Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([F:12])=[CH:5][C:6]([CH3:11])=[C:7]([NH:9]N)[CH:8]=1.[O:13]1[CH:17]=[CH:16][CH2:15][CH2:14]1.Cl>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:11][C:6]12[C:16]([CH2:15][CH2:14][OH:13])=[CH:17][N:9]=[C:7]1[CH:8]=[C:3]([Br:2])[C:4]([F:12])=[CH:5]2
Reactant: Cc1cc(F)c(Br)cc1NN
Reactant: C1=COCC1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC12C=C(F)C(Br)=CC1=NC=C2CCO
Temperature: 0 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a solution of 5-bromo-4-fluoro-2-methylphenylhydrazine hydrochloride (4.75 g, 18.6 mmol) in 20% aqueous THF (100 mL) at 0° C. was added dropwise a solution of 2,3-dihydrofuran (1.55 mL, 20.4 mmol) in THF (10 mL). After stirring for 2 hours at 0° C. and 12 hours at room temperature, the reaction mixture was diluted with ether (100 mL). The organic solution was washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in ethylene glycol (50 mL), treated with ZnCl2 (5.58 g, 40.9 mmol), and heated at 170° C. for 4 hours. The reaction mixture was cooled down to room temperature and 6 N HCl (100 mL) was added. The mixture was extracted with ether (3×100 mL) and washed with water (200 mL) and brine (200 mL). The organic solution was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 1.52 g (30%) of title compound containing inseparable impurities (<20%) as a light brown oil. 1H NMR (CDCl3): 300 MHz δ 8.68 (bs, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.76 (d, J=9.63 Hz, 1H), 3.92 (t, J=6.48 Hz, 2H), 3.21 (t, J=6.48 Hz, 2H), 2.35 (s, 3H), 2.27 (bs, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[C:11](Cl)([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)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.1 %

Procedure:
0.78 g of ethyl pyrazole-4-carboxylate was dissolved in 15 ml of methylene chloride and 1.56 g of trityl chloride and 0.86 ml of triethylamine were added thereto and then the resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was washed with 10% aqueous solution of citric acid and SSC and then dried with sodium sulfate. The solvent was distilled off to give 2.45 g of ethyl 1-tritylpyrazole-4-carboxylate as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]=[CH:21][C:20]([CH3:25])([OH:24])[CH:19]2[C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:27][SiH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:29]([SiH2:28][O:27][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:19]1[C:20]([CH3:25])([OH:24])[CH2:21][CH2:22][CH2:23][N:18]1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)(=[O:16])=[O:17])([CH3:30])([CH3:31])[CH3:32]
Reactant: [H][H]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CC=CC1(C)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1N(S(=O)(=O)c2ccc(O)cc2)CCCC1(C)O
Yield: 101.3 %

Procedure:
A mixture of 1-(4-benzyloxy-benzenesulfonyl)-2-(tert-butyl-diphenyl-silanyloxymethyl)-3-methyl-1,2,3,6-tetrahydro-pyridin-3-ol (compound of formula VIII, 0.40 g, 0.64 mmol), 10% palladium on charcoal (0.1 g) and 30 ml of methanol was stirred for about 16 hours under about 1 atmosphere of hydrogen gas. The mixture was filtered through a pad of Celite®. Concentration of the filtrate afforded 0.35 g of 2-(tert-butyl-diphenyl-silanyloxymethyl)-1-(4-hydroxy-benzenesulfonyl)-3-methyl-piperidin-3-ol (compound of formula IX) as a colorless solid.
Reaction SMILES: [NH:1]([C:8](=[O:29])[CH:9]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][N:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[NH:1]([C:8](=[O:29])[CH:9]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of methyl 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinate (66 mg, TFA salt, 0.13 mmol) in MeOH (10 mL) was added a solution of LiOH (35 mg, 1.5 mmol) in water (2 mL). The reaction mixture was stirred at room temperature for 22 h, partially concentrated, neutralized with 1 M aqueous HCl (1.5 mL), concentrated, and dried under high vacuum. 6-[2-Anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinic acid was used without further purification: ESIMS calcd 376.1 (M++H), found 376.1 (M++H).
Reaction SMILES: [C:1]12([C:8]3[C:13](Cl)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O>CN(C)C=O>[C:1]12([C:8]3[C:13]([O:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Reactant: OCc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nnc3cc(C45CCC(CC4)C5)c(OCc4ccccn4)nn23)cc1
Reaction time: 3 h

Procedure:
To a solution of 7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (0.08 g, 0.25 mM, Example 1, step b) and 2-pyridylcarbinol (0.06 ml, 0.5 mM) in N,N-dimethylformamide (2 ml) under nitrogen was added lithium bis(trimethylsilyl)amide as a 1 mol solution in hexanes (0.375 ml). The reaction was stirred for 3 hours. Water was added until the solution became cloudy and after stirring for a further 15 minutes a solid was collected by filtration. This solid was recrystallised from ethyl acetate-hexane to give the required product (0.050 g, m.p.=166-168° C.). 1H NMR (360 MHz, DMSO) δ1.55 (2H, m), 1.91 (4H, m), 1.97 (2H, m), 2.13 (2H, m), 2.49 (1H, m), 5.77 (2H, s), 7.54 (1H, m), 7.69 (4H, s), 8.00 (1H, t, J=7.6 Hz), 8.28 (1H, s), 8.34 (2H, dd, J=7.6 and 1.5 Hz), 8.80 (1H, m); MS (ES+) m/e 398 [MH]+. Anal. Found C, 72.16; H, 5.59; N, 17.41. C24H23N5O. 0.1H2O requires C, 72.20; H, 5.86; N, 17.54%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[CH:13]=[CH:14][CH2:15][C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:22](=[O:24])[CH3:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[CH:13]=[CH:14][CH2:15][C:16]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:22](=[O:24])[CH:23]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(CC=Cc1ccccc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (2.81 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(o-chlorocinnamyl)-4-phenyl-5-oxohexanoic acid (3.57 g., 0.01 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (250 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is acidified with dilute hydrochloric acid (10 ml.), and the gum that separates out is extracted into ether. The ether extract is washed with brine solution, and dried over anhydrous Na2SO4. Filtration and removal of the ether in vacuo gives a viscous yellow residue, which upon trituration with petroleum ether (30°-60°C., 150 ml.) yields 4.3 g. of material, m.p. 90°-125°C. (cloudy). Recrystallization from n-butyl chloride, followed by ethanol, produces a material with m.p. 143°-146°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11]([C@H:13]1[N:17]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=2)[CH2:16][CH2:15][S:14]1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11]([C@H:13]1[N:17]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:20]=2)[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: O=Cc1cccc(C(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@@H]1SCCN1C(=O)c1cccc(CNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-formylbenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (108 mg, 0.162 mmol) was dissolved in DCM (2 ml). Aniline (18.08 mg, 0.194 mmol) and acetic acid (9.26 μL, 0.162 mmol) were added, and the mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (51.4 mg, 0.243 mmol) was added, and the mixture was stirred at RT overnight to achieve completion. The reaction mixture was diluted with DCM and extracted with water (2×). The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-((phenylamino)methyl)benzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (120 mg, 0.161 mmol, 100% yield). The compound was used in the next step without any further purification.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.[Cl:15][C:16]1[CH:17]=[C:18]([C:25]([CH3:35])([CH3:34])[CH2:26][C:27]2([C:30]([F:33])([F:32])[F:31])[CH2:29][O:28]2)[C:19]2[O:23][CH2:22][CH2:21][C:20]=2[CH:24]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:25]([CH3:35])([CH3:34])[CH2:26][C:27]([CH2:29][C:2]2[S:1][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=2)([OH:28])[C:30]([F:31])([F:32])[F:33])[C:19]2[O:23][CH2:22][CH2:21][C:20]=2[CH:24]=1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Cl)cc2c1OCC2
Reactant: c1cc2sccc2cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cc1cc2cnccc2s1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
A solution of thieno[3,2-c]pyridine (prepared according to the procedure by J. H. Wikel, M. L. Denney, and R. T. J. Vasileff, Heterocyclic Chem. 1993, 30, pp. 289-290) (152 mg, 1.12 mmol) in 2 mL of THF was treated with 450 μL of n-BuLi (2.5 M in hexanes) in a dropwise manner at −78° C. The resulting dark reaction mixture was stirred for 30 minutes and treated with a solution of 5-chloro-7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (180 mg, 0.561 mmol) in 0.5 mL of THF. The reaction was allowed to warm to room temperature overnight and quenched with a mixture of 5 mL of saturated ammonium chloride solution and 10 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography (ethyl acetate-hexanes, 20%-30% gradient) gave 33.5 mg (13% yield) of the title product as yellow foam.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4][N:3]1[OH:12].C(=O)([O-])O.[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4][N:3]1[O:12][S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25]
Reactant: O=c1c2ccccc2nnn1O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2nnn1OS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
In water (20 ml) are dissolved 4-oxo-3,4-dihydro-3-hydroxy-1,2,3-benzotriazine (2.4 g) and sodium hydrogen carbonate (1.3 g), and thereto is added a solution of benzenesulfonyl chloride (2.65 g) in ethyl acetate (20 ml) under ice-cooling and the mixture is stirred for 2 hours. The precipitated crystals are separated by filtration. The ethyl acetate layer is separated from the filtrate and concentrated. The resulting crystals are separated by filtration and combined with the crystals obtained above. The crystals are washed with ether, dried and then recrystallized from benzene to give 4-oxo-3,4-dihydro-3-benzene-sulfonyloxy-1,2,3-benzotriazine (4.0 g), melting point: 132°-134° C. Infrared spectrum: 1705, 1390, 1195 cm-1.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][O:17][CH2:18][CH2:19][Cl:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C(O)C>[ClH:20].[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][O:17][CH2:18][CH2:19][N:23]([CH3:24])[CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: OC(COCCCl)c1ccc(SCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCOCC(O)c1ccc(SCc2ccccc2)cc1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 600 mg of 1-(4-benzylthiophenyl)-2-(2-chloroethoxy)ethanol, 4 ml of a 50% aqueous dimethylamine solution, 310 mg of potassium iodide and 5 ml of ethanol was refluxed for 4 hours. To the reaction mixture was further added 4 ml of a 50% aqueous dimethylamine solution. The resulting mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature. The solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 30 ml of ethyl acetate and 30 ml of water. The resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 15 ml of acetone. To the solution was added 0.4 ml of a 5N dry hydrogen chloride-ethanol solution. The resulting crystals were collected by filtration to obtain 590 mg of 1-(4-benzylthiophenyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol hydrochloride (compound No. 222).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[C:7]([OH:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])[CH3:4]>Br.CC(O)=O>[Br:1][C:12]1[CH:13]=[C:6]([O:5][CH2:3][CH3:4])[C:7]([OH:14])=[C:8]([CH:11]=1)[CH:9]=[O:10]
Reactant: BrBr
Reactant: CCOc1cccc(C=O)c1O
Agent: Br
Solvent: CC(=O)O
Product: CCOc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.9 %

Procedure:
Bromine (2.95 g, 15.95 mmol) was added to a stirring solution of 3-ethoxy-2-hydroxybenzaldehyde (5.30 g, 31.9 mmol), which was dissolved in 30% HBr/HOAc The solution was stirred for 1.5 hrs at r.t. The reaction was quenched with H2O and extracted with ethyl acetate. The organic layer was washed with sat. ammonium chloride and dried over anhydrous sodium sulfate. Upon filtration the filtrate was concentrated in vacuo and purified by flash chromatography (silica gel) and eluted with 5% EtOAc/hexanes to yield 1.56 g (20%) of the title compound as a colorless oil: ESHRMS m/z 242.9657 (M−H, C9H9O3Br, Calc'd 242.9662).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13]O.Cl>O1CCOCC1>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc[nH]c2c1
Reaction time: 4 h

Procedure:
A mixture of 10 g of 5-benzimidazolecarboxylic acid, 150 ml of methanol and 100 ml of a 4N solution of hydrogen chloride in 1,4-dioxane was agitated ultrasonically for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, after which 300 ml of methanol and 3.5 g of lithium borohydride were added to the residue and the mixture was stirred for 1 hour. The solvent was then removed by evaporation under reduced pressure and the residue was mixed with an aqueous solution of sodium chloride, after which it was extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure, to give 5.44 g of the title compound, melting at 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.[NH2:40][C:41]1[CH:45]=[CH:44][N:43]([CH2:46][C:47]([CH3:50])([OH:49])[CH3:48])[N:42]=1>C(Cl)Cl>[OH:49][C:47]([CH3:50])([CH3:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:41]([NH:40][C:29]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:30])=[N:42]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 12.9 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) prepared in Example 3a was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 30.0 mg, 0.30 mmol) in CH2Cl2 (2 mL) followed by reacting with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (23.3 mg, 0.15 mmol) at rt for 30 min to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (7.8 mg, 13.0%) as a white amorphous. FIRMS (ES+) m/z Calcd for C30H33Cl2F2N5O2+H [(M+H)+]: 604.20538, found: 604.2056.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[OH2:17].[CH3:18]O>>[OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[NH:5])[O:17][CH3:18]
Reactant: O
Reactant: CO
Reactant: N#Cc1cccc(Cc2c[nH]cn2)c1O
Agent: Cl
Product: COC(=N)c1cccc(Cc2c[nH]cn2)c1O
Temperature: 10 °C
Reaction time: 15 h

Procedure:
A suspension of 19.9 g (0.1 mole) of 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzonitrile (prepared in example 1.1 above) in 600 ml of methanol, cooled to 10° C., is saturated with gaseous hydrochloric acid. 60 ml of water are added, the suspension is cooled to -25° C. and is saturated once again with gaseous hydrochloric acid. The reaction mixture is kept at that temperature for 15 hours. The solution is evaporated and the residue is taken up in 500 ml of ice-cold water; the resulting suspension is neutralized with an aqueous sodium bicarbonate solution. The solution is extracted 4 times with 250 ml of ethyl acetate and the organic phases are combined. The organic phase is washed with 200 ml of a saturated aqueous sodium chloride solution, is then dried over magnesium sulfate, filtered and evaporated. 19.1 g of methyl 2-hydroxy-3-(1H-imidazol-4-ylmethyl-)benzenecarboximidate are obtained which are used as such in the following step.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][C:23]4[S:24][C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl>C(O)(C)C.O>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH2:12][N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)=[CH:14][NH:15]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 90 °C
Yield: 334.2 %

Procedure:
To a solution of 1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidine-4-carboxylic acid ethyl ester (410 mg, 0.094 mmol) in isopropanol (10 mL) was added aqueous KOH (2 M, 53 mg, 0.42 mL, 0.94 mmol) and the resulting solution was heated (90° C., 24 h). The reaction mixture was diluted with H2O (10 mL) and neutralized with aqueous 1 M HCl. The suspension was filtered and the solid was washed with EtOAc (20 mL) and dried in vacuo to provide the title compound as a tan solid (128 mg, 33%). MS (ESI): mass calcd. for C22H21N3O3S, 407.4; m/z found, 408.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 11.18 (5, 1H), 7.88 (d, J=9.7, 1H), 7.73 (d, J=10.8, 1H), 7.68 (d, J=10.0, 1H), 7.44-7.40 (m, 2H), 7.35-7.28 (m, 2H), 7.06-7.03 (m, 1H), 3.66 (5, 2H), 2.88-2.84 (m, 2H), 2.22-2.16 (m, 1H), 2.04-2.00 (m, 2H), 1.80-1.77 (m, 2H), 1.58-1.55 (m, 2H), the CO2H proton was not detected.
Reaction SMILES: [CH:1]([NH:4][C@@H:5]([CH2:10][CH3:11])[C:6]([O:8][CH3:9])=[O:7])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.ClCCl>C1CCCCC1>[Cl:17][C:18]1[N:23]=[C:22]([N:4]([CH:1]([CH3:3])[CH3:2])[C@@H:5]([CH2:10][CH3:11])[C:6]([O:8][CH3:9])=[O:7])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1
Reactant: CC[C@H](NC(C)C)C(=O)OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC[C@@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
Methyl (2S)-2-(isopropylamino)butanoate 43a (10.75 g, 67.50 mmol) was dissolved in 180 mL of cyclohexane followed by the addition of sodium bicarbonate (22.68 g, 0.27 mol) and 2,4-dichloro-5-nitro-pyrimidine (15.71 g, 0.081 mol) successively, the reaction mixture was heated to 85° C. and stirred for 2.5 hours. The resulting mixture was cooled down to room temperature, added with 200 mL of dichloromethane, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain methyl (2S)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]butanoate 43b (8.78 g, yield: 41.1%) as a yellow solid.