Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.[OH:14][CH:15]([C:21]([CH3:23])=[CH2:22])[C:16]([O:18]CC)=O.C(N(CCCC)CCCC)CCC.Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:18])[C:15](=[C:21]([CH3:22])[CH3:23])[O:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Nc1ccc(C)cc1
Reactant: C=C(C)C(O)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Ethyl N-(4-methylphenyl)carbamate (2.87 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (3.90 g, 30 mmol), tetrabutylammonium chloride (139 mg, 0.5 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 8 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, methanol (3.5 mL) acidified with hydrochloric acid was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-methylphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.07 g, yield 46.1%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)([O:16][CH3:17])[CH2:5][CH2:6][C:7]1([CH3:15])[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]1.[C:25]1([C:31]#[C:32][CH2:33]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][CH2:3][C:4]([O:16][CH3:17])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:33][C:32]#[C:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)[CH2:5][CH2:6][C:7]1([CH3:15])[O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12]1
Reactant: COCC(CCC1(C)OCC(C)(C)CO1)(OC)c1cccc(O)c1
Reactant: BrCC#Cc1ccccc1
Product: COCC(CCC1(C)OCC(C)(C)CO1)(OC)c1cccc(OCC#Cc2ccccc2)c1
Yield: 85 %

Procedure:
Using the procedure described in Example 12, 2-(3-hydroxyphenyl)-2-methoxy-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether was reacted with 3-phenylprop-2-ynyl bromide to give 2-methoxy-2-[3-(3-phenylprop-2-ynyloxy)phenyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)but-1-yl methyl ether in 85% yield, as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](OCC)(=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Li])CCC>CCCCCC.C1CCCCC1>[O:12]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1nccs1

Procedure:
Prepared from thiazole and diethyl oxalate using Method KE-A. In this case the temperature was held at −35° C. and n-butyllithium in hexane was used in place of sec-butyllithium in cyclohexane.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]3[O:15]C(C)(C)[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[N:9]=[C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:17])[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[O:11]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(F)cc4F)ncnc31)O[C@@H]2c1nc(C(C)(C)C)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1noc([C@H]2O[C@@H](n3cnc4c(Nc5ccc(F)cc5F)ncnc43)[C@H](O)[C@@H]2O)n1
Reaction time: 18 h
Yield: 84.8 %

Procedure:
A solution of 9-{(3aR,4R,6S,6aR)-6-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-N-(2,4-difluorophenyl)-9H-purin-6-amine (18.3 mg) in a cold mixture of trifluoroacetic acid:water (9:1; 1 ml) was kept at 4° C. for 18 h. The resulting solution was basified in an ice bath with a saturated solution of sodium bicarbonate (20 ml), extracted with ethyl acetate (2×20 ml), the extracts dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound (14.3 mg) as a purple solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:7]=1[NH2:6]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(N)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1N
Temperature: 25 °C
Yield: 82 %

Procedure:
Concentrated sulphuric acid (1 mL) was added to a solution of 2-amino-4-methyl-benzoic acid (1.0 g, 6.62 mmol) in dry methanol (10 mL) at 0° C., and then heated at reflux for 16 hr. The mixture was cooled to room temperature and concentrated in vacuo. The crude compound was diluted with water (25 mL) and basified with sodium bicarbonate (10 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with water (50 mL), brine (50 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure affording 2-amino-4-methyl-benzoic acid methyl ester (900 mg, 82%) as yellow liquid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:9]([CH3:19])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:19][C:9]1[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:3]=2[C:10]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: Cc1c(-c2cccc(C#N)c2)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc2n1COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
To a solution of 3-(4-chloro-6-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C7) (140 mg, 0.351 mmol) in n-butanol (5 mL) was added morpholine (30.6 mg, 0.351 mmol) and N,N-diisopropylethylamine (90.9 mg, 0.703 mmol). The reaction mixture was heated at 100° C. for 18 hours, then concentrated in vacuo to provide the product as a yellow solid. Yield: 125 mg, 0.278 mmol, 79%. LCMS m/z 450.3 [M+H+].
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:9]2[C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3].I[CH3:20]>>[CH3:20][O:1][CH:2]([C:4]1[C:9]2[C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CI
Reactant: CCOC(=O)c1oc2cccc(C(C)O)c2c1C
Product: CCOC(=O)c1oc2cccc(C(C)OC)c2c1C
Yield: 100 %

Procedure:
According to the procedure of (Example 100, Step 1), 0.21 g of ethyl 4-(1-hydroxyethyl)-3-methyl-1-benzofuran-2-carboxylate after heating with iodomethane for 8 days provided 0.22 g of ethyl 4-(1-methoxyethyl)-3-methyl-1-benzofuran-2-carboxylate. Yield: ˜100% m.p. 67-69° C.; MS: 263.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11]CC)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.Cl.NO.[N:17]1C=CC=CC=1>CCO>[CH3:1][C:2]12[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[N:17][O:11][C:9]2=[O:10]
Reactant: c1ccncc1
Reactant: CCOC(=O)C1(C)CCCCC1=O
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC12CCCCC1=NOC2=O
Temperature: 65 °C

Procedure:
To a mixture of ethyl 1-methyl-2-oxo-cyclohexanecarboxylate, 37a, (2.05 g, 11.10 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.97 g, 13.96 mmol) and pyridine (0.99 mL, 12.20 mmol). The mixture was heated to 65° C. overnight. The solution was concentrated in vacuo and the crude material was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc twice more. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-35% EtOAc/hexanes) to afford the desired product, 37b.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>N1C=CC=CC=1>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:22][CH2:21][CH:20]([CH2:23][O:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 48 h
Yield: 83.1 %

Procedure:
A solution of 2-O-octadecyl-3-O-trityl-glycerol (10 g, 17.04 mmol) in 52 mL anhydrous pyridine is added dropwise during 30 min. to a solution of p-toluenesulfonyl chloride (5.1 g, 26.75 mmol) in 39 mL anhydrous pyridine with stirring. After 2 days at room temperature, diethyl ether (162 mL) is added, and the precipitate formed is removed by filtration. The organic phase is washed successively with water (6×50 mL), 0.5N HCl (2×29 mL), 0.5N sodium carbonate (2×29 mL), and water (4×50 mL). Evaporation of the solvent in vacuo gives an oily product which becomes solid after drying in vacuo. The product, 1-O-p-toluenesulfonyl-2-O-octadecyl-3-O-trityl-glycerol (10.5 g, 85% yield), is used for the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:20])[C:16](=O)[CH2:17]Br)[CH3:13].O>CN(C=O)C>[CH2:12]([O:14][C:15]([C:16]1[N:11]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:17]=1)=[O:20])[CH3:13]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and 3-Bromo-2-oxo-propionic acid ethyl ester (1 eq.) is added and stirred 2 h at 70° C. The suspension is diluted with DMF (2 ml). After cooling to RT the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A4” is obtained as colourless powder in a yield of 78%; mp. 299.8-300.8° C.; HPLC (method C): 2.01 min; LC-MS (method A): 2.002 min, 327.95 (M+H+);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:11])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Br)cc(F)c1F
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a solution of 5-bromo-2,3-difluorophenol (19 g, 90 mmol) in acetone (180 mL), K2CO3 (18 g, 0.13 mol) and iodomethane (25.8 g, 0.18 mol) were added. The resulting mixture was refluxed for 4 h. Upon completion, the mixture was cooled to room temperature and filtered, and the filtrate was evaporated to give the crude product, which was further purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=80/1˜40/1) to give a light yellow liquid 5-bromo-1,2-difluoro-3-methoxybenzene (19 g). 1H NMR (CDCl3): δ 7.00-6.88 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[C:13]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl>O1CCCC1>[C:9]([O:8][C:6]([C:5]1[C:4]([OH:3])=[C:16]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:14][C:13]=1[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.3 %

Procedure:
A 3N aqueous sodium hydroxide solution (0.33 ml, 0.33 mmol) was added to a solution of tert-butyl 2-hydroxy-6-[({4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (467 mg, 0.90 mmol) obtained in Example (6-9) in tetrahydrofuran (8 ml), and the mixture was stirred at room temperature for 10 hours. After the reaction mixture was poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solid obtained by removing the solvent under reduced pressure was reprecipitated using n-hexane-ethyl acetate to give the title compound as a white powder (372 mg, yield: 82%).
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2(O)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1(c2ccc(Br)cc2)CCC1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
TBSOTf (360 μL, 1.57 mmol) was added to a 0° C. solution of 3-1 (235 mg, 1.04 mmol) and triethylamine (450 μL, 3.23 mmol) in dichloromethane (3 mL). The reaction was allowed to warm to room temperature and after 1 h, saturated NaHCO3 solution was added. The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined ethyl acetate solution was washed with brine. The solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (hexanes) gave 3-2 (329 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CN(C)C=O.C([O-])([O-])=O.[K+].[K+].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Cl>O>[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][O:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])[C:3](=[O:21])[C:2]=1[Br:1]
Reactant: Fc1ccc(CCl)c(F)c1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
Methyl 3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (4) (1.9 kg, 5.4 moles), N,N-dimethylformamide (4.8 L) and powdered K2CO3 (1.1 kg, 8.1 moles) were mixed together and heated to 55° C. under nitrogen. 2,4-difluorobenzyl chloride (964 g, 5.9 moles) was added at a rate such that the temperature was maintained below 65° C. After the addition, the mixture was heated at 65° C. for 3.5 hours. After 3 hours the reaction was complete and the reaction mixture was cooled to 20-25° C. with the addition of 19 L water. The solid was filtered and washed with 15 L water. The crude product was then purified by trituration in refluxing methanol (4 L). The mixture was cooled and the solid filtered to yield 2.32 kg (90%) product. 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 3H), 2.11 (s, 3H), 3.87 (s, 3H), 5.25 (s, 2H), 6.11 (s, 1H), 6.88 (dt, J=4.8, 1.8 Hz, 1H), 6.96 (t, J=4.8 Hz, 1H), 7.42 (d, J=6 Hz, 1H), 7.59 (q, J=4.8 Hz, 1H), 7.74 (s, 1H), 8.02 (d, J=6 Hz, 1H). Anal. Cald. for C22H18BrF2NO4: C, 55.25; H, 3.79; N, 2.93. Found: C, 55.34; H, 3.83; N, 3.14.
Reaction SMILES: [CH2:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-2].[Zn+2:29].[C:30](=[S:32])=[S:31]>>[CH2:15]([N:14]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:30](=[S:31])[S-:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Zn+2:29].[CH2:15]([N:14]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:30](=[S:31])[S-:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: S=C=S
Reactant: CCCCCCCCCCCCCNCCCCCCCCCCCCC
Agent: [O-2]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCN(CCCCCCCCCCCCC)C(=S)[S-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL round bottomed flask was placed 76.5 g of ditridecylamine and 8.10 g of zinc oxide. Carbon disulfide, 16.0 g, was then added dropwise, and the mixture was stirred for 30 minutes. The flask was then stirred and heated for 2 hours at 70° C., and then stirred for an addition 2 hours at 90° C. A vacuum was then applied to remove water of reaction and the temperature was increased to 130° C., and the reaction was maintained in this state for 3 hours. The pale yellow material was then filtered through Celite at 120° C., to give a pale yellow liquid with a Zn content of 5.8%.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:37])[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CN(C)CCCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(C)C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 442 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of 5-fluoro-2-nitroaniline (10 g, 64.1 mmol) in DMF (65 mL) was added tert-butyl-piperazine carboxylate (13.1 g, 70.5 mmol) and K3PO4 (13.3 g, 96.2 mmol). The reaction mixture was stirred at 100° C. overnight. After adding 100 ml H2O into the solution, the precipitated yellow solid was filtered under vacuum then dried in vacuo to afford tert-butyl 4-(3-amino-4-nitrophenyl)piperazine-1-carboxylate as yellow solid (15 g, yield: 82%).
Reaction SMILES: C([NH:4][C:5]1[C:6]([F:15])=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=O)C.Cl>>[NH2:4][C:5]1[C:6]([F:15])=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(Cl)ccc(C(=O)O)c1F
Agent: Cl
Product: Nc1c(Cl)ccc(C(=O)O)c1F
Yield: 96 %

Procedure:
The sub-title compound is prepared from 3-acetylamino-4-chloro-2-fluoro-benzoic acid and 6 M HCl-solution in analogy to step Ab.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(C)(=O)=O)c3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.350 g, 1.0 mmol) and commercially available (3-methylsulfonylphenyl)boronic acid (0.220 g, 1.0 mmol) according to the general procedure VI. Obtained as an off-white solid (0.280 g, 59%). MS (ISP) 470.1 [(M+H)+]; mp 208° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2ccco2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1coc(CCCN2CCNCC2)c1
Yield: 131.3 %

Procedure:
To 1.5 g of 1-t-butoxycarbonyl-4-[3-(2-furyl)propyl]-piperazine was added 5 ml of trifluoroacetic acid under ice-cooling, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then dissolved in ethyl acetate 10 ml. To the solution was added 4N hydrochloric acid-dioxane solution under ice-cooling to yield 1.3 g of 1-[3-(2-furyl)propyl]piperazine.2 hydrochloride.
Reaction SMILES: CN(C)CCN[C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].[NH2:44][CH2:45][CH:46]([OH:49])[CH2:47][OH:48]>>[OH:49][CH:46]([CH2:47][OH:48])[CH2:45][NH:44][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7]
Reactant: NCC(O)CO
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)NCC(O)CO)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to racemic 3-amino-1,2-propanediol under standard TBTU conditions to yield the title compound of example 140.