Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]#N)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:17]([OH:19])[CH3:18].S(=O)(=O)(O)[OH:21]>O>[CH2:17]([O:19][C:15](=[O:21])[CH2:14][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: N#CCc1ccc(C2CCCCC2)c(Cl)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 11.5 g of 3-chloro-4-cyclohexyl-phenylacetonitrile, 15 ml of absolute ethanol and 5.3 ml of concentrated sulfuric acid is refluxed overnight, then diluted with water and several times extracted with ether. The ethereal solution is washed with sodium bicarbonate solution and water and dried over sodium sulfate, evaporated, and the residue is distilled under a high vacuum, to yield 12.5 g of 3-chloro-4-cyclohexylphenylacetic acid ethyl ester boiling at 137° to 139°C under 0.3 mm Hg pressure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Yield: 74.7 %

Procedure:
A solution of 3.66 g of 3-hydroxybenzaldehyde, 3.1 g of imidazole, and 4.39 g of tert-butyldimethylsilyl chloride in 10 ml of DMF is stirred at room temperature for 18 h, then partitioned between ether and water. The organic phase is washed with water, dried (MgSO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 5% ether-hexane provides 5.14 g of the title compound as a pale yellow liquid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:15](=[O:16])[NH:14][C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1.[CH2:17](Br)[CH3:18]>CN(C)C=O>[Br:3][C:4]1[C:15](=[O:16])[N:14]([CH2:17][CH3:18])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of NaH (60% in oil, 0.15 g, 3.75 mmol) in anhydrous dimethylformamide (10 mL) was added 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2, 0.68 g, 2.50 mmol) at room temperature and the reaction was stirred at 50° C. for 0.5 h. The reaction mixture was cooled to room temperature, ethyl bromide (0.22 mL, 0.32 g, 2.93 mmol) was added, and the reaction was stirred at 50° C. for 1.5 h. The mixture was poured onto ice water (10 g), and the white precipitate was collected to give 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.57 g, 1.90 mmol, 76%). ESMS m/z 300 (M+H)+. The material was used without any further purification.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([F:23])[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClC(Cl)C>[CH:1]1([NH:5][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6](=[O:8])[CH3:7])[CH2:14][CH2:13]3)=[CH:16][C:17]=2[F:23])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(CNC3CCC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
To a solution of cyclobutanamine (1.26 mL, 14.7 mmol) and 4-(4-acetylpiperazin-1-yl)-2-fluoro-benzaldehyde (3.68 g, 14.7 mmol) in dichloroethane (50 mL) was added sodium triacetoxyborohydride (4.39 g, 20.6 mmol) followed by acetic acid (0.84 mL, 14.7 mmol) and the reaction was stirred at ambient temperature for 16 hours. 1 N aqueous NaOH was then added to basify the reaction and the product was extracted with Et2O (×3), washed with brine, dried with MgSO4, concentrated and dried in vacuo to give 1-[4-[4-[(cyclobutylamino)methyl]-3-fluoro-phenyl]piperazin-1-yl]ethanone (4.76 g, 99% yield). The product was used without purification. LCMS (m/z) ES+ 306 [M+1]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]([CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])[C:6](=[O:15])[CH:5]=1.[CH3:16]I>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][N:7]([CH2:10][CH:11]([CH3:14])[CH2:12][O:13][CH3:16])[C:6](=[O:15])[CH:5]=1
Reactant: CC(CO)Cn1ccc(Br)cc1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)Cn1ccc(Br)cc1=O

Procedure:
NaH (60% in mineral oil, 57 mg) was added to a solution of 4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridin-2-one (0.53 g) in dimethylformamide (6 mL) chilled in an ice bath. After stirring the solution with cooling for 0.5 h, methyl iodide (110 μL) was added. The cooling bath was removed and the solution was stirred at room temperature overnight. Then, the solution was concentrated under reduced pressure and the residue was diluted with water. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (acetonitrile/water) to give the title compound as an oil. Yield: 70 mg (30% of theory); Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[N+:15]([O-])=O.O>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[NH2:15]
Reactant: COc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(N)c(Br)cc1C1CCCC1
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
1-Bromo-5-cyclopentyl-4-methoxy-2-nitrobenzene (100 mg, 0.33 mmol) was dissolved in acetic acid (1 mL) and water (250 μL) and treated with Zn (109 mg, 1.67 mmol) at room temperature and stirred for 1.5 h. The reaction was diluted with ethyl acetate and filtered. The organic layer was washed with 50% saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-4-cyclopentyl-5-methoxyaniline as a clear brown oil (85 mg, 94% yield). LC/MS m/z 270.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl.[NH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:33])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of [4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.150 g, 0.30 mmol), tert-butyl glycinate hydrochloride (0.0635 g, 0.38 mmol) and N-methylmorpholine (0.10 ml, 0.91 mmol) in DCM (2 ml) was stirred at room temperature. TBTU (0.128 g, 0.40 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (4.0 ml) was added and after 2 h the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a Kromasil C8-column using 35% MeCN in 0.1M ammonium acetate buffer as eluent. The solvent was removed under reduced pressure and 0.159 g (95%) of the title product was obtained. M/z 553.02.
Reaction SMILES: [C:1](=[O:26])([O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([F:24])=[CH:17][C:16]=1[Cl:25])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[Cl:13].[H][H]>C1(C)C=CC=CC=1.[Pd]>[Cl:13][C:4]1[CH:5]=[C:6]([F:12])[C:7]([NH2:9])=[CH:8][C:3]=1[O:2][C:1](=[O:26])[O:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([F:24])=[CH:17][C:16]=1[Cl:25]
Reactant: O=C(Oc1cc([N+](=O)[O-])c(F)cc1Cl)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1cc(OC(=O)Oc2cc(N)c(F)cc2Cl)c(Cl)cc1F
Yield: 99.7 %

Procedure:
Bis (2 -chloro-4- fluoro- 5 -nitrophenyl ) carbonate (1.2 Kg, 2.9 mol), toluene (7 liters) as a solvent and 5% Pd/C (200 g) as a catalyst were placed in a 10 L three-necked flask equipped with a stirrer, and hydrogen gas was introduced while vigorously stirring. Heat generated as the reaction proceeded, and the reaction temperature was maintained at 60° to 70° C. by introducing hydrogen at such a rate that the hydrogen gas did not discharge from the system. After completion of the reaction, the reaction mixture was heated (60°-70° C.), and the catalyst was separated by filtration. The organic layer of the filtrate was separated and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain bis(2-chloro-4-fluoro-5-aminophenyl)carbonate as a white solid (1.01Kg, 2.89 mol, 99.6% yield).
Reaction SMILES: [CH3:1][N:2]([CH:4](N(C)C)OC(C)(C)C)[CH3:3].[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH3:37])[CH:32]([NH:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:31]2=[O:47])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1CCCCC1>[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:1][N:2]([CH3:4])[CH3:3])[CH:32]([NH:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:31]2=[O:47])=[O:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)c3ccccc3)C2SC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)c3ccccc3)C2SC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 37.4 %

Procedure:
bis-Dimethylamino-tert.-butoxymethane (10 g) is added, under a dry nitrogen atmosphere, to a solution of 2-benzhydryloxycarbonyl-7-benzoylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (24 g) in anhydrous N,N-dimethylformamide (100 cc). The reaction mixture is stirred at 25° C. for 23 hours and is then poured into a mixture of ethyl acetate (300 cc) and an aqeous saturated sodium chloride solution (700 cc). The aqueous phase is decanted and extracted with ethyl acetate (250 cc). The organic phases are combined, washed with 1 N aqueous hydrochloric acid (250 cc), with distilled water (500 cc) and with a saturated aqeuous sodium chloride solution (300 cc) and then dried over magnesium sulphate in the presence of decolorising charcoal, and filtered. The solvent is evaporated under reduced pressure (20 mm Hg) at 30° C. The residue is dissolved in methylene chloride (200 cc) and fixed to silica (50 g). The powder obtained is placed in a column (height 60 cm, diameter 5 cm) containing silica gel (415 g) in a 95:5 (by volume) mixture of cyclohexane and ethyl acetate. Elution is carried out with the following mixtures of cyclohexane and ethyl acetate: 95:5 (by volume) (5 liters), 90:10 (by volume) (5 liters), 80:20 (by volume) (5 liters), 70:30 (by volume) (7.5 liters) (so as to elute the impurities) and 60:40 (by volume) (8 liters) the latter being collected and concentrated to dryness. 2-Benzhydryloxycarbonyl-7-benzoylamino-3-(2-dimethylaminovinyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (10 g) is obtained in the form of a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: COc1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cccc(-c2csc(N3CCN(C(=O)Nc4cccnc4)CC3)n2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 58.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (215 mg, 0.799 mmol), 1-[4-(3-methoxyphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.726 mmol) and diisopropylethylamine (0.253 ml, 1.45 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 168 mg (58.5%) of the desired product as a solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[C:11](B(O)O)[CH:10]=[N:9][CH:8]=1.Br[C:17]1[CH:30]=[CH:29][C:28]2[O:27][C:26]3[C:21](=[CH:22][C:23]([O:31][CH3:32])=[CH:24][CH:25]=3)[C:20]3([CH:36]([CH3:37])[O:35][C:34]([NH2:38])=[N:33]3)[C:19]=2[CH:18]=1.COCCOC>CCOC(C)=O.O>[CH3:32][O:31][C:23]1[CH:24]=[CH:25][C:26]2[O:27][C:28]3[C:19](=[CH:18][C:17]([C:11]4[CH:12]=[N:7][CH:8]=[N:9][CH:10]=4)=[CH:30][CH:29]=3)[C@:20]3([C@H:36]([CH3:37])[O:35][C:34]([NH2:38])=[N:33]3)[C:21]=2[CH:22]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1ccc2c(c1)C1(N=C(N)OC1C)c1cc(Br)ccc1O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)[C@]1(N=C(N)O[C@H]1C)c1cc(-c3cncnc3)ccc1O2
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium carbonate (0.636 g, 6.00 mmol), palladium tetrakistriphenylphosphine (0.185 g, 0.160 mmol), pyrimidin-5-ylboronic acid (0.322 g, 2.60 mmol) and 2′-bromo-7′-methoxy-5-methyl-5H-spiro[oxazole-4,9′-xanthen]-2-amine (0.750 g, 1.999 mmol) in a resealable pressure tube, was added DME (6 mL) and water (2 mL) at RT. The tube was sealed and heated to 85° C. After 2 hrs, the mixture was cooled to RT, diluted with EtOAc, and washed with brine. The organic fraction was dried with sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using 2-8% MeOH in CH2Cl2 with 1% NH4OH to afford a mixture of diastereomers as an off-white foam. MH+=375.2@1.54 min. Purification of the resulting racemic product mixture using Chiralpack AD-H (2×15 cm) 30% MeOH/CO2, 100 bar, 70 ml/min afforded:
Reaction SMILES: [N:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](O)=[N:3][CH:2]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[N:8][CH:7]=3)[NH:12][C:13]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2[nH]c3ccncc3c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ncnc2[nH]c3ccncc3c12

Procedure:
A suspension of 9H-1,3,6,9-Tetraaza-fluoren-4-ol (330 mg) and 500 μL of triethylamine were stirred vigorously overnight at 100° C. in 10 mL phosphorous oxychloride. The reaction mixture was then concentrated in vacuo and a small amount of the title compound was isolated by triturating the residue with water. The filtrate was concentrated in vacuo to give 363 mg of title compound which was used without further purification. LCMS (1): Rt 1.11 min; m/z 205 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([Li])[CH2:14][CH2:15][CH3:16].[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[C:18]1([CH2:19][CH:20]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][CH2:9][CH2:10][CH2:11][S:12]2)[OH:21])[CH:22]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCOC1
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: [Li]CCCC
Product: OC(Cc1ccccc1)C1(c2ccccc2)SCCCS1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 2-phenyl-[1,3]-dithiane (65) (4.0 g, 20.4 mmol) in THF at −30° C. was added a 1.6 M solution of n-butyllithium in THF (15.3 mL, 24.4 mmol). After stirring for 30 minutes at −30° C., a solution of phenylacetylaldehyde (2.45 g, 20.4 mmol) in tetrahydrofuran was added dropwise at −30° C. The resulting reaction mixture was stirred for another hour at 0° C. The reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The combined organic extracts were washed with saturated NH4Cl solution, brine and dried over Na2SO4. After filtrating and concentrating, the crude product was purified by flash chromatography on silica gel, (25% ethyl acetate in hexanes), to afford 2.63 g (71%) of the title compound (66). 1H NMR (CDCl3, 400 MHz): δ 1.97 (m, 2H), 2.23 (dd, J=4.0, 1.2 Hz, 1H), 2.43 (dd, J=13.6, 10.2 Hz, 1H), 2.77 (m, 4H), 3.02 (d, J=13.6 Hz, 1H), 4.07 (m, 1H), 7.44–7.13 (m, 8H), 8.02 (dd, J=8.4, 1.4 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NCCCCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)CCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 97.4 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and 5-aminopentanoic acid (0.152 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.37 g (98%) 143 as dull white crystals: mp=172° C.; Rf 0.93 (A): Rf 0.83 (B): Rf 0.69 (D): 1H NMR (DMSO-d6) δ 1.83 (m, 2H), 2.29 (t, J=7.2 Hz, 2H), 3.64 (t, J=6.7 Hz, 2H), 8.01 (d, J=7.6 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H), 8.59 (dd, J=7.6, 1.9 Hz, 1H); IR (cm−1): 2750–3200 (OH), 3056 (C═CH), 2620 (C—H), 1773 (C═O), 1707 (bs, C═O), 1624 (C═C), 1543 (N═O), 1438 (C═C), 1403 (C—O), 1351 (N═O), 1217 (C—O), 1068 (C—O), 723 (C═CH); MS m/z (rel intensity) 305 (100).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:35])[CH3:36])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12i) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 699.4 [(M+H)+]
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([O:21]C)=O)[C:12]=3[N:11]=2)[CH:7]=[CH:8][CH:9]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:1])=[O:21])[C:12]=3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2[nH]c(-c3cccc(OC)c3)nc12
Reactant: N
Product: COc1cccc(-c2nc3c(C(N)=O)cccc3[nH]2)c1
Yield: 46 %

Procedure:
Following standard procedure C, a liquid ammonia solution of methyl 2-(3'-methoxyphenyl)-1-H-benzimidazole-4-carboxylate (203 mg, 0.596 mmol) was heated under constant volume. The solid residue was recrystallised from methanol to give the pure product (73.5 mg, 46%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][S:12]([O:15][CH2:16][CH3:17])(=[O:14])=[O:13])(OCC)=O)C.[H][H].[CH:20](=O)[CH:21]([CH3:23])[CH3:22]>O1CCCC1.CCCCCCC>[CH3:20][CH:21]([CH3:23])/[CH:22]=[CH:11]/[S:12]([O:15][CH2:16][CH3:17])(=[O:13])=[O:14]
Reactant: [H][H]
Reactant: CC(C)C=O
Reactant: CCOP(=O)(CS(=O)(=O)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCOS(=O)(=O)/C=C/C(C)C
Temperature: 25 °C

Procedure:
Mineral oil was removed from sodium hydride (84.4 mg, 2.110 mmol) with heptane (2×4 ml) under a nitrogen atmosphere after which anhydrous tetrahydrofuran (10 ml) was added. To this suspension was added dropwise a solution of ethyl (diethoxyphosphoryl)methanesulfonate (500 mg, 1.921 mmol) in anhydrous tetrahydrofuran (10 ml) upon which hydrogen gas evolved from the mixture. After 5 minutes a clear slightly yellow solution was obtained. Isobutyraldehyde (200 μl, 2.191 mmol) was added and the resulting mixture was stirred at room temperature over night. The reaction mixture was quenched with a mixture of brine (50 ml) and aqueous saturated ammonium chloride solution (150 ml). The aqeuous mixture was extracted with dichloromethane (3×70 ml), the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 550 mg of a slightly yellow oil that was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[O:15](S(C(F)(F)F)(=O)=O)[S:16]([C:19]([F:22])([F:21])[F:20])(=O)=[O:17]>ClCCl.N1C=CC=CC=1>[F:20][C:19]([F:22])([F:21])[S:16]([O:12][C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:13])[N:7]=[C:6]([CH3:14])[CH:5]=[CH:4]2)(=[O:17])=[O:15]
Reactant: Cc1ccc2c(Br)c(O)c(C)cc2n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-2,7-dimethylquinolin-6-ol (1.04 g, 3.1 mmol) in dichloromethane (50 mL) and pyridine (10 mL) was added Tf2O (1.1 mL, 6.2 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, quenched with slowly addition of NaHCO3 solution at 0° C. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give the desired product. Column purification gave pure product. LCMS-ESI+: calc'd for C12H9BrF3NO3S: 383.9 (M+H+); Found: 383.9 (M+H+).