Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH2:23][O:24][CH3:25])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH2:23][O:24][CH3:25])=[O:19]
Reactant: COCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N′-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 219 (0.27 g, 0.74 mmol) and Pd/C (0.10 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite and concentrated to provide 220 (0.19 g, 90%) as a white foam.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.[Cu]>[Br:14][C:15]1[CH:20]=[C:19]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:18]=[N:17][CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cncc(Br)c1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1cncc(-n2c3ccccc3c3ccccc32)c1
Temperature: 150 °C
Yield: 60 %

Procedure:
A mixture of 9H-carbazole (4.0 g, 24.1 mmol), 3,5-dibromopyridine (8.55 g, 36.1 mmol), copper powder (3.06 g, 48.2 mmol), potassium carbonate (13.3 g, 96.4 mmol) and 18-crown-6 (0.636 g, 2.4 mmol) in anhydrous DMF was degassed and heated at about 150° C. for about 40 hours. The crude mixture was then poured into water (200 mL), and then filtered. The solid was collected and dissolved in hot dichloromethane (500 mL) and an insoluble solid was then filtered off. The solution was absorbed on silica gel and purified by flash column (hexanes/ethyl acetate 12:1) to give a white solid product 2B (4.67 g, yield: 60%).
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOCC)C.P(Cl)(Cl)(Cl)=O.[CH2:18]1[C@@H:20]2[C:21](=[O:39])[CH:22]=[C:23]3[C@:36]([CH3:37])([CH:19]12)[C@@H:35]1[C@H:26]([C@H:27]2[C@@:31]([CH2:33][CH2:34]1)([CH3:32])[C:30](=[O:38])[CH2:29][CH2:28]2)[CH2:25][CH2:24]3.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]=[C:24]1[C:23]2[C@:36]([CH3:37])([CH:19]3[CH2:18][C@@H:20]3[C:21](=[O:39])[CH:22]=2)[C@@H:35]2[C@H:26]([C@H:27]3[C@@:31]([CH2:33][CH2:34]2)([CH3:32])[C:30](=[O:38])[CH2:29][CH2:28]3)[CH2:25]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@]2(C)C1=CC(=O)[C@H]1CC12
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1,2β-methylenandrost-4-en-3,17-dione (0.806 g, 2.7 mmol) is stirred at reflux for about 5 hours, i.e. until the starting material has disappeared. The suspension is allowed to cool and under vigorous stirring a saturated sodium carbonate solution is added dropwise until the pH of the aqueous layer becomes alkaline (ca. 1 hour). The organic layer is separated, neutralized with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue is purified by chromatography on silica gel using hexane/ethyl acetate as eluent. Thus the pure 6-methylen-1,2β-methylenandrost-4-ene-3,17-dione is obtained in 60% yield (0.194 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[CH2:7][CH:6]=[CH:5]2.[Br:12]Br.[Br-].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)C>[Br:12][C:6]1[CH2:5][C:4]2[C:8]([CH:7]=1)=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=2
Reactant: BrBr
Reactant: Cc1cc2c(cc1C)CC=C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc2c(cc1C)CC(Br)=C2
Reaction time: 2.5 h
Yield: 89.6 %

Procedure:
A 300 mL three-neck round bottom flask equipped with a condenser, mechanical stirrer, thermometer, and an addition funnel was charged with 5,6-dimethylindene (8.0 g, 56 mmol), tetrabutylammonium chloride (0.25 g), and water (100 mL). The addition funnel was charged with a solution of bromine (9.4 g, 0.059 mol) and potassium bromide (7.0 g, 0.059 mol) in water (100 mL total volume). The aqueous emulsion of 5,6-dimethylindene was vigorously stirred, at 45° C., during the course of a 30 minute dropwise addition of the bromine-bromide solution. Stirring was continued for another 2.5 hours at 50° C. The almost colorless reaction mixture was then cooled, diluted with water (100 mL), and diethyl ether (200 mL). The organic phase was separated, washed with water (3×200 mL), dried over anhydrous magnesium sulfate, and evaporated to near dryness. GC-MS analysis of the crude product revealed a 96% conversion of 5,6-dimethylindene. The expected 2-bromo-5,6-dimethyl-1-indanol comprised the majority of the mixture followed, in order of abundance, by 2-bromo-5,6-dimethylindene (via dehydration of the indanol), 1,2-dibromo-5,6-dimethylindane, and unreacted 5,6-dimethylindene. The entire quantity of crude product was transferred to a 300 mL three-neck round bottom flask equipped with a condenser, magnetic stir bar, and a nitrogen inlet. Toluene (200 mL), and p-toluenesulfonic acid (0.05 g) were added and the mixture was heated to reflux. GC analysis showed that the dehydration of 2-bromo-5,6-dimethyl-1-indanol was complete after 3 hours at reflux. The reaction mixture was cooled and extracted with diethyl ether (100 mL). The organic phase was separated, water washed, dried over anhydrous magnesium sulfate, and evaporated to yield crude 2-bromo-5,6-dimethylindene (11.2 g) as white oily crystals. One recrystallization from ethanol followed by two consecutive recrystallizations from hexanes gave purified 2-bromo-5,6-dimethylindene (6.5 g. 94% purity by GC) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][C:27]([C:30]([O:32]C(C)(C)C)=[O:31])([CH3:29])[CH3:28])/[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[N:13]([S:20]([OH:23])(=[O:22])=[O:21])[C:12]2=[O:24])=[O:9])[N:6]=1.[Na].FC(F)(F)C(O)=O>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][C:27]([C:30]([OH:32])=[O:31])([CH3:28])[CH3:29])/[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[N:13]([S:20]([OH:23])(=[O:22])=[O:21])[C:12]2=[O:24])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1)C(=O)O

Procedure:
2.28 g of (3S,4S)-3-[(2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid-sodium salt are stirred at 0° C. with 5 ml of trifluoroacetic acid. After additional stirring at room temperature for 30 minutes the excess trifluoroacetic acid is removed in vacuo and the remaining oil treated with 100 ml of ether. The resulting crystals are filtered off, washed with ether and dried in vacuo. The product is purified by reverse phase chromatography and lyophilized. (3S,4S)-3-[(Z)-2-(2-Amino-4-thiazolyl)-2-[[1-carboxy-1-methylethoxy]imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid is obtained; [α]D =+35.7° (c=0.3 in water).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[O:25])[O:23][C:21](=[O:22])[C:20]2=[CH:26][C:27]=1[Cl:28]>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([CH:5]=[C:6]3[S:10][C:9](=[O:11])[NH:8][C:7]3=[O:12])[CH:3]=2)=[O:25])[C:20](=[CH:26][C:27]=1[Cl:28])[C:21]([OH:23])=[O:22]
Reactant: Nc1cccc(C=C2SC(=O)NC2=O)c1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(=Cc2cccc(NC(=O)c3cc(Cl)c(Cl)cc3C(=O)O)c2)S1
Reaction time: 8 h

Procedure:
5-(3-Amino-benzylidene)-thiazolidine-2,4-dione was dissolved in THF and treated with a solution of 4,5-dichlorophthalic anhydride and a catalytic amount of DMAP. The solution was stirred for 8 hours, then filtered and concentrated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was concentrated to an oil and triturated with hexane to give the product as a solid which was collected by filtration.
Reaction SMILES: [C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][C:7]1[CH:8]=[C:9]([C:13]2(O)[CH:25]([CH2:26][N:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][C:15]3(OCC(C)(C)C[O:16]3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([Si:5]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:25]([CH2:26][N:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][C:15](=[O:16])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CC1CCC2(CC1(O)c1cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)OCC(C)(C)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CC1CCC(=O)C=C1c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 10 h

Procedure:
197 g 8-[3-(tert-Butyl-diphenyl-silanyloxy)-phenyl]-9-dimethylaminomethyl-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-8-ol were dissolved in tetrahydrofuran and the solution was cooled to 5° C. A mixture of 300 ml concentrated hydrochloric acid and 300 ml water was added dropwise at this temperature. The mixture was then stirred at room temperature for 10 hours. 400 ml ethyl acetate were then added, while cooling with ice, and the pH was then brought to 12 with 32% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted three times with 400 ml ethyl acetate each time. The combined organic phases were washed twice with 100 ml saturated sodium chloride solution each time and dried over magnesium sulfate and the solvent was then evaporated in vacuo. The residue was purified on silica gel with ethyl acetate/methanol=1/1. 68 g (42% of theory) of the title compound were obtained in this way.
Reaction SMILES: [Li]C.C(OCC)C.OS([O-])(=O)=O.[K+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2/[C:25](/[C:33]#C)=[CH:26]/[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CS(C)=O.C(Cl)Cl.CCO.C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]([CH3:33])=[CH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: C#C/C(=C\c1cccnc1)c1c[nH]c2ccc(OC)cc12
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]C
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2[nH]cc(C(C)=Cc3cccnc3)c2c1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
To a solution of MeLi in diethyl ether (5.1 mL, 1.6 M, 8.2 mmol, 6.0 eq.) and anhydrous and degazed THF (70 mL) was added, under an argon atmosphere and at 10° C., ketone tert-butyl 5-methoxy-3-(2-(pyridin-3-yl)acetyl)-1H-indol-1-carboxylate (1.2 g, 3.3 mmol, 1.0 eq.). The reaction mixture was stirred at 10° C. for 15 minutes and then, cooled to 0° C. and quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4 and evaporated under reduced pressure. To the alcohol residue taken up in toluene (70 mL) was added KHSO4 (1.1 g, 8.2 mmol) and the mixture was heated at 70° C. for 18 hours and quenched with a saturated aqueous sodium bicarbonate solution, after cooling to room temperature. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4 and evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 99/1 to 97/3) to afford the two diastereoisomers represented herein only by the compound (59), namely the major one (E), as a yellow mering (200 mg, 56%, E/Z ratio: 80/20). TLC: Rf=0.30 (CH2Cl2/EtOH, 96/4); IR νmax (cm−1): 2925 (νC—H aliphatic); 1H RMN (DMSO, 500 MHz) δ isomere E (ppm): 2.29 (3H, s, 3H3′), 3.80 (3H, s, 5-methoxy), 6.82 (1H, dd, J6-7=8.9 Hz, J6-4=2.3 Hz, H6), 6.93 (1H, s, H1′), 7.33 (1H, d, J7-6=8.9 Hz, H7), 7.39 (2H, m, H4 et H5″), 7.59 (1H, s, H2), 7.82 (1H, d, J4″-5″=7.9 Hz, H4″), 8.40 (1H, d, J6″-5″=4.6 Hz, H6″), 8.63 (1H, s, H2″), 11.21 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ isomere E (ppm): 18.5 (C3′), 55.9 (5-methoxy), 103.0 (C4), 111.8 (C6), 113.1 (C7), 118.1 (C3), 119.2 (C1′), 123.7 (C5″), 125.3 (C3a), 126.1 (C2), 132.7 (C7a), 134.8 (C3″), 135.1 (C2′), 136.2 (C4″), 146.8 (C6″), 150.4 (C2″), 154.4 (C5); ESI-MS: m/z 265.2 ([M+H]+); HRESI-MS: m/z 265.1340 (calcd for C17H17N2O+, 265.1341).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([N:11]([CH2:33][CH3:34])[CH:12]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:23]([CH3:24])=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=3)[NH:21][N:20]=2)=[O:18])[CH2:13]1)[CH3:10]>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]#[C:31][C:27]2[CH:26]=[C:25]([C:22]3[NH:21][N:20]=[C:19]([C:17]([N:14]4[CH2:15][CH2:16][CH:12]([N:11]([CH2:33][CH3:34])[CH2:9][CH3:10])[CH2:13]4)=[O:18])[C:23]=3[CH3:24])[CH:30]=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4cccc(Cl)c4)c3)c2C)C1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 65.1 %

Procedure:
A solution of 0.086 g (0.36 mmol) of 1-chloro-3-iodobenzene in 1.5 ml piperidine was degassed (argon) and treated with 17 mg (0.01 mmol) Pd(PPh3)4 and 3 mg (0.01 mmol) CuI. The reaction mixture was stirred at 50° C. for 10 min and then slowly (60 min) treated with 0.105 g (0.30 mmol) of (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone in 1.55 ml piperidine. After 30 min the bath was slowly (30 min) heated to 80° C. The reaction mixture was stirred at this temperature for 1 h and then partitioned between chilled water sat. KHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 97.5:2.5 to 95:5) yielded 0.090 g (65%) of the title compound as light yellow foam. MS: 461.1 (MH+, 1 Cl).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11]2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:13]1[C:12]2([CH2:17][CH2:18][NH:19][CH:10]([CH2:9][NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:11]2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cccc(NCC2CC3(CCCC3)CCN2C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NCC2CC3(CCCC3)CCN2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
(±)tert-butyl 7-(((6-methylpyridin-2-yl)amino)methyl)-8-azaspiro[4.5]decane-8-carboxylate (intermediate 73, 1.3 g, 3.62 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0° C., then trifluoroacetic acid (30 ml) was added. After 1 hour at 0° C. and 2 hours at room temperature the solution was evaporated, the residue re-dissolved in dichloromethane was washed with saturated NaHCO3 aqueous solution. The organic layers were dried (Na2SO4) and concentrated under vacuum to obtain 900 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][C:38]([C:40]1([O:44][C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH3:36].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:35]([O:37][C:38]([C:40]1([O:44][C:45]2[CH:50]=[CH:49][C:48]([O:15][CH2:14][CH:13]([N:12]3[C:11]4[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=4[N:9]=[C:8]3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:47][CH:46]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH3:36]
Reactant: CCOC(=O)C1(Oc2ccc(O)cc2)CCC1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C1(Oc2ccc(OCC(C3CCCCC3)n3c(-c4ccc(Cl)cc4)nc4cc(F)c(F)cc43)cc2)CCC1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c), 1-(4-hydroxy-phenoxy)-cyclobutanecarboxylic acid ethyl ester (CAS RN: 879094-83-4), tri-n-butylphosphin and N,N,N′,N′-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow foam (45%). MS (Turbo Spray): m/z=609.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:22])[NH:10][C:11](=[O:21])[N:12]([CH2:14][CH2:15][CH:16](OC)[O:17]C)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:22])[NH:10][C:11](=[O:21])[N:12]([CH2:14][CH2:15][CH:16]=[O:17])[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(CCn1cc(-c2cccnc2Cl)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: O=CCCn1cc(-c2cccnc2Cl)c(=O)[nH]c1=O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
5-(2-Chloro-pyridin-3-yl)-1-(3,3-dimethoxy-propyl)-1H-pyrimidine-2,4-dione (Prep96, 150 mg, 0.46 mmol) was dissolved in THF (5.6 ml) and 1N HClaq (0.46 ml) was added. The solution was then stirred at 40° C. for 1.5 hours. TEA (0.067 ml, 0.48 mmol) was added and the solvent was carefully removed in vacuum at room temperature. Residue was freeze dried to give a white powder that was used in the next step without further purification (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[I:8].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[I:8])[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)ccc1I

Procedure:
A suspension of 40.4 g (160 mmol) of the compound from Example XXXI in 400 ml of carbon tetrachloride, 31.3 g of N-bromosuccinimide (176 mmol) and 2.63 g of azobisisobutyronitrile (16 mmol) is heated under reflux overnight. After cooling, the precipitate is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are concentrated and the residue is further reacted in the crude state.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[CH:9][C:6]=1[CH:7]=[O:8].Cl>O1CCCC1.O>[CH3:14][O:13][C:11]1[C:10]([CH3:15])=[CH:9][C:6]([CH:7]([OH:8])[CH3:1])=[C:5]([CH3:4])[CH:12]=1
Reactant: COc1cc(C)c(C=O)cc1C
Reactant: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(C(C)O)cc1C
Yield: 74 %

Procedure:
Methyl magnesium bromide (2.4 mL, 1.2 eq) was dropwise added at −78° C. to a solution of 2,5-dimethyl-4-methoxybenzaldehyde (1.0 g, 6.0 mmol) in 30 mL of tetrahydrofuran (THF) with stirring and the reaction mixture was allowed to react at that temperature while being stirred. After completion of the reaction, the reaction mixture was adjusted to pH 7 at 0° C. with 1N-HCl and concentrated in a vacuum. The residue thus obtained was stirred in water (20 mL) and extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated in a vacuum to remove the solvent. The concentrate was purified through silica gel chromatography to yield 1-(4-methoxy-2,5-dimethylphenyl)ethanol as a white oil (0.87 g, yield 74%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([NH:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH3:8].C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:9]([CH2:7][CH3:8])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1
Reactant: COC(=O)CBr
Reactant: CCNc1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCN(CC(=O)OC)c1cccc(O)c1
Temperature: 100 °C

Procedure:
Methyl bromoacetate (10.7 g, 70 mmole), 3-(ethylamino) phenol from above (4.8 g, 35 mmole), and ethyl diisopropyl amine (4.45 g, 35 mmole) were combined in 25 ml of toluene. The mixture was heated at 100° C. for 30 min. and then evaporated under vacuum and chromatographed on a silica gel column using 5% (v/v) methanol/methylene chloride. The combined fractions were washed with saturated sodium bicarbonate and neutralized with 0.1N HCL. The combined fractions were dried over Na2SO4 and evaporated to give 7.24 g of N-ethyl-N-3-hydroxyphenyl glycine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24](I)[N:23]=[C:22]2[CH:27]([CH3:29])[CH3:28])=[CH:17][CH:16]=1.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:24]2[N:23]=[C:22]([CH:27]([CH3:29])[CH3:28])[N:21]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)[CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(I)cn1-c1ccc(F)cc1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CC(C)c1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=340.1 (M+H+), was prepared in accordance with the general method of example B, step 2, from 2-chloro-4-trimethylsilanylethynyl-pyridine and 1-(4-fluoro-phenyl)-4-iodo-2-isopropyl-1H-imidazole and crystallization from methanol and 1.05 eq fumaric acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Reaction time: 3 h

Procedure:
Piperazine-4-carboxylic acid tert-butyl ester (3.74 g), cyclobutanone (3.00 mL), and acetic acid (1.15 mL) were dissolved in methanol (100 mL). To the resultant solution, sodium cyanoborohydride (1.89 g) was added at room temperature, followed by stirring for 3 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (4.43 g, 92%).