Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([OH:25])=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cn1cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cn(CC(=O)O)c2ccccc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A suspension of ethyl 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetate (248 mg, 0.626 mmol) and LiOH (74.9 mg, 3.13 mmol) in THF/water 1/1 (10 ml) was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and carefully acidified by slow addition of 1N HCl (pH=1). The phases were separated and the aqueous layer was extracted with ethyl acetate; the combined organic layers were dried over Na2SO4 and evaporated to dryness to give 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid as a yellow solid (220 mg, 0.597 mmol, 95% yield). MS/ESI+ 369.1 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1.P(C#N)(=O)(OCC)OCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Yield: 90 %

Procedure:
A mixture of 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 10, Step 2, 10.00 g, 41.72 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357-60) (15.20 g, 70.93 mmol), diethyl phosphorocyanidate (10.76 mL, 70.93 mmol) and diisopropylethylamine (18.17 mL, 104.4 mmol) in N,N-dimethylformamide (267 mL) was stirred at room temperature for 43 h. The solvent was removed by evaporation. The residue was basified with aqueous sodium bicarbonate (40 mL), and extracted with dichloromethane (5×100 mL). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue eluting with dichloromethane/methanol (100:1 to 20:1) afforded 19.08 g (90%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=O)NCCO)([CH3:4])([CH3:3])C.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17]C=CC=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:40]([C:48](OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:12][C:13]1[CH:4]=[C:1]([CH:3]=[CH:17][C:18]=1[Cl:19])[O:5][CH2:6][CH2:48][NH2:40]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cccc(Cl)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCCOc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.0 g of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester, 0.96 g of 2,3-dichlorophenol, and 1.54 g of triphenylphosphine in THF (20 mL) was stirred as 1.19 g of diisopropyl azodicarboxylate was added. After stirring at ambient temperature for 72 h, the solvent was removed and the residue was dissolved in 10% sulfuric acid (10 mL) and warmed to 80° C. After 16 h, the reaction was cooled to ambient temperature and the mixture diluted with water and washed with EtOAc (2×). The organic layers were washed with water, and the pH of the combined aqueous layers was adjusted to 9 with 10 N NaOH solution. The mixture was extracted with chloroform (3×) and the combined organic layers were washed with sat. sodium chloride solution, dried over sodium sulfate, filtered and concentrated to provide the title compound as an orange oil. MS (M+H−)=204.2.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH:7]([NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:25](=[O:26])[N:24]([CH3:27])[C:23]3[CH:28]=[CH:29][C:30]([C:32](=[O:43])[NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)=[CH:31][C:22]=3[S:21]2(=[O:45])=[O:44])=[CH:15][CH:14]=1)[CH:8]([CH3:10])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:32]([C:30]2[CH:29]=[CH:28][C:23]3[N:24]([CH3:27])[C:25](=[O:26])[N:20]([CH2:19][C:16]4[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:47])=[O:5])=[O:46])=[CH:14][CH:15]=4)[S:21](=[O:45])(=[O:44])[C:22]=3[CH:31]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: COc1ccc(CNC(=O)c2ccc3c(c2)S(=O)(=O)N(Cc2ccc(C(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc2)C(=O)N3C)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNC(=O)c2ccc3c(c2)S(=O)(=O)N(Cc2ccc(C(=O)NC(C(=O)O)C(C)C)cc2)C(=O)N3C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of 0.18 g 2-{4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoylamino}-3-methyl-butyric acid tert butyl ester (0.27 mmol, Step 1) was added 10 mL 50% trifluoroacetic acid in CHCl3 The resulting mixture was stirred 2 hours at room temperature, then concentrated. Obtained 0.14 g of the title compound as a solid from EtOAc/hexane. Anal. (C30H32N4O8S1) C,H,N. MS: M++1=609.4 Da
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]2[CH:7]([CH2:24][C:25]([OH:27])=O)[CH2:8][O:9][C:10]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:14][C:11]=3[C:12]=2[N:13]=1)(=[O:3])[NH2:2].Cl.[CH3:29][NH:30][CH3:31].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:29][N:30]([CH3:31])[C:25]([CH2:24][CH:7]1[C:6]2[S:5][C:4]([C:1]([NH2:2])=[O:3])=[N:13][C:12]=2[C:11]2[CH:14]=[C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)=[O:27]
Reactant: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(CC(=O)O)CO2
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a mixture of [2-Carbamoyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-4-yl]-acetic acid (60 mg, 0.155 mmol) in DCM (20 mL) were added Dimethylamine Hydrochloride (31.7 mg, 0.388 mmol), HOBt (31.5 mg, 0.233 mmol), EDCI (44.7 mg, 0.233 mmol) and DIPEA (60.3 mg, 0.466 mmol). The mixture stirred in autoclave at 60° C. overnight. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc and hexane (1:1) to afford 4-Dimethylcarbamoylmethyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (30 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 8.61 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 5.45 (s, 1H), 4.5 (m, 1H), 4.10 (m, 1H), 3.93 (m, 1H), 2.90 (d, J=16 Hz, 6H), 2.82 (m, 1H), 2.69 (m, 1H), 1.47 (s, 6H); LC-MS (ESI & APCI): 414.5 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:40][CH3:41])=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH3:41][O:40][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:2]2[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:3]=2)=[C:37]2[C:33]=1[CH2:34][N:35]([CH3:39])[C:36]2=[O:38]
Reactant: COc1ccc(N)c2c1CN(C)C2=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-4-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 205A). MS (ES+): m/z 581.20 (100) [MH+]; HPLC: tR=1.08 min (UPLC, purity).
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)O.Br[CH2:10][C:11]1[CH:27]=[C:26]([Cl:28])[C:14]([CH2:15][C:16]2[CH:17]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[NH:20][N:21]=2)=[C:13]([Cl:29])[CH:12]=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[Cl:29][C:13]1[CH:12]=[C:11]([CH2:10][C:1]#[N:2])[CH:27]=[C:26]([Cl:28])[C:14]=1[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[NH:20][N:21]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CBr)cc2Cl)n[nH]c1=O
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1cc(Cc2c(Cl)cc(CC#N)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium cyanide (270 mg, 5.51 mmol) in dimethyl sulfoxide (2 mL) at room temperature was treated with concentrated sulfuric acid (0.1 mL, 1.88 mmol) and a solution of 6-(4-bromomethyl-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (54) (70 mg, 0.180 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at room temperature for 30 min and then at 50° C. for 1 h. The reaction was cooled to room temperature, poured into a saturated aqueous sodium bicarbonate solution (50 mL), was diluted with water (20 mL) and then extracted with ethyl acetate (3×75 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was dried under high vacuum to afford [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetonitrile (55) as an orange oil (assume 0.180 mmol) which was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C(N([CH2:14][CH3:15])CC)C.[C:16]1(C)[CH:21]=C[C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl>[N:1]1([CH2:6][CH2:7][O:8][S:22]([C:19]2[C:14]([CH3:15])=[CH:21][CH:16]=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCn1ccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OCCn1ccnc1
Temperature: -10 °C
Yield: 101.8 %

Procedure:
To a stirred solution of 2-(imidazol-1-yl)ethanol (1.9 g, 0.0156 mol), triethylamine (2.8 ml, 0.0187 mol), and 4-N,N-dimethylaminopyridine (20 mg) in dichloromethane (20 ml) at a temperature of -78° C. under nitrogen atmosphere, was added p-toluenesulphonyl chloride (3.6 g, 0.0187 mol) in dichloromethane (10 ml). The reaction mixture was allowed to warm to -10° C. and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. The organic phase was separated and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield colorless crystals of 2-(imidazol-1-yl)-1-toluenesulphonyloxyethane (4.23 g). n-Butyllithium (3.9 ml, 0.0059 mol, 1.5M in hexane) was added to a stirred solution of 1-(2,4-dichlorophenyl)-4,5-dihydro-2-phenylmethylimidazole (1.5 g, 0.0049 mol) in dry tetrahydrofuran (10 ml) at -78° C. under a nitrogen atmosphere. Copper(I)bromide-dimethyl sulphide complex (50 mg, 0.0024 mol) was added to the reaction mixture. After a period of one hour, a solution of 2-(imidazol-1-yl)-1-toluenesulphonyloxyethane (2 g, 0.0072 mol) in tetrahydrofuran (7 ml) was added to the reaction mixture. The resulting mixture was allowed to warm to room temperature and allowed to react for 15 hours before being quenched with saturated aqueous ammonium chloride. The phases were separated and the aqueous phase extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel with ammonia/methanol/ethyl acetate (1:4:45) to yield 1-(2,4-dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole (1 g) which upon treatment with ethereal hydrogen chloride yielded the hydrochloride salt of 1-(2,4-dichlorophenyl)-4,5-dihydro-2-[3-(imidazol-1-yl)-1-phenylpropyl]imidazole. (Found C, 49.00; H, 5.03; N, 10.76. C21H22N4Cl4.9/4 H2O requires C, 49.19; H, 5.21; N, 10.93) having the formula ##STR44## The anti-anaerobic activity of the compounds of the present invention is demonstrated by the following examples:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])=[CH:11][CH:10]=2)#[N:13]
Reactant: C1CCOC1
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C=C)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1.00 g (3.52 mmol) 6-amino-4-[(3-ethynylphenyl)amino)-3-quinolinecarbonitrile in 2 ml hot DMF, added 12 ml THF and chilled to 0° C. under N2. Added 539 μl (3.87 mmol) triethylamine and 322 μl (3.87 mmol) acryloyl chloride. Removed ice bath at 15 minutes and stripped solvent at 1.5 hours. Slurried residue in water, collected solids and air dried overnight. Recrystallized from ethyl acetate, dried in vacuo, giving 302 mg of orange solid: mass spectrum (electrospray m/e): 339.1.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:10](=O)[O:9][C:8](=O)[C:5]2=N[CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[C:23](=O)([O-])[O-:24].[K+].[K+]>O1CCCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:24][CH2:23][C:3]2[CH:2]=[CH:7][C:8]([O:9][CH3:10])=[CH:5][CH:4]=2)=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(=O)c2ncc(O)cc21
Reactant: COc1ccc(CBr)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(COCc2ccc(OC)cc2)cc1

Procedure:
For example, 3-hydroxy-furo[3,4-b]pyridine-5,7-dione 28.11 (German Patent 4343923) is reacted in tetrahydrofuran solution at 50° with 4-methoxybenzyl bromide and potassium carbonate, to give the 4-methoxybenzyl ether 28.12. The product is then converted, as described above, into the silyl-protected bicyclic ester 28.13. The 4-methoxybenzyl ether is then removed by reaction with dichlorodicyanobenzoquinone in dichloromethane at ambient temperature, as described in Tet. Lett., 27,3651, 1986, to give the phenol 28.14. The product is then reacted in tetrahydrofuran solution with a dialkyl bromomethyl phosphonate 29.15 (Lancaster) and potassium carbonate, to produce the phosphonate 28.16; the product is then converted, by desilylation, amide formation, bromination, reaction with methylamine and carbamate formation, using the procedures described above, into the hydroxyamide 28.17.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[CH:12]=[C:13](N2CCCC2)[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][CH2:22][O:23][C:24](/[C:26](/Cl)=[N:27]\[OH:28])=[O:25].O>ClCCl>[CH3:14][C:13]1[O:28][N:27]=[C:26]([C:24]([O:23][CH2:22][CH3:21])=[O:25])[C:12]=1[C:11](=[O:20])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(=CC(=O)Nc1ccc([N+](=O)[O-])cc1)N1CCCC1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1noc(C)c1C(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A suspension of 12.38 g (45 mmol) of the crude N-(4-nitrophenyl)-3-pyrrolidyl-2-butenamide in 200 ml of dry dichloromethane was cooled to 0° C. and 7.50 g (49.5 mmol) of ethyl chlorooximidoacetate were added in one portion. The reaction mixture was stirred at -5° C. to 0° C. for 2 hours and was then poured into 200 ml of water. The aqueous layer was extracted with 100 ml of dichloromethane and the combined organic extract was washed with 100 ml of 10% HCl, 5% NaHCO3 solution and then dried over MgSO4. Evaporation of the solvent gave 10.91 g (76%) of ethyl 5-methyl-4-[N-(4-nitrophenyl)]carbamoyl-3-isoxazolecarboxylate as a white crystalline solid melting at 151°-53° C. (from ethyl acetate);
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][S:15][C:16]1[N:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH:19]=[CH:18][N:17]=1>ClCCl>[CH3:14][S:15][C:16]1[N:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)=[O:11])=[CH:25][CH:24]=2)[CH:19]=[CH:18][N:17]=1
Reactant: CSc1nccc(Oc2ccc(N)cc2)n1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CSc1nccc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)n1
Reaction time: 5 h
Yield: 79.7 %

Procedure:
A solution of 41.7 g (219 mmol) 3-trifluoromethyl-phenyl isocyanate in 50 ml dichloromethane was added within 45 min. drop by drop at 5-10° C. to a solution of 51.0 g (219 mmol) 4-(2-Methylsulfanyl-pyrimidin-4-yloxy)-phenylamine and stirring continued for 5 h at 5° C. The reaction mixture was kept in a cooling room overnight at 4° C. The formed precipitate was isolated by cold filtration and washed thrice with 40 ml ice cold dichloromethane. After an additional washing with portions of isohexane (250 ml total) the product was dried at 40° C. in vacuum to give 73.4 g (80%) 1-[4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea.
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)NCCBr
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)OCO4)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine (100 mg, 0.24 mmol) in 5 mL of dry DMF was added N-(2-bromoethyl)methanesulfonamide (150 mg, 0.7 mmol) and Cs2CO3 (150 mg, 0.46 mmol). The resulting mixture was stirred at a temperature of about 25° C. for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound WS35 as white solid (35 mg, 27% yield).
Reaction SMILES: [CH3:1][S:2][CH:3]([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[Cl:14][C:15]1[C:19]([NH:20][CH2:21][C:22]#[CH:23])=[CH:18][N:17]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:16]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[Cl:14][C:15]1[C:19]([N:20]([CH2:21][C:22]#[CH:23])[C:4](=[O:5])[CH:3]([S:2][CH3:1])[CH3:7])=[CH:18][N:17]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:16]=1
Reactant: CSC(C)C(=O)O
Reactant: C#CCNc1cn(-c2cccnc2)nc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN(C(=O)C(C)SC)c1cn(-c2cccnc2)nc1Cl
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 2-(methylthio)propanoic acid (0.36 g, 3.00 mmol) in DCM (3 mL) was added oxalyl dichloride (0.29 ml, 3.31 mmol) followed by one drop of DMF. The reaction mixture was stirred for 30 min before all of the solvent was evaporated. The resulting residue was dissolved in DCM (2 mL) and the solution was added to a pre-stirred solution of 3-chloro-N-(prop-2-yn-1-yl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.35 g, 1.50 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.57 ml, 3.31 mmol) in DCM (5.5 mL). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and the residue was purified using silica gel chromatography (0-100% EtOAc/hexanes) to afford the title compound as a yellow oil (432 mg, 1.23 mmol, 85%): 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.5 Hz, 1H), 8.66-8.60 (m, 1H), 8.25 (s, 1H), 8.08-8.01 (m, 1H), 7.49-7.42 (m, 1H), 4.86 (s, 1H), 4.29-3.97 (m, 1H), 3.31 (d, J=6.5 Hz, 1H), 2.30-2.24 (m, 1H), 2.09 (s, 3H), 1.46 (d, J=6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.30, 148.66, 140.71, 140.18, 135.71, 127.87, 126.35, 124.11, 122.12, 78.53, 72.92, 53.39, 37.97, 16.42, 11.07; ESIMS m/z 335 ([M+H]+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[S:7]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: C[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 g of p-toluene sulfonyl chloride in 200 ml of toluene was slowly added to 50 g (0.505 mole) of L-alanine dissolved in 1 l 1N-sodium hydroxide cooled to below 5° C. and stirred at room temperature for 24 hours. Then, the aquose layer was cooled to below 5° C. and with a slow addition of concentrated hydrochloric acid, pH was adjusted to 1.5. After standing in the refrigerator for 3 to 4 hours, the white solid, so formed,.was filtered, washed with water sufficiently and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].[F:15][CH:16](F)[CH2:17]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.ClCCl>[F:15][CH2:16][CH2:17][O:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Reactant: CS(=O)(=O)OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2cc(OCCF)cnc12
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A solution of 8-nitro-quinolin-3-ol (500 mg, 2.63 mmol), methanesulphonic acid 2,2-difluoro-ethyl ester (463 mg, 2.9 mmol), ad potassium carbonate (810 mg, 5.86 mmol) in dimethylformamide (7 ml) was heated at 100° C. for 16 hours. For the workup, the reaction mixture was cooled to room temperature, then saturated aqueous sodium carbonate solution and dichloromethane were added. The organic layer was separated, dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of cyclohexane/ethyl acetate=10:1 to 1:1 as the eluent yielding 150 mg (24%) of the 3-(2-fluoro-ethoxy)-8-nitro-quinoline as a yellow solid; (calculated) C11H9FN2O3 [236.2]; (found) [M+H]+=237.