Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][OH:6])[CH3:2].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH3:7])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
20.8 g (0.20 mol) of 2-ethoxypropanol are added slowly during 20 minutes with stirring to a mixture of 43.3 g (0.227 mol) of toluene-p-sulphonylchloride and 20 ml of dry pyridine. The temperature of the reaction mixture is kept at 20° with external cooling. After stirring for 2 hours at 20°, the mixture is poured into ice-water and extracted with ether. The ether layer is washed with 2N sulphuric acid, with water and with saturated sodium hydrogencarbonate solution. After drying over sodium sulphate, filtration and evaporation in vacuo, 2-ethoxypropyl toluene-p-sulphonate is obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[S:23][C:18]=2[C:17]=1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>O1CCCC1.O>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[S:23][C:18]=3[C:17]=2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:2]([NH:1][C:45](=[O:46])[CH2:44][Cl:43])[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3N)c(C3CCCCC3)c2s1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3NC(=O)CCl)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
To a suspension of methyl 5-(2-amino-4-benzyloxyphenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (6.30 g, 13.8 mmol), sodium acetate (1.36 g, 16.6 mmol) and acetic acid (0.95 ml, 16.6 mmol) in tetrahydrofuran (100 ml) was added dropwise chloroacetyl chloride (1.32 ml, 16.6 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The obtained crude product of methyl 5-[4-benzyloxy-2-(2-chloroacetylamino)phenyl]-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (8.22 g) was used for Step 6 without further purification.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:25]([N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:37][CH2:38][CH:39]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+].[OH-].[Na+]>C(O)C.C(#N)C>[CH2:25]([N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:37][CH2:38][CH2:39][NH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:4])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=CCCc1nccn1Cc1ccccc1
Reactant: COc1ccc(S(=O)(=O)NCCc2ccc(C(C)(C)N)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: COc1ccc(S(=O)(=O)NCCc2ccc(C(C)(C)NCCCc3nccn3Cc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-{2-[4-(1-amino-1-methylethyl)phenyl]ethyl}-4-methoxybenzenesulphonamide (0.97 g), 3-(1-benzylimidazol-2-yl)propionaldehyde (0.66 g), 4A molecular sieves (0.7 g) and acetonitrile (15 ml) was stirred at ambient temperature for 18 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to give a residue which was dissolved in absolute ethanol (15 ml). Sodium borohydride (0.18 g) was added to the ethanolic solution and the mixture was boiled under reflux for 3 hours. The solvent was removed under reduced pressure and water was added to the residue followed by dilute hydrochloric acid to give an acidic mixture. After 20 minutes the mixture was basified with dilute sodium hydroxide solution and extracted with ethyl acetate to give an oil which was purified with flash column chromatography on silica to give N-[2-(4-{1-[3-(1-benzylimidazol-2-yl)propylamino]-1-methylethyl}phenyl)ethyl]-4-methoxybenzenesulphonamide. A mixture of this product (0.61 g), absolute ethanol (30 ml), ammonium formate (0.42 g) and 10% palladium on carbon (0.91 g) was boiled under reflux for 1 hour. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a residue which was purified by flash column chromatography on silica using ethyl acetate/methanol/triethylamine (18:1:1) as the mobile phase to give N-[2-(4-{1-[3-(imidazol-2-yl)propylamino]-1-methylethyl}phenyl)ethyl]-4-methoxybenzenesulphonamide as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=1)[CH2:9][CH3:10].[NH3:29]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH2:29])=[O:19])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)cn1
Reactant: N
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[N-(5-bromo-2-benzyloxybenzyl)-N-ethylamino]pyridine-5-carboxylic acid (1.4 g) [table 1a, compound 2] and 1,1-carbonyldiimidazole (0.62 g) were heated in DMF at 55° C. for 3 hours. The mixture was cooled to ambient temperature, aqueous ammonia (20 ml) was added and the mixture was stirred for 18 hours. The solvent was evaporated and the residue purified by MPLC eluting with methanol: dichloromethane (5:95) to give 2-[N-(5-bromo-2-benzyloxybenzyl)-N-ethylamino]pyridine-5-carboxamide (671 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a 100 mL roundbottom flask was charged 4-bromopyrazole (13.6 mmol, 2.00 g), K2CO3 (20.4 mmol, 2.82 g), and DMF (20 mL). To this suspension was added 2-(trimethylsilyl)ethoxymethyl chloride (15.0 mmol, 2.64 mL). This suspension was allowed to stir at room temperature 18 hours. The reaction mixture was then concentrated in vacuo, dissolved in 20 mL DCM, and filtered through celite. The crude mixture was purified via silica gel chromatography (0% to 80% ethyl acetate in hexanes gradient) to yield 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.53 g, 9.12 mmol, 67% yield) as clear oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.[N:18]1[NH:19][C:20](=[O:24])[CH:21]=[CH:22][CH:23]=1.CNCCNC>N1C=CC=CC=1.C(Cl)Cl.[Cu]I>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:19]2[C:20](=[O:24])[CH:21]=[CH:22][CH:23]=[N:18]2)=[CH:3][CH:4]=1
Reactant: O=c1cccn[nH]1
Reactant: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(-n2ncccc2=O)cc1

Procedure:
A solution of the product from Example 8F, 1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine (100 mg, 0.340 mmol), pyridazin-3(2H)-one (52.3 mg, 0.544 mmol), N1,N2-dimethylethane-1,2-diamine (0.088 mL, 0.816 mmol) and copper(I) iodide (78 mg, 0.408 mmol) in pyridine (2 mL) under a nitrogen atmosphere in a sealed vial was heated in an oil bath to 135° C. for 16 hours. The reaction mixture was cooled and diluted with DCM (10 mL), filtered through diatomaceous earth and washed with DCM. The filtrate was washed sequentially with H2O, 28-30% NH4OH (10 mL×2), and H2O, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with concentrated concentrated NH4OH/MeOH/DCM (0.4/4/96) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 0.90-0.97 (m, 1H), 1.03-1.09 (m, 1H), 1.15 (d, J=6 Hz, 3H), 1.23-1.33 (m, 1H), 1.39-1.49 (m, 1H), 1.70-1.80 (m, 2H), 1.82-2.05 (m, 3H), 2.26-2.42 (m, 2H), 3.16 (dd, J=12 Hz, J=6 Hz, 1H), 3.21-3.28 (m, 1H), 7.07 (d, J=6 Hz, 2H), 7.21 (dd, J=6 Hz, J=1.5 Hz, 2H), 7.43 (d, J=6 Hz, 2H), 7.47 (dd, J=9 Hz, J=3 Hz, 1H), 8.02 (dd, J=6 Hz, J=1.5 Hz, 1H). MS (DCI—NH3) m/z 310 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH3:35])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: COC(=O)Cl
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (1 mL) was added methyl chloroformate (2.7 μL, 0.035 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.4 mg, 12%). LCMS calculated for C19H22N5O2S (M+H)+: m/z=384.1. Found: 384.0.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1>CN(C=O)C.O>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: Cc1cc(CBr)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(C)c2)c1-c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (15 mg, 0.036 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. Sodium hydride (0.175 mmol, 7 mg, 60% dispersion in oil) was added followed by dropwise addition of 4-(bromomethyl)-1-fluoro-2-methylbenzene. The reaction was stirred at ambient temperature 15 minutes, diluted with water and extracted with ethyl acetate, dried over sodium sulfate and purified by silica-gel chromatography (0-50% ethyl acetate/hexanes gradient elution) to give the title compound as a colorless oil 17 mg, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.52-7.46 (m, 1 H), 7.42-7.35 (m, 1 H), 7.34-7.26 (m, 2 H), 7.16 (d, J=7.2 Hz, 1 H), 7.11 (td, J=2.3, 5.3 Hz, 1 H), 7.02-6.92 (m, 2 H), 6.15 (d, J=3.5 Hz, 1 H), 5.44-5.39 (m, 2 H), 3.77 (s, 3 H), 2.74 (s, 3 H), 2.47 (s, 3 H), 2.26 (d, J=1.4 Hz, 3 H), 1.67 (s, 1 H), 0.93 (s, 9 H); LCMS (m/z) ES+=489 (M+1).
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([S:30]([NH:33][CH:34]2[CH2:38][CH2:37][O:36][NH:35]2)(=[O:32])=[O:31])[C:24]=1[OH:39])=[S:21].[Si:40](Cl)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].N1C=CN=C1>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([S:30]([NH:33][CH:34]2[CH2:38][CH2:37][O:36][NH:35]2)(=[O:31])=[O:32])[C:24]=1[O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])=[S:21]
Reactant: O=S(=O)(NC1CCON1)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1c(NC(=S)Nc2cccc(Cl)c2Cl)ccc(Cl)c1S(=O)(=O)NC1CCON1
Yield: 49.3 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 1, N-(2,3-dichlorophenyl)-N′-[4-chloro-2-hydroxy-3-(N″-tetrahydroisoxazylaminosulfonyl)phenyl]thiourea (898 mg, 1.81 mmol), tert-butyldimethylsilyl chloride (1.4 g, 9.05 mmol) and imidazole (246 mg, 3.62 mmol) were reacted to form the desired product (546 mg, 49%). EI-MS m/z 611.81 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC(C)C)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.67 (br s, 1H, NH), 8.45 (d, 1H, J=1.8 Hz), 7.75 (d, 1H, J=8.8 Hz), 7.68 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (d, 2H, J=9.0 Hz), 7.50 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.32 (d, 1H, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 4.43 (septet, 1H, J=6 Hz), 2.65 (s, 3H), 1.28 (d, 3H, J=6 Hz). MS: m/z 445 (M+1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)[N:10]3[N:17]=[CH:18][C:19]([CH:20]=O)=[C:9]3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:22]1[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24].N1CCCCC1>C(O)C>[CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)[N:10]3[N:17]=[CH:18][C:19](/[CH:20]=[C:28]4/[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22]/4)=[C:9]3[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(NC3CCCC3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(NC4CCCC4)nc23)N1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
5-(Cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (1.0 eq, 20 mg, 0.070 mmol) was mixed in a vial with hydantoin (2.8 eq, 20 mg, 0.20 mmol) in Ethanol (0.3 ml). Piperidine (2.9 eq, 20 ul, 0.202 mmol) was added and the mixture was stirred at 90° C. for 3 hours. The mixture was cooled down, the precipitate was filtered, washed with ethanol and dried. (Z)-5-((5-(cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione was isolated as a solid (25 mg, 100%). LCMS (ES):>95% pure, m/z 368 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1SC(CO)=N[N:6]=1.CSC(=NC#N)SC.[NH2:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[C:27]([Br:28])=[CH:26][CH:25]=[CH:24][N:23]=1.CN.Br.Br.NCCSC[C:38]1C(Br)=CC=[CH:40][N:39]=1>C(O)C>[C:2]([NH:6][C:40]([NH:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[C:27]([Br:28])=[CH:26][CH:25]=[CH:24][N:23]=1)=[N:39][CH3:38])#[N:1]
Reactant: Nc1nnc(CO)s1
Reactant: NCCSCc1ncccc1Br
Agent: Br
Agent: CN
Agent: CSC(=NC#N)SC
Solvent: CCO
Product: CN=C(NC#N)NCCSCc1ncccc1Br
Reaction time: 8 h

Procedure:
A solution sodium nitrite (2.28 g) in water (10 ml) was added dropwise to a stirred mixture of 3-amino-2-hydroxymethylpyridine (4.8 g) in aqueous hydrobromic acid (48%, 10 ml) and water (5 ml) at 0.5° C. This solution of the diazonium salt was added to a hot solution of cuprous bromide (2.5 g) in 60% hydromic acid and following cessation of nitrogen evolution the mixture was heated on the steam bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. Filtration, concentration to low bulk and extraction with chloroform yielded 3-bromo-2-hydroxymethylpyridine (4.8 g). This was dissolved in aqueous hydrobromic acid (48%, 50 ml), cysteamine hydrochloride (3.22 g) added and the solution obtained was heated under reflux for 6 hours. Concentration, followed by recrystalliation from aqueous ethanol afforded 2-((2-aminoethyl)thiomethyl)-3-bromopyridine dihydrobromide (6.1 g), m.p. 252°-254°. (Found: C, 23.7; H, 3.4; N, 6.7; S, 7.9; C8H11Br N2S.2HBr. requires: C, 23.5; H, 3.2; N, 6.9; S, 7.8). (ii) Sequential reaction of dimethylcyanodithioimidocarbonate with 2-((2-aminoethyl)thiomethyl)-3-bromopyridine) and excess methylamine at room temperature in ethanol, the methylamine being added after initial standing overnight and the solution then allowed to stand for a further four hours, followed by chromatographic purification on a column of silica gel with elution by ethyl acetate and final recrystallisation from ethyl acetate-petroleum ether gave N-cyano-N'-[2-((3-bromo-2-pyridyl)methylthio)ethyl]-N"-methylguanidine m.p. 114°-116°. (Found: C, 40.6; H, 4.4; N, 21.4; S, 9.8. C11H14Br N5S. requires: C, 40.3; H, 4.3; N, 21.3; S, 9.8).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].Cl[C:25]1C=CC=CC=1Cl>>[CH3:25][C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([S:14]([NH2:13])(=[O:16])=[O:15])=[C:18]([S:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:19]1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccccc1Cl
Product: CC1(C)C=CC(S(N)(=O)=O)=C(S(=O)(=O)c2ccccc2)C1

Procedure:
4-Methylbenzenesulfonyl chloride (3.80 g, 0.02 mol) and N-methyl-4-methylbenzene sulfonamide (3.70 g, 0.02 mol) were added to 1,2-dichlorobenzene (50 ml) and the solution refluxed for 48 hrs. The solvent was evaporated in vacuo and the residue recrystallized from hexane-acetone to give N*-methyl-N*-4-methylphenysulfonyl-4-methylbenzene sulfonamide mp 109–111° C. MS m/z 339. (M+ calcd for C15H17NO4S=339). H NMR (300 Mhz, CDCl3) d 2.43 (s, 6, CH3), 3.25 (s, 3, NCH3), 7.34 (m, 4, aromatic), 7.88 (m, 4, aromatic).
Reaction SMILES: C(O)[C@@H]([C@@H]([C@@H](CO)O)O)O.C(O)[C@@H]([C@H]([C@@H](CO)O)O)O.[OH:21][CH2:22][CH:23]([CH:25]([CH:27]([CH:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26])[OH:24].[CH2:33]([OH:44])[C@@H:34]([OH:43])[C@H:35]([OH:42])[C@H:36]([OH:41])[C@@H:37]([OH:40])[CH2:38][OH:39].[CH2:45]([OH:56])[C@@H:46]([OH:55])[C@@H:47]([OH:54])[C@@H:48]([OH:53])[C@@H:49]([OH:52])[CH2:50][OH:51]>>[CH2:31]([OH:32])[C@H:29]1[O:30][C@H:22]([O:21][C@@H:35]([C@H:36]([OH:41])[C@@H:37]([OH:40])[CH2:38][OH:39])[C@H:34]([OH:43])[CH2:33][OH:44])[C@H:23]([OH:24])[C@@H:25]([OH:26])[C@@H:27]1[OH:28].[CH2:38]([OH:39])[C@H:37]1[O:44][C@H:33]([O:54][C@H:47]2[C@H:48]([OH:53])[C@@H:49]([OH:52])[C@H:50]([OH:51])[O:55][C@@H:46]2[CH2:45][OH:56])[C@H:34]([OH:43])[C@@H:35]([OH:42])[C@@H:36]1[OH:41]
Reactant: OCC(O)C(O)C(O)C(O)CO
Reactant: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO
Reactant: OC[C@@H](O)[C@@H](O)[C@@H](O)[C@@H](O)CO
Agent: OC[C@@H](O)[C@@H](O)[C@@H](O)CO
Agent: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Examples of the sugar-alcohol include D,L-arabitol, ribitol, xylitol, D,L-sorbitol, D,L-mannitol, D,L-iditol, D,L-talitol, dulcitol and allodulcitol. In addition, maltitol resulting from the hydrogenation of maltose as a disaccharide and a reduction product (reduced starch syrup) obtained by the hydrogenation of oligosaccharide may be suitably used.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][OH:11].[CH2:12](Cl)[O:13][CH3:14].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][O:11][CH2:12][O:13][CH3:14]
Reactant: COCCl
Reactant: COc1nccc(I)c1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1c(I)ccnc1OC
Yield: 99.8 %

Procedure:
Following the procedure in Example 2, the reaction was carried out with 2b (1.77 g, 6.68 mmol), MOMCl (1.52 mL, 20 mmol) and iPr2EtN (3.49 mL, 20 mmol) in dry CH2Cl2 (40 mL) to afford 3b as an orange-yellow oil (2.06 g, 100%). The crude product was sufficiently pure for the subsequent reaction. IR (CH2Cl2, NaCl, cm−1) 2949, 1561, 1459, 1380, 1265, 1039, 741; 1H NMR (300 MHz, CDCl3) δ3.45 (s, 3H), 3.96 (s, 3H), 4.72 (s, 2H), 4.75 (s, 2H), 7.35 (d,J=5.4 Hz, 1H), 7.71 (d,J=5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ54.35, 55.80, 67.89, 96.70, 114.20, 123.97, 128.10, 147.11, 162.39; HRMS (EI) m/z calcd for C9H12NO3I (M+) 308.9862, found 308.9860; LRMS (EI) m/z 309(M+, 19), 277(20), 264(45), 248(100), 218(68), 152(39), 92(50), 79(35).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].Cl>O1CCCC1.O.ClCCl>[NH2:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(O[C@H]2CC[C@H](N)CC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-hydroxycyclohexylcarbamate (0.250 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.186 g). After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.256 g) was added as a solution in tetrahydrofuran (1 mL). The reaction was heated to 60° C. for 1.5 hours, cooled and poured into a mixture of dichloromethane (100 mL) and water (25 mL). The aqueous layer was adjusted to pH-4 with 1N aqueous HCl and the organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto silica gel (GraceResolv 40 g) and eluted using a gradient of 0.5% to 7.5% methanol/dichloromethane over 30 minutes. This solid was immediately treated with HCl (4.0M in dioxane, 5 mL) at room temperature for 1 hours and concentrated to give the title compound.