solid from top. After stirring 1 h at room temperature, the reaction mixture became clear and it was stirred for an additional 5 hours. After this time, 1 M HCl (1 mL) was added and the reaction stirred for 30 minutes at room temperature, the solvent was the evaporated to half the volumen and extracted 3 times with 10% MeOH/CH2Cl2 (10 mL). The organic phase was dried over MgSO4 and evaporated. The residue purified by flash column chromatography (80% EtOAc in hexanes) to eliminate unreacted pyrone and reduced 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde, then 3% MeOH/CH2Cl2 to give the product (0.1 g, 24%) as a white solid. 1H NMR (DMSO-d6): δ 1.14 (d, J=6.3, 6H), 1.4-1.53 (m, 8H), 1.7-1.75 (m, 2H), 1.95-1.98 (m, 1H), 2.35-2.44 (m, 8H), 3.19 (s, 2H), 3.57 (d, J=16 Hz, 1H), 3.69 (d, J=16 Hz, 1H), 4.41-4.47 (m, 1H), 6.91-6.93 (s, 1H), 7-7.07 (m, 2H), 7.10 (d, J=2.0, 1H), 10.7 (brs, 1H). Anal. Calcd. For C29H35N4O4: C, 64.61; H, 6.54; N, 10.39. Found: C, 64.30; H, 6.81; N, 10.35. ESIMS (MH+): 540
Reaction SMILES: [S:1]=[C:2](C(S)C(OCC)=O)[CH3:3].[NH:11]([C:13]([O:15][CH3:16])=[O:14])[NH2:12].C(Cl)(Cl)Cl.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>ClCCl>[S:1]=[C:2]([NH:12][NH:11][C:13]([O:15][CH3:16])=[O:14])[CH3:3]
Reactant: COC(=O)NN
Reactant: CCOC(=O)C(S)C(C)=S
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)NNC(C)=S
Yield: 65.3 %

Procedure:
A mixture of 129 g of 2-(1-thioxoethyl)thioglycolic acid, ethyl ester, 67.5 g of methyl hydrazinocarboxylate and 500 ml of chloroform was heated at reflux for 8 hours, then concentrated in vacuo. The oily residue was concentrated further under high vacuum, giving a yellow oil. This oil was dissolved in 500 ml of dichloromethane and passed through a bed of hydrous magnesium silicate, washing with additional dichloromethane. The resulting light yellow oil was crystallized from toluene-methylcyclohexane, giving 70 g of the desired compound as ivory crystals, mp 99-100.5° C. Proton nuclear magnetic resonance (δ [ppm], CDCl3) 90MHz: 2.42 (s, 3H, CH3CS); 3.76 (s, 3H, OCH3); 8.55 (bs, 1H, NH); 9.56 (bs, 1H, NH).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[C:10]1(C)C(O)=CC=C[CH:11]=1>>[CH2:10]([C:5]1[C:4]2[O:9][CH:2]=[CH:1][C:3]=2[CH:8]=[CH:7][CH:6]=1)[CH3:11]
Reactant: Cc1ccccc1O
Reactant: CCc1ccccc1O
Product: CCc1cccc2ccoc12

Procedure:
7-Ethyl-benzofuran is prepared by the method described in J.Chem.Soc. 1920, 1534, but using o-ethylphenol inste of o-cresol. The MS. of the product thus obtained shows the following ion peaks with the relative intensities given within brackets: 131 (100%), 146 (38%) and 77 (10%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[O:27][CH2:26]1>CCOC(C)=O>[N+:9]([C:5]1[CH:4]=[N:3][C:2]2[NH:1][CH:25]([CH2:26][OH:27])[CH2:24][O:8][C:7]=2[CH:6]=1)([O-:11])=[O:10]
Reactant: BrCC1CO1
Reactant: Nc1ncc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2c(c1)OCC(CO)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
Into a 75 mL sealed tube were combined 2-amino-3-hydroxy-5-nitropyridine (0.138 g, 0.000890 mol), N,N-dimethylformamide (4.1 mL) and potassium carbonate (0.39 g, 0.0028 mol). The mixture was allowed to stir at room temperature for 10 minutes then 1-bromo-2,3-epoxypropane (0.12 g, 0.00089 mol) was added in one portion. The flask was sealed, then heated to 110° C. and stirred overnight. After allowing to cool, the mixture was concentrated under vacuum to give a crude solid which was dissolved in EtOAc (75 mL), washed with water and brine, then dried (Na2SO4), filtered and concentrated under vacuum to leave a crude residue. The residue was purified by column chromatography on silica gel using MeOH/CH2Cl2 (0-10% gradient) as eluent to give a solid (0.092 g, 46%). LC-MS 1.92 min. M/Z=212.0 (M+1). 1H NMR (d6-DMSO) δ 8.8 (d, 1 H), 7.8 (d, 1 H), 5.1 (t, 1H),4.2 (m, 1 H), 4.0 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>C(N(CC)CC)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1cnc2ccccc2c1
Yield: 136.9 %

Procedure:
A solution of 3-bromoquinoline (13.57 mL, 0.10 mol) and 3-butyn-1-ol (9.0 mL, 0.12 mol) in 40 mL of triethylamine and 75 mL of dichloromethane is degassed by bubbling in dry nitrogen for 15 minutes, and 0.7 g (0.001 mol) of bis(triphenylphosphine)palladium chloride and 0.013 g of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is heated to reflux for 5 hours. The cooled mixture is diluted with dichloromethane and washed with water, dried (sodium sulfate), and concentrated to give 27 g of an oil. The oil is triturated with diethyl ether to give 18.2 g of the title compound as a tan solid; mp 95.7°-96.7° C.
Reaction SMILES: C(O[C:4](=[O:30])[N:5]([C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:16]=[C:15]([NH2:26])[C:14]=1[N+:27]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>C(O)(=O)C.CO.[Zn]>[NH2:26][C:15]1[C:14]2[NH:27][C:4](=[O:30])[N:5]([CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:13]=2[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:16]=1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(-c2ccccc2F)nc(N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(-c2ccccc2F)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
[2-Amino-6-(2-fluoro-phenyl)-3-nitro-pyridin-4-yl]-benzyl-carbamic acid ethyl ester (31 mg) was dissolved in acetic acid (1 ml). Zinc powder (Aldrich, 99%, 20 mg) was added and the mixture left to stir at room temperature under nitrogen for 2 hours. Additional zinc powder (30 mg) was added and mixture left to stir for a further 1 hour. The reaction mixture was diluted with methanol (2 ml) then filtered directly onto a cation exchange cartridge (Bakerbond SCX, sulphonic acid bonded-phase, 1 g). The SCX cartridge was washed with methanol (2×5 ml) to remove impurities and then the product was released with ammonia in methanol (2 M, 5 ml). The desired fraction was evaporated to a pale brown solid. This was triturated with ethyl acetate then filtered and washed with more ethyl acetate to yield the title compound (8 mg) as a pale purple solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 2 H) 5.82 (s, 2 H) 6.87 (d, J=1.95 Hz, 1 H) 7.15-7.29 (m, 3 H) 7.29-7.39 (m, 5 H) 7.81 (td, J=8.01, 1.95 Hz, 1 H) 10.51 (s, 1 H), LCMS Rt=2.21 m/z 335 [MH]+
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[C:30]([NH2:39])(=[O:38])[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[C:30](=[O:38])[NH2:39])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Reactant: NC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
200 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 2.0 ml of 1-methyl-2-pyrrolidone, and 85 mg of salicylamide and 129 mg of potassium carbonate were added thereto. The mixture was stirred at 100° C. for 2 hours. After the reaction mixture had been cooled to room temperature, 5.0 ml of water was added thereto. After the mixture had been stirred at room temperature for 1 hour, the white precipitate was collected by filtration. The resulting white solid was washed with water and ether to give of 221 mg of the title compound (89%).