Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ccccc4)CC3)C2)cc1OC
Yield: 90.3 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (36.3 mg, 0.135 mmol), 1-phenylpiperazine (20.0 mg, 0.123 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (78.4 mg, 0.369 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 45.5 mg (90.1%) of the target compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(C(S(O[CH2:30][CH2:31][Cl:32])(=O)=O)=O)=CC=1>C(C(C)=O)C>[Cl:32][CH2:31][CH2:30][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: Cc1ccc(C(=O)S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NS(=O)(=O)c1ccccc1OCCCl
Temperature: 25 °C

Procedure:
A mixture of 9.0 g of 2-hydroxyphenylsulfonamide, 7.9 g of potassium carbonate, 13.3 g of 2-chloroethyl p-toloylsulfonate and 80 ml of ethylmethylketone is refluxed for 40 hours. The reaction mixture is cooled to room temperature, filtrated and evaporated to dryness. From the oily residue crystallise after addition of a small portion of methylene chloride 7.0 g of 2-(2-chloroethoxy)-phenylsulfonamide, m.p. 110° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:16])[CH:15]=1)=[O:8].[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:16][C:14]1[CH:15]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[CH:3]=[CH:4][C:5]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[N:12][CH:13]=1
Reactant: O=C(Nc1cncc(F)c1)c1cc(Br)ccc1OCc1ccccc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1cncc(F)c1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 130 °C

Procedure:
To a microwave vial was added 5-bromo-N-(5-fluoro-3-pyridinyl)-2-[(phenylmethyl)oxy]benzamide (may be prepared as described in Example 98; 200 mg, 0.50 mmol), 1,4-dioxane (2 ml), 4-pyridinylboronic acid (73.5 mg, 0.60 mmol), 1M sodium carbonate (1.00 ml, 1.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.6 mg, 0.03 mmol). The vial was sealed and heated to 130° C. for 30 min under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified using MDAP (twice) to yield the title compound. 9 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:13](=[O:14])[NH:21][NH:22]2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1F
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: O=c1[nH][nH]c2cc(OCc3ccccc3)ccc12
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Methyl 4-(benzyloxy)-2-fluorobenzoate (52.4 mg) which can be prepared according to the method described in Reference example 30, etc. was dissolved in n-butanol (1 mL; manufactured by Kanto Chemical Co., Inc.), added with hydrazine monohydrate (96 μL; manufactured by Sigma-Aldrich Co.), and stirred in a sealed tube under microwave for 1 hour at 160° C. Precipitates from the reaction solution were filtered and washed with n-butanol to obtain the title compound (39.6 mg).
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.C(S[CH:20]1[NH:24][CH2:23][CH2:22][NH:21]1)CCC>C(O)CCCC>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:11]=[C:20]3[NH:24][CH2:23][CH2:22][NH:21]3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: CCCCSC1NCCN1
Agent: Br
Solvent: CCCCCO
Product: c1cc(C2CCCCC2)ccc1N=C1NCCN1

Procedure:
9.1 g of p-cyclohexylaniline and 11.9 g of 2-n-butylthioimidazolidine hydrobromide in 60 ml of amyl alcohol are refluxed for 6 hours. The solvent is then distilled off in vacuo. The residue is taken up in methylene chloride and successively washed with dilute sodium hydroxide solution and water. The methylene chloride is distilled off and the crude final product is recrystallised from acetonitrile. The resylting 2-(4-cyclohexylphenyl)imino-imidazolidine decomposes at 163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:24](=[O:33])[C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=1>>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)/[C:25](=[C:26](\[C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[Cl:1])/[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)/[C:24]2=[O:33])[CH:17]=1
Reactant: FC(F)(F)c1ccc(Cl)c(I)c1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cc(C(F)(F)F)ccc3Cl)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-2-iodo-4-trifluoromethyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.63-7.67 (m, 2H), 7.33-7.52 (m, 7H), 7.10 (t, 1H), 6.64-6.71 (m, 2H), 5.98 (d, 1H), 4.87-5.04 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:5]=1[CH:22]=[C:23]([C:29]#[N:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>C(O)C>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:5]=1[CH:22]1[O:1][C:23]1([C:29]#[N:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: OO
Reactant: CCOC(=O)C(C#N)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C#N)OC1c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl

Procedure:
1.4 g (12 mmol) of 30% strength aqueous hydrogen peroxide solution were added to 2.7 g (6 mmol) of ethyl 3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)Phenyl)-2-cyanopropenoate in 30 ml of ethanol. After 12 hours the mixture was poured into water. The product was extracted from the aqueous phase using ethyl acetate, after which the organic phase was dried over magnesium sulfate and then concentrated. Purification of the crude product was carried out by means of column chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 1 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:17]CC2C=CC=CC=2)[CH:8]=1.[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1O
Yield: 96.8 %

Procedure:
Methyl 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoate (530 mg, 1.1373 mmol) was dissolved in methanol (20 ml), added to a methanolic suspension (20 ml) of 10% palladium-carbon (100 mg) and stirred for 16 hours at room temperature in a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (414 mg, 1.101 mmol, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:10][C:9](=[O:22])[NH:8][C:7]=2[N:23]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:39][C@@H:40]2[CH2:42][O:41]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:10][C:9](=[O:22])[N:8]([CH2:39][C@@H:40]3[CH2:42][O:41]3)[C:7]=2[N:23]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COc1ccc2c(n1)NC(=O)CN2C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(C[C@@H]1CO1)C(=O)CN2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 130.6 %

Procedure:
Phenylmethyl 6-(methyloxy)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (11 g, 35.1 mmol) was dissolved in DMF (300 ml) at room temperature under argon to give a yellow solution. The solution was then cooled with an ice bath and treated with sodium hydride (1.685 g, 42.1 mmol). The solution was allowed to warm to room temperature. After 20 minutes (2S)-2-oxiranylmethyl 3-nitrobenzenesulfonate (9.56 g, 36.9 mmol) was added. After 1 h all the starting material was consumed so the reaction was treated with a saturated solution of NaHCO3 (350 ml) and the aqueous layer was extracted with DCM (3×400 ml). The combined organic layers were dried over MgSO4, filtered and evaporated to afford a light brown oil (16.93 g). The product was used as crude in the next step.
Reaction SMILES: CNC.C1COCC1.[CH3:9][N:10]([CH:12]=O)[CH3:11].ClC[C:16](=[NH:49])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:48])[C:28](=[C:39]2[NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[NH:40]2)[C:29]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)=[O:30])[CH:22]=1)(=[O:20])=[O:19]>O>[F:37][C:35]1[CH:36]=[C:31]([C:29](=[O:30])[C:28](=[C:39]2[NH:40][C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[NH:43]2)[C:27]([C:23]2[CH:22]=[C:21]([S:18]([NH:17][C:16](=[NH:49])[CH2:12][N:10]([CH3:9])[CH3:11])(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=2)=[O:48])[CH:32]=[C:33]([F:38])[CH:34]=1
Reactant: CN(C)C=O
Reactant: N=C(CCl)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 M dimethylamine/THF solution (0.85 mL) was added to a DMF (5 mL) solution of 2-chloro-N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)ethanimidamide (181 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-(dimethylamino)ethanimidamide (76 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.ClCCl.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:6]1[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C1OCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1C1OCCO1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
2-(5-Chloro-2-nitrophenyl)-1,3-dioxolane (13.4 g, 58.4 mmol) was dissolved in morpholine (150 mL). The mixture was then heated to reflux for 16 hours. Cooling to room temperature, dichloromethane was added. The organic phase was washed with water, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product 4-(3-(1,3-dioxolan-2-yl)-4-nitrophenyl)morpholine (15.9 g, yield 97.1%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[C:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][S:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: CC(C)(C)n1nc2c(c1-c1ccsc1)CCNCC2
Yield: 65.2 %

Procedure:
The title compound (83 mg) was prepared according to Example 215 using 204 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215, Step A) and 177 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C15H21N3S, 275.15. found, m/z 276.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.59-7.57 (m, 1H), 7.43-7.42 (m, 1H), 7.08-7.06 (m, 1H), 3.38-3.36 (m, 2H), 3.25-3.23 (m, 2H), 3.13-3.11 (m, 2H), 2.56-2.54 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C=O)C>[ClH:2].[ClH:1].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: C1COCCN1
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Agent: Cl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCN4CCOCC4)cc23)c1
Yield: 50.9 %

Procedure:
The title product from Example 30 (107 mg, 0.245 mmol) in DMF (2 mL) was treated with morpholine (214 μL, 2.45 mmol) at 80° C. for 24 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (168 mg) was chromatographed on silica using 7.5% methanol/CH2Cl2 to provide 65 mg of pure title product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid (88 mg; 59%; M.P. 115°-130° C. (dec); LC-MS: 449 (MH+); anal. RP18-HPLC RT: 4.00 min.).
Reaction SMILES: [C:1]([O:4][CH:5]1[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:6]1[NH2:7])(=[O:3])[CH3:2].[I:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([I:34])[C:29]([CH2:35][CH3:36])=[C:28]([I:37])[C:27]=1[C:38]1[CH:43]=[CH:42][C:41]([C:44](Cl)=[O:45])=[C:40]([N+:47]([O-:49])=[O:48])[CH:39]=1>>[N+:47]([C:40]1[CH:39]=[C:38]([C:27]2[C:28]([I:37])=[C:29]([CH2:35][CH3:36])[C:30]([I:34])=[C:31]([CH2:32][CH3:33])[C:26]=2[I:25])[CH:43]=[CH:42][C:41]=1[C:44]([C:5]1([O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:6]1[NH2:7])[O:4][C:1](=[O:3])[CH3:2])=[O:45])([O-:49])=[O:48]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I
Product: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)C3(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3N)c([N+](=O)[O-])c2)c1I

Procedure:
1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3′,5′-bis(ethyl-3-nitrobiphenyl-4-carbonyl chloride (19) to yield 2-nitro-4-[3′,5′-bis(ethyl)-2′,4′,6′-triiodophenyl]benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (20).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:37][CH2:38][CH2:39][CH2:40]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:40][CH2:39][CH2:38][Br:37])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(C(=O)OCc2ccccc2)c1
Yield: 79.5 %

Procedure:
A mixture of 5.0 g (0.01 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester, 10.2 ml (0.1 mol) of 1,3-dibromopropane and 7.0 g (0.05 mol) of potassium carbonate in 75 ml of acetone and 15 ml of DMF was stirred at reflux for 22 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure to an oil. Purification by HPLC using 5% ethyl acetate-hexane gave 4.91 g (79% yield, mp 57°-58°) of 3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[H-].[Na+].FS([C:19](C(O)=O)([F:21])[F:20])(=O)=O.O>CC#N>[Cl:1][C:2]1[C:7]([O:8][CH:19]([F:21])[F:20])=[N:6][CH:5]=[C:4]([CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)c1c[nH]c(=O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cnc(OC(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of methyl 5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (3.810 g; 20.31 mmol) in anh. MeCN (400 ml) was treated portionwise with NaH (60% dispersion in mineral oil; 2.193 g; 54.84 mmol), and stirring at rt, under nitrogen, was continued for 20 min. FSO2CF2CO2H (6.149 g; 34.52 mmol) was then added dropwise, and the resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 45 min. Water (10 ml) was slowly added, and MeCN was removed under reduced pressure. Water (150 ml) and AcOEt (150 ml) were added, and the separated aq. layer was further extracted with AcOEt (3×100 ml). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded methyl 5-chloro-6-(difluoromethoxy)nicotinate as an off-white solid. LC-MS (conditions A): tR=0.81 min.; no ionisation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].[Cl:14][CH2:15][C:16](Cl)=[O:17]>>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@:2]([NH:1][C:16](=[O:17])[CH2:15][Cl:14])([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: C[C@](N)(CO)c1cc(Br)ccc1F
Reactant: O=C(Cl)CCl
Product: C[C@@](CO)(NC(=O)CCl)c1cc(Br)ccc1F

Procedure:
In a manner analogous to that described for intermediate IX-1 the acylation of (R)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol with chloro-acetyl chloride yielded the N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide as a light yellow oil (9.30 g, 90% of theory; e.e. >96%). MS (ISP): m/z=322.0 [M+H]+, 324.0 [M+2+H]+, 326.0 [M+4+H]+.
Reaction SMILES: ClN1[C:7]2=[C:8]([C:12]3[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[NH:9][N:10]([CH3:11])[C:6]2=CN(C)C1.ClC1[N:27]=[CH:26][N:25]=[C:24]2[N:28](C)N=C(C3OC([N+]([O-])=O)=CC=3)[C:23]=12>>[NH2:27][C:26]1[N:25]=[C:24]([CH3:23])[N:28]=[C:6]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:7]=12
Reactant: CN1C=C2C(=C(c3ccc([N+](=O)[O-])o3)NN2C)N(Cl)C1
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Product: Cc1nc(N)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1

Procedure:
The procedure described in Example 3b was repeated using 4-chloro-1,6-dimethyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4]pyrimidine as starting material instead of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, the reaction conditions being the same. The crystalline product was collected, washed with water and dried. Recrystallisation from dimethyl formamide gave 4-amino-1,6-dimethyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having decomposition point > 300°C. identical with the product obtained in Example 2.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1.[CH3:16]O>>[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]1
Reactant: CO
Reactant: O=C(O)CCC1CCNCC1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC1CCNCC1
Reaction time: 8 h

Procedure:
46.7 g (0.39 mol) of thionyl chloride are slowly added to 500 ml of methanol at -20° C., while stirring. When the addition has ended, the mixture is stirred for a further 20 minutes and 56.1 g (0.357 mol) of 3-(4-piperidinyl)-propionic acid are then slowly added, also at -20° C. The mixture is stirred at -20° C for a further hour and the temperature is then allowed to rise to room temperature overnight, with further stirring. The clear solution thus obtained is concentrated to dryness in vacuo and the residue is crystallized from acetone.
Reaction SMILES: [C:1]([NH:9][C:10](=[S:29])[NH:11][C:12]1[S:21][C:15]2[CH2:16][O:17][CH:18]([CH3:20])[CH2:19][C:14]=2[C:13]=1[C:22]([O:24]C(C)(C)C)=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:9][C:10](=[S:29])[NH:11][C:12]1[S:21][C:15]2[CH2:16][O:17][CH:18]([CH3:20])[CH2:19][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1Cc2c(sc(NC(=S)NC(=O)c3ccccc3)c2C(=O)OC(C)(C)C)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1Cc2c(sc(NC(=S)NC(=O)c3ccccc3)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.6 %

Procedure:
To tert-butyl 2-(3-benzoylthioureido)-5-methyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.028 g, 0.065 mmol, 1 eq.) was added a 40% v/v solution of trifluoroacetic acid in dichloromethane (2.5 mL). After stirring the solution for 4 hours at rt, the solvent was evaporated in vacuo, and the residue purified by reverse-phase chromatography to yield the product as a white semi-solid (0.011 g, 0.029 mmol, 46% yield). 1H NMR (400 MHz, Acetone) δ 8.07 (d, J=7.4, 2H), 7.68 (t, J=7.0, 1H), 7.56 (t, J=7.5, 2H), 4.76 (q, J=14.7, 2H), 3.82-3.68 (m, 1H), 3.05 (d, 1H), 1.47 (d, J=6.5, 1H), 1.32 (d, J=6.1, 3H). 13C NMR (126 MHz, Acetone) δ 175.37, 166.92, 165.37, 161.89, 148.65, 134.12, 133.28, 131.39, 129.62, 129.28, 126.49, 71.61, 65.11, 35.05, 21.82. LCMS retention time: 3.095 min; Purity at 214 nm=93.3%. HRMS m/z calculated for C17H17N2O4S2 [M++1] 377.0624. found 377.0622.