Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:49])[CH2:14][CH:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27](=[O:48])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[C:31]([O:46][CH3:47])[CH:30]=1)[CH2:22][CH2:21][NH:20]2)[CH3:16])[CH3:11].C(N(CC)CC)C.O>O1CCCC1>[CH2:10]([O:12][C:13](=[O:49])[CH2:14][CH:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27](=[O:48])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[C:31]([O:46][CH3:47])[CH:30]=1)[CH2:22][CH2:21][N:20]2[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16])[CH3:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)c1ccccc1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzoyl chloride (22 μl) was added to a stirred mixture of 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinoxalin-6-yl)-butyric acid ethyl ester (0.110 g, Reference Example 17) and triethylamine (87.8 μl) in tetrahydrofuran (10 ml) cooled to 0° C. under an argon atmosphere. The mixture was stirred for 1 hour at 0° C., then allowed to warm to 20° C., then stirred at this temperature for 2 hours and then treated with a further aliquot of benzoyl chloride (11 μl). After stirring overnight the reaction mixture was treated with water (20 ml) then extracted three times with ethyl acetate (25 ml). The combined extracts were dried over magnesium sulfate then evaporated (40° C., 40 mbar). The crude residue (147 mg) was subjected to flash chromatography on silica (20 g, 0.040-0.063 mm particle size) eluting with a mixture of dichloromethane and methanol (99:1, v/v) to give the title compound as a white foam (132 mg). TLC: RF 13/56 (cyclohexane:ethyl acetate, 9:1, v/v). 1H NMR [400 HMz, (CD3)2SO, at a temperature of 383° K.]: δ0.96 (d, J=7 Hz, 3H); 1.16 (t, J=7 Hz, 3H); 2.24 (d, J=7.5 Hz, 2H); 2.28 (s, 3H); 2.93 (m, 1H); 3.83 (s, 3H); 3.94 (m, 2H); 3.96 (s, 21H); 4.02 (m, 2H); 4.04 (q, J=7 Hz, 2H); 6.63 (broad s ,1H); 6.76 (broad d, J=8 Hz, 1H); 6.90 (broad s, 1H); 6.99 (m, 2H); from 7.10 to 7.20 (m, 4H); 7.34 (broad t, J=7.5 Hz, 2H); 7.41 (broad t, J=7.5 Hz, 1H); 7.57 (d, J=8 Hz, 1H); 7.67 (broad d, J=8 Hz, 1H); 8.02 (d, J=8.5 Hz, 1H); 8.16 (broad s, 1H); 8.24 (broad s, 1H). MS (EI): 648 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:15][OH:16])([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[C:19](OC)([CH3:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:20][C:19]1([CH3:21])[O:1][CH2:2][C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][O:16]1
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)C(CO)(CO)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1(c2cccnc2)COC(C)(C)OC1
Reaction time: 12 h

Procedure:
To a mixture of 1.25 g of ethyl 3-hydroxy-2-(hydroxymethyl)-2-(pyridin-3-yl)propanoate in 13 ml of acetone were added 0.75 ml of 2,2-dimethoxypropane and 105 mg of p-toluenesulfonic acid monohydrate, followed by stirring for 12 hours. Then, 1.06 g of p-toluenesulfonic acid monohydrate was added thereto, followed by stirring for 6 hours. Further, 0.75 ml of 2,2-dimethoxypropane was added thereto, followed by stirring at 50° C. for 30 minutes, and the solvent was evaporated under reduced pressure. To the obtained residue were added 13 ml of acetone and 0.78 ml of 2-methoxy-1-propene at room temperature, followed by stirring for 30 minutes. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.16 g of ethyl 2,2-dimethyl-5-(pyridin-3-yl)-1,3-dioxane-5-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12.C(N(CC)CC)C.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>C1C=CC=CC=1>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12
Reactant: C[Si](C)(C)Cl
Reactant: Oc1cccc2c1CC2
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1cccc2c1CC2
Temperature: 5 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A larger batch of 4-trimethylsiloxybenzocyclobutene was synthesized from 6.56 gms of 4-hydroxybenzocyclobutene and 5.54 gms of triethylamine, taken up in 15 ml anhydrous benzene followed by the addition of a nearly three molar excess of chlorotrimethylsilane (20 ml in 15 ml dry benzene) to the reaction mixture maintained at 5° C. An instant white precipitation of triethylamine hydrochloride was observed. The solution was allowed to warm up on its own to 15° C. in about 5 hours and the reaction mixture was kept stirred overnight, It was warmed to 40° C. and maintained for about three hours. The reaction mixture was cooled and the isolation of the product was done exactly as described before. The weight of the light yellow oil (crude) was 7.93 g, 76% yield. Total amount of the colorless oil obtained from vacuum distillation was 7.07 grams. Anal. Calc.: C, 68.69%; H, 8.38%. Found: C, 69.15%; H, 8.44%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.P(Cl)(Cl)([Cl:23])=O>C(#N)C>[ClH:23].[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1COCCN1
Solvent: CC#N
Product: Cl
Product: c1ccc(N2CCOCC2)c(N=C2COCCN2)c1

Procedure:
A mixture of 3-morpholinone (4 g) in dry acetonitrile (40 ml), 4-(2-aminophenyl)morpholine (3.6 g) in dry acetonitrile (20 ml) and phosphorous oxychloride (3.6 ml) was heated for 40 hours at 65°-70° C. to give oil which was purified by column chromatography on neutral alumina (72 g) using (a) hexane, (b) dichloromethane:hexane (1:1) and (c) dichloromethane as eluant. The resulting oil was treated with a saturated solution of hydrogen chloride in methanol (25 ml) to give a pale yellow solid which was recrystallised from a 1:1 mixture of methanol and ether to give 4-[2-(3-morpholinylideneamino)phenyl]-morpholine hydrochloride (m.p. 262°-263° C.).
Reaction SMILES: [CH2:1]([CH:6]([C:12]([O:14]CC)=[O:13])[C:7]([O:9]CC)=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]>[OH-].[Na+]>[CH2:1]([CH:6]([C:12]([OH:14])=[O:13])[C:7]([OH:9])=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)C(CCC(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCC(C(=O)O)C(=O)O

Procedure:
Diethyl isoamylmalonate (71.7 g) was added to a 50% aqueous solution of sodium hydroxide (60 ml), and the mixture was heated under reflux for 6 h. After cooling, the mixture was extracted with ether; the water layer was acidified with hydrochloric acid and, after saturation with sodium chloride, was extracted with ether. The extracts from the acidic aqueous layer were concentrated under reduced pressure to give isoamylmalonic acid. The obtained dicaboxylic acid was heated at 180° C. for 2 h. After distillation under reduced pressure, 5-methyl-caproic acid was obtained. Yield: 30 g (75%), b.p. 107-108° C./11 mmHg.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[C:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:15]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:28]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH:20]=[C:21]2[CH2:26][CH2:25][N:24]([C:34]([NH:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:23][CH2:22]2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C#CCCCOc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.8 %

Procedure:
5-(Pent-4-ynyloxy)-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.26 g, 0.746 mmol) and phenyl pyridin-3-ylcarbamate (0.159 g, 0.746 mmol) were dissolved in DMSO (3 mL) and triethylamine (0.3 mL) was added dropwise. The reaction was stirred for 12 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (acetone:hexane, 2:5) to give the title compound (0.23 g, 65%). 1H NMR (500 MHz, CDCl3): δ 8.60 (s, 1H), 8.24 (s, 1H), 8.16 (d, J=7.5 Hz, 1H), 7.88 (s, 1H), 7.29 (m, 3H), 6.98 (d, J=7.5 Hz 2H), 6.93 (d, J=11 Hz, 2H), 6.86 (d, J=9 Hz, 1H), 6.38 (s, 1H), 4.07 (t, J=6 Hz, 2H), 3.64 (m, 2H), 3.53 (m, 2H), 2.59 (m, 2H), 2.46 (m, 2H), 2.40 (d, J=7 Hz, 2H), 1.98 (t, J=7 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 157.51, 155.22, 154.49, 151.84, 143.19, 140.58, 138.81, 137.68, 136.57, 133.71, 129.44, 127.90, 126.87, 124.84, 124.63, 123.78, 120.59, 118.35, 112.56, 83.15, 69.15, 67.28, 45.74, 44.74, 35.76, 29.17, 28.09, 15.08; m/z (469.2, MH+); HPLC: 97.8%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])(O)[CH2:10][CH2:9]1)=O)(C)(C)C.S(=O)(=O)(O)O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cccc(C2=CCNCC2)c1F
Yield: 53.6 %

Procedure:
To a solution of tert-butyl-4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carboxylate (7.48 g, 23.9 mmol) in toluene (50 ml) was added sulfuric acid (18 M, 1.33 ml, 23.9 mmol) and the mixture was refluxed under a Dean-Stark water separator. The mixture was poured on to ice and was basified with aqueous sodium hydroxide solution (15%). The mixture was extracted with ethylacetate (3×50 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (MeOH) to give the title compound (2.5 g). MS m/z (rel. intensity, 70 eV) 195 (M+, bp), 194 (42), 166 (30), 151 (33), 127 (35).
Reaction SMILES: [OH:1][C:2]1([C:13]([NH:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:19].O1CCOCC1>CO>[ClH:19].[OH:1][C:2]1([C:13]([NH:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:5][NH:4][CH2:3]1
Reactant: C=CCNC(=O)C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C=CCNC(=O)C1(O)CNC1

Procedure:
1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90 mmol) was suspended in methanol (40 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. 20 wt % Palladium hydroxide on carbon (100 mg) was added to the solution and the mixture was treated with hydrogen at 40 psi for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-hydroxyazetidine-3-carboxylic acid hydrochloride which was dissolved in tetrahydrofuran (5 mL) and water (5 mL) and treated with potassium carbonate (1.615 g, 11.7 mmol) and di-tert-butyl dicarbonate (935 mg, 4.29 mmol) were added. The mixture was stirred at ambient for 17 h and then the mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate and then was acidified to pH ˜3-4 and extracted twice more with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-hydroxyazetidine-3-carboxylic acid which was dissolved in DMF (3 mL). Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.028 g, 3.90 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.03 mmol) were added. The mixture was stirred at ambient for 5 minutes and then allylamine (0.6 mL, 8.03 mmol) was added and the mixture was stirred for 17 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol, 78% yield from 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide). 1,1-Dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol) was dissolved in methanol (10 mL) and 4 N hydrochloric acid in dioxane (2 mL, 8 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH:17][CH3:18].P(Cl)(Cl)Cl.ClC1C=CC=CC=1>CCCCCC>[F:12][C:13]([F:26])([F:27])[C:14]1[CH:15]=[C:16]([N:17]([CH3:18])[C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: CN(C(=O)c1cc(Cl)ccc1O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A mixture of 5-chlorosalicylic acid (173 mg, 1 mmol), 3,5-bis(trifluoromethyl)-N-methylaniline (243 mg, 1 mmol). phosphorus trichloride (44 μl, 0.5 mmol) and monochlorobenzene (5 mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, n-hexane (50 mL) was added, and the separated crude crystal was filtered and dissolved in ethyl acetate (50 mL). After the ethyl acetate solution was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (75 mg, 13.9%) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:9].[H-].[Na+].S(OC)(O[CH3:28])(=O)=O.N>CN(C)P(=O)(N(C)C)N(C)C.O>[CH3:28][O:9]/[C:8](/[C:7]1[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[CH:3]=1)=[CH:10]/[C:11]([O:13][CH3:14])=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)CC(=O)c1ccccc1Oc1cccc(C)c1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)/C=C(/OC)c1ccccc1Oc1cccc(C)c1
Yield: 22.3 %

Procedure:
A solution of 5 g (18 mmol) of methyl 2-(3-methylphenoxy)benzoylacetate in 30 ml of hexamethylphosphoric triamide (HMPT) is added dropwise to a suspension of 500 mg (21 mmol) of sodium hydride in 20 ml of HMPT, and the mixture is stirred until evolution of gas ceases. Then 2.5 g (20 mmol) of dimethyl sulfate are added dropwise, the mixture is stirred for 30 min, and then 30 ml of concentrated ammonia solution are added. The mixture is poured into water and extracted with MTB ether. The organic phase is dried and concentrated. Chromatography of the residue on silica gel with hexane/MTB ether yields in the first fractions 1.2 g (22%) of methyl (E)-β-methoxy-2-(3-methylphenoxy)cinnamate (trans product) as yellow oil.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][C@@H:10]([NH:25]C(OC(C)(C)C)=O)[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:3])[CH3:2].Cl.O.C(OCC)C>C(O)C>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][C@@H:10]([NH2:25])[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](N)CN(C2CCCCC2)c2ccccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
To a solution of 63.5 g of (R)-1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine in 100 ml of ethanol was added 100 ml of 6N hydrochloric acid. The mixture was stirred at 60° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, a mixed solvent of water and diethyl ether (1:1) was added. The aqueous layer was separated, neutralized with a 6N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure, whereby 46.3 g of (R)-(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was obtained.
Reaction SMILES: [Br:1]Br.IBr.[F:5][C:6](I)([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]>>[F:5][C:6]([Br:1])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: BrBr
Agent: BrI
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Temperature: 160 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
The same reactor as in Example 1 was used. Into the flask was placed 200 ml (747 mM) of perfluorooctyl iodide (PFOI), which was then heated at 160° C. and irradiated with a 400-W high-pressure mercury lamp. After the reaction mixture started to reflux, 54.5 ml (1.07M) of bromine was added dropwise to the mixture at a rate of 0.4 ml/min over a period of about 2 hours. The resulting IBr was drawn off at a suitable time through the IBr withdrawing Dimroth condenser. The reaction was continued for 3 hours, and the reaction mixture was thereafter cooled and washed with a 5% aqueous solution (200 ml) of sodium hydroxide, giving 349.0 g (93.6% in yield) of perfluorooctyl bromide.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 3-iodo-1H-indazole-6-carbaldehyde (50 mg, 0.18 mmol), pyridin-3-ylboronic acid (27 mg, 0.22 mmol), PdCl2(PPh3)2 (13 mg, 0.018 mmol) and 2M Na2CO3 (0.10 mL, 0.18 mmol) in DME/H2O/EtOH (1.4 mL/0.4 mL/0.2 mL) was degassed by evacuation and refilling with Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 125° C. for 60 min. The crude reaction mixture was concentrated under reduced pressure. Ethyl acetate (5 mL) was added and the solution was washed with brine (2×20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using MeOH (5%) in DCM as the eluent to provide the title compound a pale yellow solid (24 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1H), 8.88 (d, J=2.3 Hz, 1H), 8.69 (d, J=4.8 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.45 (dd, J=8.0, 5.0 Hz, 1H); MS ESI 224.0 (100) [M+H]+, calcd for [C13H9N3O+H]+ 224.07.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH:48]1[CH2:54][CH2:53][C:52](=[O:55])[NH:51][CH2:50][CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:48]4[CH2:54][CH2:53][C:52](=[O:55])[NH:51][CH2:50][CH2:49]4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:5])[CH3:4]
Reactant: O=C1CCNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCNC(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with [1,4]diazepan-5-one (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C40H50Cl2N7O4 [(M+H)+] 762.3296, observed 762.3297.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[CH:50](O)[CH2:51][CH2:52][CH2:53][CH3:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:50]([C:44]2[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=2[F:42])[CH2:51][CH2:52][CH2:53][CH3:54])=[CH:4][CH:3]=1
Reactant: CCCCC(O)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
At 0° C., 4-chlorobenzenethiol (435 mg, 3.00 mmol), triphenylphosphine (798 mg, 3.00 mmol), and diisopropyl azodicarboxylate (588 μl, 3.00 mmol) were successively added to a solution of 1-(2,5-difluorophenyl)-1-pentanol (300 mg, 1.50 mmol) in methylene chloride (6 ml). The reaction mixture was stirred at room temperature for 15 hours, diluted with methylene chloride, and then washed successively with a 1N aqueous solution of sodium hydroxide and brine. After drying over MgSO4, the mixture was concentrated. The residue thus obtained was purified twice by medium-pressure chromatography on a silica gel column (first time with 1% ethyl acetate-hexane, and second time with hexane), whereby the title compound (266 mg, 54%) was obtained as a colorless oil.