Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>ClCCl.C(O)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][NH:11][O:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Clc1ccc(C=NOCCCN2CCOCC2)cc1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc(CNOCCCN2CCOCC2)cc1Cl
Temperature: 60 °C
Yield: 94 %

Procedure:
A solution of 3,4-dichlorobenzaldehyde O-(3-morpholin-4-yl-propyl)-oxime (0.160 g, 0.5 mmol) in a mixture of dichloromethane (2 ml) and acetic acid (1 ml) was treated with borane-pyridine complex (0.17 ml, 1.36 mmol) and the resulting mixture was heated under reflux (bath temperature 60° C.) for 4 h. The solvent was then evaporated under reduced pressure and the residue was treated with 10% aqueous hydrochloric acid (3 ml). The reaction mixture was then basified with solid sodium carbonate and extracted with ethyl acetate. The organic phase was then washed with brine, dried (anhydrous magnesium sulfate) and concentrated to give 0.150 g (93% yield) of the crude title hydroxylamine as a light yellow oil which was used as such for the acylation step. 1HNMR 400 MHz (C6D6) δ (ppm): 1.66 (2H, m, CH2), 2.22 (2H, t, J=7.1 Hz, NCH2), 2.24 (4H, m, NCH2), 3.56 (2H, s, NCH2), 3.69 (4H, m, OCH2), 3.70 (2H, t, J=6.5 Hz, OCH2), 5.2 (1H, broad, NH), 6.82 (1H, dd, J=1.9 Hz and J=8.5 Hz, aromatic), 7.13 (1H, d, J=8.5 Hz, aromatic), 7.33 (1H, d, J=1.9 Hz, aromatic).
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce].[CH2:7]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([CH:18]=1)=[C:16]([O:19]C)[CH:15]=[CH:14][C:13]=2[O:21]C)[CH3:8]>O.C(#N)C>[CH2:7]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:13](=[O:21])[CH:14]=[CH:15][C:16](=[O:19])[C:17]=2[CH:18]=1)[CH3:8]
Reactant: CCc1cc2c(OC)ccc(OC)c2[nH]c1=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCc1cc2c([nH]c1=O)C(=O)C=CC2=O
Reaction time: 0.08 h
Yield: 108.3 %

Procedure:
Cerium ammonium nitrate (284 mg, 0.5 mmol) was added in small portions to a stirred suspension of 3-ethyl-5,8-dimethoxy-1H-quinolin-2-one(50 mg, 0.2 mmol) in water (0.5 ml) and acetonitrile (1 ml). After 5 minutes at room temperature, water (3 ml) was added and the reaction mixture was extracted with chloroform (3×20 ml), yielding 3-ethyl-1H-quinoline-2,5,8-trione (44 mg, 100 %). The analytical sample was obtained by rapid silica gel chromatography, eluting with ethyl ether.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:29])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:29])[C:26]=1[O:27][CH3:28])[C:21]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:22]
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1Cl
Reactant: c1ccc2c(c1)NCS2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (50 mL), and triethylamine (17.4 mL) and 3,5-dichloro-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (d).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.Cl.[CH:24]([N:27]([CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O>[CH:33]([N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29][C:30]([O:32][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:31])([CH3:35])[CH3:34]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)N(CCC(=O)O)C(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)N(CCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)C(C)C
Yield: 27.7 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.9 g) in anhydrous dimethylformamide (70 cc), 3-diisopropylaminopropionic acid hydrochloride (4.4 g) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (7.45 g), and after the residue obtained has been recrystallized successively, first in acetonitrile and then in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 3-diisopropylaminopropionate (2.7 g), m.p. 135° C., is obtained.
Reaction SMILES: [N:1]#[C:2]Br.C([O-])([O-])=O.[K+].[K+].Cl.C[N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)[CH2:14][CH2:13]1.O>CS(C)=O>[C:27]1([N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:2]#[N:1])[CH2:13][CH2:14]3)=[N:19]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a mixture of cyanogen bromide (5.76 g, 0.054 moles) and K2CO3 (8.82 g, 0.064 moles) in dimethylsulfoxide (110 ml) was added 3-(1-methyl-4-piperidinyl)-1-phenyl-1H-indazole (14.8 g, 0.051 moles) of Example 66 in dimethylsulfoxide (DMSO) (15 ml). The reaction was stirred at ambient temperature for 16 hours and then poured into water and extracted with ether. A precipitate formed in the ether which was collected and then the ether was concentrated to yield additional product. The crude product (11.5 g) was recrystallized three times from isopropyl alcohol which yielded 6.75 g (37%) of 4-(1-phenyl-1H-indazol-3-yl)-piperidine- 1-carbonitrile, m.p. 124°-125° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[CH:23]=3)[CH:11]=[CH:12][C:6]=2[N:5]=1.CCN(C(C)C)C(C)C.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>ClCCl>[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:18][C:17]=4[CH:23]=3)[CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N1CCOc2ccc(-c3ccc4nc(C)[nH]c4c3)cc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-(2-methyl-1H-benzimidazol-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine dihydrochloride (6.95 g, 19.73 mmol) was suspended in dichloromethane (100 mL) and cooled to 0° C. To the resulting mixture was added DIPEA (19 mL, 109 mmol) followed by allyl chloroformate (4.6 mL, 43.4 mmol) and stirring was continued at 0° C. for 30 minutes then warmed to room temperature. The reaction mixture was then charged with additional DIPEA (3.4 mL) and allyl chloroformate (1 mL) then stirred an additional 30 minutes at room temperature. The resulting solution was then concentrated and the residue azeotroped once from methanol (100 mL). The residue was then taken back into methanol (100 mL) followed by portionwise addition of 2 M aqueous sodium hydroxide (20 mL) and the mixture was allowed to stir for 1 h at room temperature. The solution was then concentrated and the residue partitioned with chloroform and dilute brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to give prop-2-en-1-yl 7-(2-methyl-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate as an amorphous residue which was carried forward directly into step 6.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:20])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>C(OCC)(=O)C.CO>[CH3:23][N:24]([CH3:26])[CH:25]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:20])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccc(N(C)S(=O)(=O)c2ccccc2)c1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C=CC(=O)c1cccc(N(C)S(=O)(=O)c2ccccc2)c1
Yield: 84 %

Procedure:
1.25 g (4.32 mmol) of N-(3-acetyl-phenyl)-N-methyl-benzenesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.25 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-benzenesulfonamide as a yellowish-white solid were obtained (yield 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[Cl:16][C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19]>CN(C=O)C.O>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]2[C:6]=1[C:11](=[O:12])[O:10][C:8]12[C:20]2[CH:21]=[CH:22][C:23]([OH:24])=[C:17]([Cl:16])[C:18]=2[O:19][C:23]2[C:22]1=[CH:21][CH:20]=[C:18]([OH:19])[C:17]=2[Cl:16]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Oc1cccc(O)c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC2(c3ccc(O)c(Cl)c3Oc3c2ccc(O)c3Cl)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 91.8 %

Procedure:
Treatment of tetrachlorophthalic anhydride (5 g, 17.49 mmol) and 2-chlororesorcinol (7.58 g, 41.98 mmol) according to the procedure described in Example 1, Step 1, provided 9.3 g of the crude product. Suspension of 8 g of the crude 9.3 g in DMF:water (1:1), followed by filtration provided 8.65 g (16.05 mmol, 91.7% AUC yield) of 4,4′,5,5′,6,7-hexachloro-3′,6′-dihydroxy-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one that was isolated as an orange solid. 1H NMR (300 MHz; DMSO d6) δ 11.09 (S, 2H), 7.03 (d, J=9 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[CH3:19][C@H:20]1[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][O:21]1.[Cl-].[NH4+]>C1COCC1>[Cl:13][C:14]1[S:15][C:16]([C@@:24]2([OH:26])[CH2:23][CH2:22][O:21][C@@H:20]([CH3:19])[CH2:25]2)=[CH:17][N:18]=1
Reactant: Clc1nccs1
Reactant: C[C@H]1CC(=O)CCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@H]1C[C@@](O)(c2cnc(Cl)s2)CCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
n-Butyl-lithium (2.5M in hexane, 57.5 ml) was dropwise added during 30 minutes to a solution of di-isopropylamine (19.3 ml) in THF (180 ml) which had been cooled to -78° C. The mixture was stirred at -78° C. for 1 hour. The reaction vessel was shielded from light and 2-chlorothiazole (15.0 g) was added dropwise during 20 minutes, whilst keeping the temperature of the reaction mixture below -70° C. The mixture was stirred at -78° C. for 1.5 hours. (2S)-2-Methyltetrahydropyran-4-one (12.9 g) was added during 20 minutes. The mixture was stirred and allowed to warm briefly to -25° C. to obtain a homogeneous solution. The mixture was recooled to -70° C. and stirred at that temperature for 1 hour. A 5% aqueous solution of ammonium chloride was added and the mixture was extracted with diethyl ether. The organic solution was washed with brine, dried (MgSO4) and evaporated. There was thus obtained a mixture (29.4 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 1:4. The mixture so obtained was dissolved in diethyl ether (250 ml) and the solution was cooled to 0° C. A concentrated (25% v/v) aqueous solution of sulphuric acid was added and the mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (750 ml) and neutralised to pH3 by the addition of sodium bicarbonate. The organic solution was washed with brine, dried (MgSO4) and evaporated to give a mixture (26 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 9:1. The material was purified by column chromatography using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran (21 g, 79%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[S:31][C:8]2[NH:9][C:10]([C:12]([NH:14][CH:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][C:26]([O:28]C)=O)[C:16]3=[O:30])=[O:13])=[CH:11][C:7]=2[CH:6]=1>CCO>[Cl:4][C:5]1[S:31][C:8]2[NH:9][C:10]([C:12]([NH:14][CH:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][C:26]([NH:2][NH2:3])=[O:28])[C:16]3=[O:30])=[O:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: NN
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Yield: 76 %

Procedure:
Hydrazine monohydrate (1 mL, 20.6 mmol) was added to a suspension of methyl [3-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate (Example 1); 221 mg, 0.53 mmol) in EtOH (10 mL) and heated to reflux for 20 hours. On cooling the mixture was concentrated under reduced pressure and H2O (20 mL) added and the white precipitate filtered off and dried in vacuo to give the title product (169 mg, 76%) as an off white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@:10]([CH2:29][O:30][S:31]([CH3:34])(=[O:33])=[O:32])([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][CH:6]1OC)(=[O:3])[CH3:2].[C:35]1([S:41][Si](C)(C)C)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>ClCCl>[C:1]([O:4][C@@H:5]1[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@:10]([CH2:29][O:30][S:31]([CH3:34])(=[O:33])=[O:32])([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:9][C@H:6]1[S:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Sc1ccccc1
Reactant: COC1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](Sc2ccccc2)O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 8.8 %

Procedure:
Method a. A stirred solution of 209 (738 mg, 1.49 mmol) in anhydrous dichloromethane (6.4 mL) was added phenylthiotrimethylsilane (2.42 mL, 12.8 mmol) and cooled to 0° C. Trimethylsilyl triflate (0.67 mL, 3.67 mmol) was added dropwise and the solution was stirred at room temperature for 4 h. The reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (100 mL) and extracted with dichloromethane (2×200 mL). The combined extract was dried (MgSO4) and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel with dichloromethane as eluent to given the product 210 as a clear oil (564 mg, 66%) and unreacted starting material (191 mg, 26%); Method b. A stirred solution of 211 (86 mg, 0.165 mmol) in anhydrous dichloromethane (0.49 mL) was added phenylthiotrimethylsilane (0.16 mL, 0.825 mmol) and cooled to 0° C. Trimethylsilyl triflate (0.037 mL, 0.206 mmol) was added and the solution was stirred at room temperature for 2 h. The reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and the resulting mixture was extracted with dichloromethane (2×25 mL). The combined extract was dried (MgSO4) and the solvent removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel with dichloromethane as eluent to give the product 210 as a clear oil (75 mg, 79%); 1H NMR (CDCl3); δ7.47-7.19 (15H, m, Bn, SPh), 5.48 (1H, d, J 3.6 Hz, H-2), 5.34 (1 H, dd, J 3.7, 5.2 Hz, H-1), 4.54-4.36 (7H, m, H-3, H-5′, Bn), 3.66 (1H, d, J 9.7 Hz, H-5), 3.48 (1H, d, J 9.5 Hz, H-5), 2.89 (3H, s, SO2CH3), 2.09 (3H, s, OCCH3); 13C NMR (CDCl3): δ169.93 (C═O), 137.69, 137.08, 132.65, 32.45, 129.15, 128.53, 128.52, 128.18, 128.14, 128.08, 127.91, 127.85 (Bn, SPh), 87.99, 84.35, 80.34, 75.33, 74.20, 73.67, 70.83, 69.34 (C-1, C-2, C-3, C-4, C-5, C-5′, Bn), 37.27 (SO2CH3), 20.68 (OCCH3); MS FAB: 463 (M−Sph, 100%), 595 (M+Na, 24%); Found: C, 61.17; H, 5.55; C29H32O8S2 requires C, 60.82; H, 5.63%.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[C:7]1([S:13]([NH:16][C:17]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:18]=2[NH2:19])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([NH:16][C:17]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:18]=2[NH:19][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)N=C=O
Reactant: N#Cc1ccc(N)c(NS(=O)(=O)c2ccccc2)c1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccc(C#N)cc1NS(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a solution of isopropylisocyanate (31.2 mg, 0.37 mmol) in DMF (0.5 ml), 2-benzenesulfonylamino-4-cyanoaniline (100 mg, 0.37 mmol) was added. The reaction mixture was stirred at 80° C. for 3 hours. Chromatography of the resulting liquid on silica gel gave the desired product (85 mg, 65%). EI-MS m/z 359.4 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20]OC2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[C:33]1([C:39]2[CH:46]=[CH:45][C:42]([CH2:43][OH:44])=[CH:41][CH:40]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:44][CH2:43][C:42]2[CH:41]=[CH:40][C:39]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:46][CH:45]=2)[CH2:14][CH2:13]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: OCc1ccc(-c2ccccc2)cc1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccc(-c3ccccc3)cc2)CC1

Procedure:
Compound 23 was prepared in a similar manner to compound 7, substituting the commercially available 4-phenylbenzylalcohol for 2-propanol in part C. MS (M+1)=488.42
Reaction SMILES: CN(C=O)C.O[C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:8]=12.O=S(Cl)[Cl:22]>O>[Cl:22][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:8]=12
Reactant: CSc1nc2ncc(C#N)c(O)c2s1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ncc(C#N)c(Cl)c2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1f (34.6 g, 120 mmol), DMF-dimethyl acetal (34.0 mL, 240 mmol, 94% purity) and DMF (200 mL) were combined and heated to 80° C. for 90 minutes. The conversion to the cyclized intermediate, 7-hydroxy-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile was confirmed by LCMS (MS 298, MH+). The mixture was then cooled to 0° C. and SOCl2 was added dropwise (44 mL, 600 mmol). The reaction mixture was stirred for 2 hrs at ambient temperature. The mixture was then cooled back down to 0° C. and water (approximately 300 mL) was added dropwise. The resulting brown solid was collected by filtration and subsequently washed with water and MeOH to provide 7-chloro-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile Compound 1g (16.1 g) as a tan solid. 1H NMR (CDCl3) δ 8.82 (s, 1H), 2.91 (s, 3H). MS 242, 244 (MH+), 264, 266 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14]O)=[CH:4][CH:3]=1.[Li+].[Br-].P(Br)(Br)[Br:19].O>CN(C=O)C>[Br:19][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1-c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2ccccc2CBr)cc1
Reaction time: 1 h

Procedure:
To a mixture of Example 37A (7.9 g) and LiBr (3.45 g) in DMF (100 mL) at 0° C. was added PBr3 (3.77 mL) and the reaction was stirred for 1 hour. The reaction was poured into water (400 mL), and the mixture was extracted with ether (3×200 mL). The combined ether layers were washed with 3× water, and brine, dried over Na2SO4, and condensed to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[N:7]=[C:6]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1nccc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 40 °C

Procedure:
A mixture of 9.9 g (0.0664 mol) of 2,4-dichloropyrimidine, 200 ml of water and 11.7 ml (0.0673 mol) of 1-(phenylmethyl)piperazine was heated to 40° C. for 2 hours in an ultrasound bath. After cooling the mixture was made alkaline with potassium carbonate and extracted thoroughly with ethyl acetate. The crude product obtained after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM2 and FM4 (2/1 v/v) as eluant. Working up the appropriate fractions yielded 7.4 g (38.6% of theory) of a colourless oil, Rf=0.51 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])=[CH2:2].[Cl:10]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[CH2:3]
Reactant: C=C(C)c1ccccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(CCl)c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.4 %

Procedure:
A mixture of 4.0 g of 2-isopropenylpyridine, 4.5 g of N-chlorosuccinimide and 8 ml of carbon tetrachloride was stirred at 150° to 160° C. for 20 minutes. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1) to obtain 1.0 g of the objective compound.