Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: N#CSc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 4-Aminophenyl thiocyanate (10.0 g (66.6 mmol)) in pyridine (70 ml), p-toluenesulfonyl chloride (12.7 g (66.6 mmol)) was added with stirring at room temperature, and the mixture was stirred at room temperature for 16 hours. Then, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 19.4 g (98%) of 4′-thiocyano-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH2:20][CH3:21])[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1.OO.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:1][N:2]1[C:6]2[C:7](=[O:8])[NH:9][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:10][C:5]=2[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: CCCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 58.8 %

Procedure:
1-Methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrazole-5-carboxamide (0.34 g, 0.99 mmol) was added to a stirred mixture of 30% hydrogen peroxide solution (1.0 ml), potassium carbonate (0.54 g, 3.92 mmol), water (10 ml) and ethanol (5 ml). The mixture was heated under reflux for 38 hours and then evaporated under vacuum. The residue was suspended in water (20 ml), then the mixture acidified with 2N hydrochloric acid and extracted with dichloromethane (3×20 ml). The extracts are combined, dried (Na2SO4) and evaporated under vacuum. The resulting residue was chromatographed on silica gel (6 g), using a methanol in dichloromethane elution gradient (0.0-1.0%), to give an oil, successive trituration of which with ether gave the required product as a white solid (0.19 g, 59%), m.p. 111-114° C. Found: C, 66.26; H, 6.92; N, 17.15. C18H22N4O2 requires C, 66.23; H, 6.80; N, 17.17%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1.C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:17])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Br:1])[OH:5])[CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: O=Cc1ccccc1Br
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)C(O)c1ccccc1Br

Procedure:
146 g (0.8 mol) of 2-bromobenzaldehyde, 85.6 g (0.8 mol) of 3-pyridinealdehyde, 20 g (0.08 mol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide and 40.4 g (0.4 mol) of triethylamine in 500 ml of ethanol were heated at 75° C. for 16 hours. Thereafter, the ethanol was distilled off and the residue was taken up in methylene chloride. The solution was washed twice with water and then extracted twice with 300 ml of 4N hydrochloric acid. The acidic aqueous phase was then rendered slightly alkaline with 4N sodium hydroxide solution and extracted three times with methylene chloride. After the solvent had been distilled off, the crude product was stirred with isopropanol, filtered off under suction and dried to give a product of melting point 105°-108° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[CH:14][C:13]1=[O:20].N12CCCN=C1CCCCC2.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.C([O-])(O)=O.[Na+]>CN(C)C=O>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][O:19][C:15]1[CH:16]=[C:17]([CH3:18])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[F:1])[C:6]([O:8][CH3:9])=[O:7])[C:13](=[O:20])[CH:14]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(F)c(-n2c(C)cc(O)cc2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reaction time: 18 h

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 3 (14.4 g, 51.9 mmol) and N,N-dimethyl formamide (40 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (10.9 mL, 72.8 mmol) was added followed by 2,4-difluorobenzyl bromide (9.3 mL, 72.8 mmol). The reaction mixture was stirred at 65 C for 18 h, was poured into saturated aqueous NaHCO3 and was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to give the title product, as an orange oil (21.59), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.20 (dddd, J=2.2, 4.8, 7.2 and 8.8 Hz, 1H), 8.00 (dd, J=2.2 and 7.2 Hz, 1H), 7.56 (td, J=2.4, 6.4 and 9.2 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J=0.8 and 2.6 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 1.98 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.34 (1F), −116.00 (1F), −117.35 (1F) ppm. ES-HRMS m/z 404.1104 (M+H calcd for C21H17F3NO4 requires 404.1104).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:56]1[CH:60]=[C:59]([CH2:61][C:62]([OH:64])=O)[N:58]=[CH:57]1>C1COCC1>[NH:56]1[CH:60]=[C:59]([CH2:61][C:62]([N:2]([CH3:1])[C@@H:3]2[CH2:7][CH2:6][N:5]([C:8]3[C:9]4[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=4[N:11]=[CH:12][N:13]=3)[CH2:4]2)=[O:64])[N:58]=[CH:57]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)Cc1c[nH]cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.29 mmol), TBTU (0.35 mmol) and DIPEA (0.58 mmol) in THF was slowly added 2-(1H-imidazol-4-yl)acetic acid (0.29 mmol). The mixture was stirred at room temperature overnight, then concentrated, diluted with water, and extracted with EtOAc. The combined extracts were dried, filtered and concentrated. The residue was purified by flash chromatography to give the title compound.
Reaction SMILES: N1C=CC=CC=1.[S:7]1[CH2:11][CH2:10][S:9][CH:8]1[CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][OH:20].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([O:20][CH2:19][C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]1[CH2:12][CH:8]1[S:9][CH2:10][CH2:11][S:7]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: OC[C@@H]1CCCC[C@@H]1CC1SCCS1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1CCCC[C@@H]1CC1SCCS1
Reaction time: 0.25 h

Procedure:
At 0° C., 290 μL (3.5 mmol) of pyridine was added to 0.740 g (3.18 mmol) of rac-cis-2-(1,3-dithiolan-2-yl methyl)cyclohexanemethanol in 5 mL of dichloromethane, followed by dropwise addition of 235 μL (3.5 mmol) of acetyl chloride. After 15 min at 0° C. and 30 min at 20° C., the reaction mixture was partitioned between water and dichloromethane and the organic solution washed with 1.0N HCl and with 5% KHCO3 solutions, dried (MgSO4) and concentrated under vacuum to 865 mg (98%) of racemic cis-2-(1,3-dithiolan-2-yl methyl)cyclohexanemethanol acetate. TLC Rf 0.48 (SiO2, dichloromethane, I2 -brown).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>C1(C)C=CC=CC=1.ClCCl>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccnc(-c2ccc(Cl)cc2)[nH]1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1ccc(-c2nccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
2-(4-chlorophenyl)pyrimidin-4(3H)-one (100 mg, 0.4840 mmol), suspended in toluene (2 ml), was treated with phosphoryl trichloride (443.0 μl, 4.840 mmol) at ambient temperature. The suspension was heated to reflux at which point the reaction became a colorless solution. After 4 hours, the reaction was cooled to ambient temperature and concentrated in vacuo to afford a white solid. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organics were dried with sodium sulfate, filtered, concentrated, and purified on silica gel. Elution with 2-20% ethyl acetate/hexanes provided the title compound (99 mg, 0.4399 mmol, 90.89% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].CC1C=CC(S(O[CH:22]2[CH2:25][CH2:24][CH2:23]2)(=O)=O)=CC=1.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH:22]1[CH2:25][CH2:24][CH2:23]1
Reactant: Sc1ccccc1Br
Reactant: Cc1ccc(S(=O)(=O)OC2CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1SC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 390 mg, 9.75 mmol) in anhydrous DMF (20 mL) was added 2-bromobenzenethiol (1.03 mL, 8.37 mmol) dropwise over 5 minutes. After stirring for 10 minutes at room temperature a solution of cyclobutyl 4-methylbenzenesulfonate (2.0 g, 8.85 mmol) in dry DMF (3 mL) was added dropwise. The resulting solution was then stirred for 2 hours at room temperature, and 2 hours at 50° C. Water was then added, and the mixture extracted with ethyl acetate (×3). The combined organics were washed with brine (×3), then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with neat petrol) to give (2-bromophenyl)(cyclobutyl)sulfane (1.19 g, 4.89 mmol, 58%) as a colourless oil.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:6]Cl.[Cl:12][CH2:13][C:14](=[O:16])[CH3:15].Cl>CCOCC.O1CCCC1>[Cl:12][CH2:13][C:14]([CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[CH:10]=[C:9]([CH3:11])[CH:8]=1)([OH:16])[CH3:15]
Reactant: CC(=O)CCl
Reactant: Cc1cc(C)cc(CCl)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)cc(CC(C)(O)CCl)c1
Reaction time: 2 h
Yield: 51.7 %

Procedure:
25 g of magnesium turnings and 155 g of 3,5-dimethylbenzyl chloride were reacted in 300 ml of ether. After dilution with 200 ml of tetrahydrofuran, a mixture of 92.5 g of chloroacetone and 100 ml of tetrahydrofuran was added dropwise with ice cooling in the course of one hour. After reacting for 2 hours at 25° C., the mixture was poured onto a mixture of ice and 2.5 mol hydrochloric acid. The upper layer was separated off and the aqueous layer was extracted with ether. The combined organic layers were washed with water until neutral, dried using Na2SO4, filtered and distilled. 110 g of 1-chloro-2-(3,5-dimethylbenzyl)-propan-2-ol were obtained at 110°-112° C./0.2 mbar. 109 g of this compound were stirred at 30° C. for 2 hours with 20 ml of methyl tert.-butyl ether and a solution of 31 g of NaOH in 750 ml of water. The layers were then separated, and the organic phase was washed with water until neutral, dried using Na2SO4 and distilled. 65 g of 2-(3,5-dimethylbenzyl)-propylene oxide were obtained at a boiling point of 68°-70° C./0.3 mbar. 80 g of this compound were dissolved in 100 ml of cyclohexane and put into a 0.5 l shaking autoclave with 0.8 g of 5% Pd on active carbon. After flushing with inert gas, the autoclave was pressuried with hydrogen (130 bar) and heated at 150° C. for 8 hours. The cooled mixture was depressurized, flushed with inert gas, the catalyst was filtered off and the filtrate was distilled through a 30-cm long column containing steel helices. 18 g of 2-methyl-3-(3,5-dimethylphenyl)-propan-1-ol passed over at 80°-81° C./0.07 mbar.
Reaction SMILES: [H-].[Na+].[O:3]1[C:11]2[CH:10]=[CH:9][NH:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4]1.C([O:15][CH:16]([O:19]CC)[CH2:17]Br)C.O>CN(C=O)C>[OH:15][CH:16]([OH:19])[CH2:17][N:8]1[CH:9]=[CH:10][C:11]2[O:3][CH:4]=[CH:5][C:6]=2[C:7]1=[O:12]
Reactant: CCOC(CBr)OCC
Reactant: O=c1[nH]ccc2occc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccoc2ccn1CC(O)O
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 0.36 g) was suspended in DMF(10 ml), and was cooled to 0° C. in an ice water bath. 5H-Furo[3,2-c]pyridin-4-one(1.0 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde diethylacetal(2.6 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochloric acid(5.8 ml) was added to an acetone solution (20 ml) of the residue, and the liquid was stirred at 60° C. for 5 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound(0.90 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[CH3:37][S:38](N1CCC(N)CC1)(=[O:40])=[O:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1cccc(OC)c1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(OC)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with 1-[4-[4-amino-5-(2,6-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone (Example 333) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,6-dimethoxy-phenyl)-methanone. MS (M+H)+, 436
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[O:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl>[Br:22][C:5]1[C:6](=[O:7])[C:2]([CH3:14])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CC1(C)OC(c2ccncc2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.81 g, 4.28 mmol) CHCl3 (20 mL), NBS (1.3 g, 7.28 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (100 mL). The organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.25 g, 21%) as a solid
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8]([CH3:52])([CH2:50][CH3:51])[CH2:9][C:10]1[N:11]=[C:12]([CH2:34][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][N:44]=3)=[CH:39][CH:38]=2)[OH:36])[N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1.CI>C(O)(C)(C)C>[CH3:7][C:8]([CH3:52])([CH2:50][CH3:51])[CH2:9][C:10]1[N:11]=[C:12]([CH2:34][CH:35]([C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][N:44]=3)=[CH:41][CH:42]=2)[O:36][CH3:1])[N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1
Reactant: CC(C)(C)[O-]
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (21 mg, 0.19 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanol (104 gm, 0.17 mmol) and methyl iodide (19 μL, 0.31 mmol) in tert-butanol (17 mL) at ambient temperature. After stirring overnight, the reaction mixture was washed with brine (100 mL), dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 2-(4-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-methoxyethyl}phenyl)-5-fluoropyridine as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[N:13]=[C:12]([C:15](=[O:26])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[NH:11][C:10]=2[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:5])C.[Cl:33][C:34]1[S:38][C:37]([C:39]2[O:43][N:42]=[C:41]([CH2:44]OS(C)(=O)=O)[CH:40]=2)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[S:38][C:37]([C:39]2[O:43][N:42]=[C:41]([CH2:44][N:11]3[C:10]4[CH:9]=[CH:8][C:7]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:6]([C:4]([OH:3])=[O:5])[C:14]=4[N:13]=[C:12]3[C:15](=[O:26])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:24])[CH3:25])[CH2:19][CH2:18]3)[CH:40]=2)=[CH:36][CH:35]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(Cl)s2)on1
Reactant: CCOC(=O)c1c(OCC(F)(F)F)ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)c(OCC(F)(F)F)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-5-(2,2,2-trifluoro-ethoxy)-1H-benzoimidazole-4-carboxylic acid was prepared by a procedure according to example 81 starting from 299.0 mg (0.66 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-5-(2,2,2-trifluoro-ethoxy)-1H-benzoimidazole-4-carboxylic acid ethyl ester and 192.4 mg (0.66 mmol) methanesulfonic acid 5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl ester. Hydrolysis of the resulting ethyl ester by treatment with LiOH in MeOH and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compound as its formiate in form of a white amorphous solid. Yield: 90 mg MS (ES+): m/e=626, chloro pattern.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35]Cl)[C:22]=1[CH2:37][CH2:38][CH3:39])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:37][CH2:38][CH3:39])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 70.4 %

Procedure:
A mixture of 2.94 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.85 g of [4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethyl ester, 4.2 g of anhydrous potassium carbonate, and 2.25 g of potassium iodide in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux. Additional 2.0 g portions of potassium carbonate were added after 19, 26 and 51 hours. Reflux was continued for a total of 8 days and then the reaction mixture was concentrated in vacuo. The crude product was purified by liquid chromatography using 35% ethyl acetate-hexane to give 5.8 g (70% yield) of [4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]([P:21]([OH:23])[OH:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[Na+].O.O1CCOCC1>[CH2:5]([O:4][C:2]([NH:12][CH:13]([P:21]([OH:23])[OH:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(Cc1ccccc1)P(O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(Cc1ccccc1)P(O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2.25 ml (14.25 mmol) of benzyl chloroformate are added dropwise, at 0° C. and within the space of 30 min., to a suspension of 1.76 g (9.5 mmol) of 1-amino-2-phenylethylphosponous acid in 15 ml of 1M NaOH, 5 ml of water and 5 ml of dioxane. During a further 2.5 h of stirring at 0° C., the pH of the mixture is maintained at 9-10 using 1M NaOH (approximately 10 ml). After removing the cooling medium, the mixture is stirred at RT overnight. The reaction solution is then washed several times with diethyl ether. The aqueous phase is adjusted to pH 2, at 0°-5° C., using 6M HCl and extracted several times with ethyl acetate. The combined extracts are washed with a saturated solution of NaCl, dried with Na2SO4, filtered and subjected to rotary evaporation i.V. A solid residue remains which is recrystallized from ether/petroleum ether.
Reaction SMILES: [ClH:1].[C:2]1([CH3:14])[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH2:18]=O>C(O)=O>[ClH:1].[CH3:18][N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1
Reactant: C=O
Reactant: Cc1ccc(C23CNCC2C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: Cc1ccc(C23CC2CN(C)C3)cc1

Procedure:
A mixture of 4.19 g. of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride and 20 ml. of water is made basic with sodium hydroxide. This mixture is extracted with ether and the ether is evaporated to give an oil. This oil is combined with 40 ml. of 97% formic acid and 35 ml. of 37% formaldehyde and the solution is heated on a steam bath for 2 hours. The solution is cooled, made basic with sodium hydroxide and extracted with ether. The extract is dried over magnesium sulfate, filtered, and the filtrate is saturated with hydrogen chloride. The precipitated crystals are collected and recrystallized from isopropyl alcohol to give 3-methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 197°-198° C.