Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)=[O:5].[C:25]([Sn](CCCC)(CCCC)CCCC)(C)=C>>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]([CH3:25])=[CH2:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)=[O:5]
Reactant: C=Cc1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Product: C=C(C)c1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
The title compound was prepared using a procedure similar to that of 2-chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-vinyl-benzamide with isopropenyl tributylstannane replacing tributyl(vinyl)tin. Data: LCMS (M/Z): 356 (M+H); 1H NMR (DMSO-d6) δ: 1.44 (s, 6 H) 2.14 (s, 3 H) 5.24 (s, 1 H) 5.57 (s, 1 H) 7.38 (d, J=8.2 Hz, 1 H) 7.57 (ddd, J=1.5, 1.0, 0.8 Hz, 2 H) 7.62-7.66 (m, 1 H) 7.69 (dd, J=8.2, 2.0 Hz, 1 H) 8.05 (dd, J=1.6, 0.6 Hz, 1 H) 9.09 (br. s., 1 H) 10.49 (s, 1 H).
Reaction SMILES: I[CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C-:11]#[N:12].[Na+]>CS(C)=O>[C:11]([CH2:2][CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:12]
Reactant: [C-]#N
Reactant: CCOC(=O)C[C@H](O)CI
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(O)CC#N

Procedure:
The recombinant E. coli HB101(pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 0.5 g, 3.2 mg of NADP, and then 0.5 g of ethyl 4-iodoacetoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 72 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 900 mg of ethyl (S)-4-iodo-3-hydroxybutyrate. The optical purity of the ethyl (S)-4-iodo-3-hydroxybutyrate was analyzed as follows and found to be 91.6% e.e. That is, the sample was heated together with sodium cyanide in dimethyl sulfoxide to obtain ethyl 4-cyano-3-hydroxybutyrate, which was then changed to a benzoic ester using benzoyl chloride under the presence of pyridine. The optical purity of the benzoic ester was measured by an HPLC method. NMR(CDC13)δ(ppm): 1.28(3H,t), 2.65(2H,d), 3.31(3H,m), 4.00(1H,m), 4.20(2H,q); Column: Chiralpak AS (0.46×25 cm) manufactured by Daicel Chemical Industries, Co., Ltd.; Column temperature: 25° C.; Eluent: n-hexane/ethanol of 95/5; Flow rate: 1 ml/min.; Detection: 254 nm; Elution time: 19.6 minutes for (S), 21.3 minutes for (R).
Reaction SMILES: [C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N12CCN(CC1)CC2.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[S:41]>CN(C)C=O.C(OCC)(=O)C>[C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][C:40](=[S:41])[N:39]([CH3:43])[CH3:38])=[C:11]([Cl:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCCc1cc(Cl)c(O)c(Cl)c1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=S)Oc1c(Cl)cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of 4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,6-dichloro-phenol (70) (289 mg, 0.78 mmol) in N,N-dimethylformamide (4 mL) at 25° C. was treated with 1,4-diazabicyclo[2.2.2]octane (172 μL, 1.56 mol) and dimethylthiocarbamoyl chloride (154 mg, 1.25 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with ethyl acetate and was then washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 petroleum ether/ethyl acetate) afforded dimethyl-thiocarbamic acid O-{4-[2-(tert-butyl-diphenyl-silanyloxy)ethyl]-2,6-dichloro-phenyl}ester (71) (376 mg, 90%) as a white solid; EI(+)-HRMS m/e calcd for C27H31Cl2N2O2SSi (M+H)+ 532.1295, found 532.1292. Exact Mass=531.1222; Molecular weight=532.61
Reaction SMILES: C[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:9]([N+:22]([O-:24])=[O:23])=[CH:8][C:3]=1[S:4]([NH2:7])(=[O:6])=[O:5].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].[C:31](=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH2:29]([O:28][C:26]([N:7]([CH3:31])[S:4](=[O:5])([C:3]1[CH:8]=[C:9]([N+:22]([O-:24])=[O:23])[C:10]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])=[C:11]([N+:12]([O-:14])=[O:13])[CH:2]=1)=[O:6])=[O:27])[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cl
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(S(N)(=O)=O)c(C)c1[N+](=O)[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)N(C)C(=O)OCC)cc1[N+](=O)[O-]

Procedure:
A mixture of 3.6 g (0.01 mol) N1 methyl-3,5-dinitro-N4,N4 -dipropylsulfanilamide, 2.2 g (0.02 mol) ethyl chloroformate, 2.8 g (0.02 mol) potassium carbonate, and 50 ml dimethoxyethane was heated at reflux until gas evolution ceased. The reaction mixture was filtered and evaporated under reduced pressure. The residue was recrystallized from ethanol to give 2.5 g of the product, m.p. 104°C (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([Si](C)(C)C)[C:31](=[O:38])[N:30]([CH3:39])[N:29]=3)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Br-:40].[K+].[C:42]([O-:45])(=[O:44])[CH3:43].[K+].BrBr>>[Br:40][C:32]1[C:31](=[O:38])[N:30]([CH3:39])[N:29]=[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:17]([N:10]3[N:9]=[CH:8][C:7]4[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)[C:11]3=[O:16])[C:18]=2[CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH:33]=1.[C:42]([OH:45])(=[O:44])[CH3:43]
Reactant: [Br-]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCc1c(-c2cc([Si](C)(C)C)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: BrBr
Agent: [K+]
Product: CC(=O)O
Product: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 67 %

Procedure:
In round bottom flask with reflux condenser was placed 2.54 g acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(1-methyl-6-oxo-5-trimethylsilanyl-1,6-dihydro-pyridazin-3-yl)-benzyl ester, 5.51 g potassium bromide, 4.55 g potassium acetate, followed by ca 18.4908 g bromine. The mixture warmed on addition of the bromine. The mixture was stirred for 2 minutes at room temperature, then set in a bath at 55° C. and stirred. A stopper was placed lightly in the top of the reflux condenser to contain the bromine vapors. After 70 minutes, the mixture was cooled to room temperature, excess bromine removed under a stream of nitrogen. The mixture was taken up in 500 mL of dichloromethane, washed 1×150 mL brine, containing 12 g sodium bisulfite with some resultant exotherm, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel (Silicycle 120 g, 3.5×21.5 cm, 207 vol), applied in dichloromethane, eluting with dichloromethane-ethyl acetate (80:20), followed by chromatography on silica gel (Silicycle 120 g, 3.5×21.5 cm, 207 vol), applied in dichloromethane, eluting with dichloromethane-ethyl acetate (80:20) to afford the desired product (1.91 g) as an off white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:43])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:18]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:17][C:16]=2[N:15]([CH3:42])[C:13]1=[O:14])([O-])=O.O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:43])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:18]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:17][C:16]=2[N:15]([CH3:42])[C:13]1=[O:14]
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1N)c(=O)n2C

Procedure:
Prepared by treating 1-[2-(2-nitrophenyl)-2-oxoethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert-butyloxycarbonylamino)piperidin-1-yl]xanthine with powdered iron in a mixture of ethanol, water, and glacial acetic acid (150:50:14) at 90° C. Mass spectrum (ESI+): m/z=566 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 1-(4-bromophenyl)propan-1-one (10 g, 46.9 mmol) in toluene/ethanol (47/47 ml) is added 4-trifluoromethylphenylboronic acid (10.63 g, 51.6 mmol), tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol), and 2 N potassium carbonate (47 mL). The reaction mixture is heated at reflux overnight, cooled to rt, and partitioned between ethyl acetate and water. The organic layer is dried and concentrated, then loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 60% giving 1-(4′-trifluoromethylbiphenyl-4-yl)propan-1-one (11.52 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].[CH3:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[CH:31]=O>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([NH:1][CH2:25][C:26]3[NH:27][CH:28]=[N:29][C:30]=3[CH3:31])=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: COc1ccccc1CN
Reactant: Cc1nc[nH]c1C=O
Product: COc1ccccc1CNc1ccc2c(NCc3[nH]cnc3C)cccc2n1

Procedure:
The title compound, MS: m/e=374.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 2-methoxybenzylamine and 4-methyl-5-imidazole-carboxaldehyde as described in example 26.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[BH4-].[Na+]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(C2CCC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1

Procedure:
To a solution of 11.1 g (0.048 mol) of 4-(4-dimethylaminomethylphenyl)-cyclohexanone in 100 ml of absolute methanol, which has been cooled to -10° C., is added 1.82 g (0.048 mol) of sodium borohydride in batches with stirring. The reaction mixture is allowed to react for 1.5 hours at ambient temperature and then evaporated down in vacuo. The residue remaining is mixed with water, acidified with concentrated hydrochloric acid, stirred for 30 minutes at ambient temperature, made alkaline with 50 sodium hydroxide solution and extracted several times with chloroform. The combined extracts are dried with sodium sulphate and evaporated down in vacuo. The residue remaining, which consists of a mixture of trans/cis-4-(4-dimethylaminomethylphenyl)-cyclohexanol (cis fraction <10%) is purified by column chromatography (aluminium oxide neutral, activity stage III, ICN; petroleum ether/methylethyl ketone=5:1). White crystals are obtained, melting point 63-65° C. Yield: 8.8 g (79% of theory), C15H23NO (233.36) Calculated: C 77.21 H 9.93 N 6.00 Found: 77.34 10.02 5.89
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[Br:11]Br.C(OCC)(=O)C>CO.C(O)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1.[BrH:11]
Reactant: BrBr
Reactant: COc1cccc(C)c1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Br
Product: COc1cc(Br)cc(C)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To solution of (2-methoxy-6-methyl-phenyl)-amine (14.5 g, 0.11 mol) in methanol (45.6 ml) and acetic acid (14.5 ml) is added dropwise a solution of bromine (5.45 ml) in acetic acid (45.6 ml) via an addition funnel at 0° C. The reaction mixture is allowed to warm to RT and stirred for 2 h at RT. Ethyl acetate (90 ml) is added and the solid is collected by filtration. The solid thus obtained is washed with ethyl acetate to obtain (4-bromo-2-methoxy-6-methyl-phenyl)-amine as hydrobromide.
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1.O>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1)[C:5]#[CH:6]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsilylacetylene (1.00 g, 10 mmol) (Aldrich) in dry THF (100 mL) under argon at −78° C. was added n-butyllithium (4.4 mL, 11 mmol, 2.5 M solution in hexanes) (Aldrich) dropwise. The reaction was stirred for 30 min at −78° C., after which time 4-hydroxybenzaldehyde (0.50 g, 4 mmol) (Aldrich) was added and the reaction was allowed to slowly warm to room temperature. A saturated solution of ammonium chloride (5 mL) was then added and the reaction was stirred at room temperature for 2 h. The solution was then diluted by the addition of 30 mL water, and THF was removed in vacuo. The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give clean 3-hydroxy-3-(4-hydroxyphenyl)-1-propyne which was used directly, without further purification. (Yield 501 mg, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])([O-])=[O:2].[PH2]([O-])=O.[Na+]>O1CCCC1.CS(C)=O.O.[Pd]>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:4]([NH:1][OH:2])[CH:9]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(Cl)cc1NO
Reaction time: 1 h
Yield: 110.3 %

Procedure:
Methyl (2-nitro-4-chlorophenyl)acetate (5.0 g, 21.7 mmol) was dissolved in 250 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide. To this was added 900 mg of 10% Pd/C. A solution of 5.38 g of sodium hypophosphite in 18 ml of water was added dropwise over a 40 minute period. After stirring for 4 hours another 2.68 g of sodium hypophosphite (in 8 ml of water) was added over a 10 minute period. After stirring for one hour the reaction mixture was filtered through Celite and the filtrate diluted with 500 ml of CH2Cl2. The filtrate was washed with saturated aqueous NaHCO3 then brine and dried with Na2SO4. The solvents were evaporated under reduced pressure leaving 5.16 g of a yellow oil (110% of theory). NMR (300 MHz, CDCl3): 3.51 (2 H, s), 3.69 (3 H, s), 5.50 (1 H, br s), 6.88 (1 H, dd, J=1,8), 7.01 (1 H, d, J=8), 7.34 (1 H, d, J=1), 7.56 (1 H, br s).
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.O.[S:13]([Cl:17])(Cl)(=[O:15])=[O:14]>ClC1C=CC=CC=1>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([S:13]([Cl:17])(=[O:15])=[O:14])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: CSc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Temperature: 10 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
A 2-liter, 4-necked flask equipped with a stirrer, thermometer, condenser and a dropping funnel having a by-pass was charged with 20.4 g (0.10 mole) of 4-nitrophenyl methyl sulfide, 10 g of water and 200 g of monochlorobenzene. Then, 94.5 g (0.70 mole) of sulfuryl chloride was added dropwise at 10° C. over a period of about 2 hours. Thereafter the mixture was stirred at 10° C. for 6 hours to complete the reaction. After completion of the reaction, the oil layer was separated and 10 g of water was added to accomplish washing. Then, the oil layer was separated and left to stand for about 1 hour with the addition of about 5 g of anhydrous sodium sulfate to remove the water. The solvent was distilled off to give crude crystals. The crude crystals were dissolved in monochlorobenzene and a poor solvent was added for recrystallization, giving 21.1 g of 4-nitrobenzenesulfonyl chloride as white crystals in a yield of 95% as calculated based on 4-nitrophenyl methyl sulfide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]4[C:25](=[O:26])[O:24][C:23](=[O:27])[C:12]=4[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:28][OH:29].[CH3:30][Si](C=[N+]=[N-])(C)C>C1COCC1>[CH3:28][O:29][C:23]([C:12]1[CH:13]=[C:14]2[C:22](=[C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:11]=1[C:25]([O:24][CH3:30])=[O:26])[C:18]1[O:19][CH2:20][O:21][C:17]=1[CH:16]=[CH:15]2)=[O:27]
Reactant: O=C1OC(=O)c2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C(=O)OC)OCO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
Compound 1 (108.6 mg, 0.3 mmol) was dissolved to a mixture of MeOH (4 mL) and THF (8 mL). Trimethylsilyldiazomethane (2 M in hexanes, 1.0 mL, 2.0 mmol) was added to the solution. The mixture was stirred for 12 h at room temperature, and then concentrated in vacuo. The residue was purified by chromatography on silica gel using n-hexane/EtOAc (2:1, v/v) to afford 30 (67 mg, 55%) as a pale yellow powder. mp 157-159° C.; 1H NMR (CDCl3) δ 8.53 (s, 1H, H4), 7.58 (d, 1H, H5, J=8.7 Hz), 7.27 (d, 1H, H6, J=8.7 Hz), 6.79-6.82 (m, 3H, H2′+H5′+H6′), 6.03 (AB, 2H, 3′,4′-OCH2O—, Δδ=10.2 Hz, J=1.5 Hz), 5.89 (AB, 2H, 7,8-OCH2O—, Δδ=7.2 Hz, J=1.5 Hz), 3.94, 3.66 (each s, 2×3H, 2×OCH3); MS (EI) m/z 408 [M]+.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=2)=[CH:20][C:19]=1[C:34]([F:37])([F:36])[F:35].[CH2:38](O)C>>[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:3]3[N:4]([CH3:38])[CH:5]=[C:6]([CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[N:15][CH:16]=4)[C:7](=[O:9])[N:8]=3)=[CH:25][CH:24]=2)=[CH:20][C:19]=1[C:34]([F:35])([F:36])[F:37]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCO
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Product: Cn1cc(Cc2cncnc2)c(=O)nc1NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 125 °C
Reaction time: 48 h

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (18.6 mg, 0.079 mmol, 1 eq) and 2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (39.3 mg, 0.119 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 125° C. for 48 h. Reaction mixture was evaporated and crude residue was purified via Biotage SP-1 Snap Si 10 g; 15 ml/min in the gradient of MeOH in DCM: 1% for 1 CV then from 1-5% for 20 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product which was not pure enough and it was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-{2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-1-methyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.0095 mmol; yield: 10%, HPLC-MS/UV: [M+H]+=516.93; rt: 11.49 min; purity: 96%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.82 (t, J=8.17 Hz, 2H), 3.40-3.52 (m, 4H), 6.92 (m, 1H), 7.05 (d, J=8.59 Hz, 2H), 7.22 (dd, J=9.11, J=2.72, 1H), 7.28 (d, J=8.29, 2H), 7.38-7.44 (m, 2H), 7.67 (d, J=8.84, 1H), 8.67 (s, 2H), 8.97 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1C(=O)N([Br:31])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>FC(F)(F)C1C=CC=CC=1>[C:13]([O:12][C:10]([N:9]([C:3]1[CH:4]=[CH:5][C:6]([CH2:8][Br:31])=[CH:7][C:2]=1[Br:1])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cc1Br

Procedure:
A solution of di-tert-butyl (2-bromo-4-methylphenyl)imidodicarbonate (Compound 108C, 5.0 g, 13 mmol), NBS (2.56 g, 14.2 mmol) and 2,2′-Azo-bis-isobutyronitrile (0.217 g, 1.29 mmol) in α,α,α-trifluorotoluene (16 mL) was heated at 80° C. under an atmosphere of nitrogen for 3 h. Solvent was removed in vacuo and the residue was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=1.77 Hz, 1H), 7.34 (dd, J=2.02, 8.08 Hz, 1H), 7.19 (d, J=8.08 Hz, 1H), 4.44 (s, 2H), 1.41 (s, 18H); MS (ES+): m/z: N/A [MH+]. HPLC: tR=1.83 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][SH:34])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][S:34][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: CC(C)(C)OC(=O)NCCS
Product: Cc1ccc(NC(=O)Nc2ncc(SCCNC(=O)OC(C)(C)C)s2)c(C(=O)C2CCCC2)c1
Yield: 40 %

Procedure:
(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-ethyl)-carbamic acid tert-butyl ester (202 mg, 40%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and (2-mercapto-ethyl)-carbamic acid tert-butyl ester (354 mg, 2 mmol) following the general procedure Q.