Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([CH2:6][CH:7]1[CH2:8][CH2:9]O)[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15].S(Cl)([Cl:18])=O.Cl>C1C=CC=CC=1>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([CH2:6][CH:7]1[CH2:8][CH2:9][Cl:18])[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15]
Reactant: CC1(C)C(=O)C2(C)CCC1CC2CCO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CC1(C)C(=O)C2(C)CCC1CC2CCCl
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a 100 ml microflask equipped with thermometer, reflux condenser, dropping funnel and magnetic stirrer is charged 12.3 g of 1,3,3-trimethyl-6-(2-hydroxyethyl)bicyclo(2.2.2)-octan-2-one prepared according to the process of Example XVII, and 20 ml benzene. The dropping funnel is charged with 12 g thionyl chloride. The thionyl chloride is added to the reaction mass from the dropping funnel, slowly, over a period of five minutes as the temperature of the reaction mass rises to 35° C. The reaction mass is then refluxed for a period of 10 hours at 90° C. The flask is then vented to the atmosphere and heated on a steam bath in order to volatilize the unreacted thionyl chloride and any hydrogen chloride reaction product remaining. The reaction mass is then cooled and hydrolyzed with 50 g ice. The organic layer is separated, and the aqueous phase is extracted with four 20 ml portions of anhydrous diethyl ether. The organic layers are bulked and washed with (i) three 20 ml portions of saturated sodium bicarbonate solution and (ii) one 20 ml portion of water. The organic phase is then dried over anhydrous magnesium sulfate and stripped of the diethyl ether. The reaction product is then distilled at 105°-115° C. at a pressure of 0.2 mm Hg. Its structure, confirmed by NMR and mass spectral analyses is as follows: ##STR37##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]>>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1
Reactant: OCCc1cccc(Br)c1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1cccc(CCO)c1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 2-(3-bromophenyl)ethanol and 2-pyrrolidinone. Purification was achieved by flash chromatography on silica gel eluting with ethyl acetate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[CH2:33][OH:34].O>CN(C=O)C>[OH:34][CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][N:27]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OCC1CCCCN1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4CO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 2-piperidinemethanol (19lmg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[2-(hydroxy-methyl)piperidinomethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 68) (120 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:39]>CN(C=O)C>[Cl:39][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:25]=1[CH2:24][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Clc1cccc(OCc2ccccc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2c(Cl)cccc2OCc2ccccc2)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9) (0.360 g, 1.61 mmol) and potassium carbonate (0.308 g, 2.23 mmol) was added a solution 2-(bromomethyl)-1-chloro-3-[(phenylmethyl)oxy]benzene (for a preparation see Intermediate 8)(0.50 g, 1.61 mmol) in DMF (5 ml). The suspension was stirred overnight at ambient temperature. The suspension was partitioned between ethyl acetate (30 ml) and water (30 ml). The phases were separated and the organic phase washed with ethyl acetate (30 ml). The combined organic extracts were washed with brine (30 ml) and the solvent removed in vacuo. The residue was loaded in dichloromethane and purified on silica 50 g using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.212 g); LCMS: (System 1) MH+=455, tRET=3.59 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][N:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([NH2:7])=[CH:12][O:11][N:10]=2)=[N:14][CH:15]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCCc2ccccc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1conc1-c1ccc(OCCc2ccccc2)cn1
Reaction time: 14 h
Yield: 22 %

Procedure:
[3-(5-Phenethyloxy-pyridin-2-yl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (60 mg, 0.158 mmol) was dissolved in dioxane (9 mL) and treated with conc. HCl (1.8 mL). After stirring for 14 h, the reaction mixture combined with satd aqueous NaHCO3 (10 mL). The organic layer was separated and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave a beige solid from which 3-(5-phenethyloxy-pyridin-2-yl)-isoxazol-4-ylamine (9.8 mg, 22%) was isolated by chromatography (30% ethyl acetate in hexane). HRMS: 281.1285 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12].C([Li])CCC.[B:19](OC)([O:22]C)[O:20]C>C1COCC1>[F:1][C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[CH:4][C:5]([B:19]([OH:22])[OH:20])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)c(C(C)C)cc1I
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene (2.61 g, 8.88 mmol) in THF at −78° C., n-butyl lithium (2.5 M, 4.26 mL, 10.65 mmol) was added dropwise. The solution was stirred at −78° C. for 30 min. Trimethyl borate (2.98 mL, 26.6 mmol) was added. The solution was then stirred at −78° C. for 3 h. The reaction was quenched at −78° C. with saturated NH4Cl and the mixture was warmed to room temperature. The organic was extracted with EtOAc (3×50 mL). The combined EtOAc layers were washed with brine and dried over Na2SO4. The title compound was obtained as a solid pure enough for next step. Further purification with silica gel caused decomposition of product. 1H NMR (CDCl3, 500 MHz) δ 7.74 (d, J=10.0 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H), 5.65 (br s, 2H), 3.92 (s, 3H), 3.20 (m, 1H), 1.22 (m, 6H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CN1CCCC1=O.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21](F)[CH:20]=1.CC([O-])(C)C.[K+]>CCCCCCC>[Br:18][C:19]1[CH:26]=[C:25]2[C:22]([CH:23]=[N:10][N:9]2[C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NNc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCCCCCC
Product: Fc1ccc(-n2ncc3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.4 %

Procedure:
A flask was charged with (4-fluorophenyl)hydrazine hydrochloride (25.0 g, 154 mmol), 1-methyl-2-pyrrolidinone (500 mL) and 4-bromo-2-fluorobenzaldehyde (31.2 g, 154 mmol). The mixture was stirred at rt for about 14 h then potassium 2-methylpropan-2-olate (18.98 g, 169 mmol) was added. The mixture was stirred for about 1 h then a second portion of potassium 2-methylpropan-2-olate (17.25 g, 154 mmol) was added. The mixture was stirred for about 15 min then warmed in an oil bath heated to about 160° C. for about 24 h. The mixture was cooled to rt then about 250 mL solvent was removed under reduced pressure. The mixture was diluted with about 750 mL water then allowed to stand overnight. The supernatant was decanted and the resulting residue was stirred with EtOAc (350 mL) for about 1 h. The solids were collected by filtration. The filtrate was concentrated then stirred in a mixture of DCM (350 mL), water (250 mL) and 6 N HCl (25 mL) for about 3 h. The layers were separated then the organic layer was dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified on silica gel (330 g) using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to give a solid which was treated with heptane (100 mL) and stirred overnight at room rt. The solids were collected by filtration and washed with heptane (25 mL). The solids from the initial EtOAc trituration and the material from the column and heptane trituration were combined to yield 6-bromo-1-(4-fluorophenyl)-1H-indazole (1, R1=4-fluorophenyl) (23.94 g, 54%); LC/MS, method 3, Rt=2.83 min, MS m/z 291, 293 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.97 (s, 1H), 7.88-7.79 (m, 3H), 7.46-7.42 (m, 3H).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH2:47])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH:47][C:7](=[O:9])[C@@H:2]([NH:1][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:3][CH:4]([CH3:5])[CH3:6])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C

Procedure:
The title compound was prepared substantially in a similar manner as Step 1 of Example 10 using N-Z-Leu-OH and [(R)-3-((S)-2-amino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride as the starting materials. The title compound was purified by SiO2 chromatography using 0-4% MeOH/CH2Cl2 as the eluent. 1H NMR (CD3OD, 300 MHz): δ 7.34 (m, 10H), 5.50 (m, 4H), 4.19 (m, 2H), 4.01-3.94 (m, 1H), 3.30 (m, 2H), 2.15 (m, 1H), 1.92 (m, 2H), 1.77-1.64 (m, 8H), 1.50 (m, 2H), 1.40-1.12 (m, 4H), 1.11-0.97 (m, 14H). 31P NMR (CD3OD, 300 MHz): δ 60.56, 59.87. LCMS m/z: [M+H]+=672.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10](=[O:14])[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1.C(=O)=O.CC(C)=O>[OH:13][C:11]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)([CH3:12])[C:10]([N:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: COc1ccc(N(C(=O)C(C)=O)c2ccc(OC)cc2)cc1
Reactant: COc1ccc([Mg]Br)cc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)C(C)(O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
N,N-bis(4-methoxyphenyl)-2-oxopropanamide (0.53 g, 1.77 mmol) was placed in a 250 mL three-necked round-bottomed flask fitted with a stiffing bar, a rubber stopper and a nitrogen inlet, and dissolved in 30 mL anhydrous THF. The solution was cooled to −78° C. in dry ice-acetone bath. 4-Methoxyphenylmagnesium bromide solution (3.89 mL of 0.5 M THF solution, 7.25 mmol) was added dropwise with stiffing at −78° C. under nitrogen atmosphere. The resulted solution was stirred at −78° C. for one hour and then at room temperature for one hour. The reaction was quenched by adding 20 mL of saturated NH4Cl solution. EtOAc (3×30 mL) was added to extract the solution. The organic layers were separated, washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give a white solid product, 2-hydroxy-N,N,2-tris(4-methoxyphenyl)propanamide, 0.61 g, 84.7% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[H][H]>CO.O>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH:4]([OH:5])[C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(=O)c2ccc(Cl)cc2Cl)CCCC1
Solvent: CO
Solvent: O
Product: CCOC(=O)C1(C(O)c2ccc(Cl)cc2Cl)CCCC1
Yield: 51.2 %

Procedure:
(S)-tBuBisP*-RuBr2 (16 mg) was placed in a reactor and deaerated. After substitution with argon, a mixture of ethyl 1-(2,4-dichlorobenzoyl)cyclopentanecarboxylate (2.8 g, 5.6 mmol) and methanol-water (101) (30 ml) was added. Under 70° C. and hydrogen pressure (6 kg/cm2), the mixture was stirred for 30 h and concentrated. This was diluted with ethyl acetate (50 ml), washed with water and concentrated to dryness. This was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (0.91 g, 41.3%) as a colorless oil. The enantiomer excess of this product was measured by high performance liquid chromatography (Condition F) and found to be 92%.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[N:50]1([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C)C=O>[F:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:58]5[CH2:59][CH2:60][CH:55]([N:50]6[CH2:54][CH2:53][CH2:52][CH2:51]6)[CH2:56][CH2:57]5)=[O:7])[CH:24]=4)=[C:27]([F:48])[CH:28]=3)=[O:34])[CH2:37][CH2:36]2)=[O:47])=[CH:41][CH:42]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC(N2CCCC2)CC1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added 4-(pyrrolidin-1-yl)piperidine (61.3 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (48.0 mg, 80%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:26]2[CH:20]1[CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:25]=12.[CH3:34][N:35]([Si](C)(C)C)[S:36]([CH2:39][CH3:40])(=[O:38])=[O:37]>>[N+:31]([C:28]1[CH:29]=[CH:30][C:24]2[O:23][CH2:22][CH2:21][C@@H:20]([OH:19])[C@H:26]([N:35]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH3:34])[C:25]=2[CH:27]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1CCO2
Reactant: CCS(=O)(=O)N(C)[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCS(=O)(=O)N(C)[C@@H]1c2cc([N+](=O)[O-])ccc2OCC[C@H]1O
Temperature: 65 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
2 g of tetrabutylammonium fluoride were added with stirring to a mixture of 6 g of 4,5-epoxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepine and 9.5 g of N-methyl-N-trimethylsilylethanesulfonamide. The reaction mixture was then heated for 3 h at 65° C., stirred overnight at RT and poured onto ammonium chloride solution. It was extracted several times with EA, and the organic phase was washed with water and dried over sodium sulfate. After concentration and recrystallization of the solid residue from isopropanol, 7.1 g of trans-7-nitro-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepin-4-ol were obtained, m.p. 133-135° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60]([O:64][C:65]([NH:67][C@H:68]([C:70](O)=[O:71])[CH3:69])=[O:66])([CH3:63])([CH3:62])[CH3:61].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:60]([O:64][C:65]([NH:67][C@H:68]([C:70]([O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1)=[O:71])[CH3:69])=[O:66])([CH3:62])([CH3:63])[CH3:61]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)[C@H](C)NC(=O)OC(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution containing the compound of Example 111 (0.100 g, 0.124 mmol), N-(tert-butoxycarbonyl) L-alanine (0.028 g, 0.147 mmol)), and 4(dimethylamino)pyridine (0.018 g, 0.147 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (0.029 g, 0.151 mmol) and the mixture was stirred at room temperature for 2 hours. Two subsequent additions of N-(tert-butoxycarbonyl) L-alanine (0.028 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (0.029 g) were made at two hour intervals. The solvent was evaporated and the reaction mixture was partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with chloroform and ending with 66% ethyl acetate in chloroform, to give the title compound (0.100 g, 82%).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[C:8]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])(=[O:10])[CH3:9].CN1CCOCC1.[NH2:24][C:25]1[C:26]([Cl:44])=[C:27]([C:40]([Cl:43])=[CH:41][CH:42]=1)[CH2:28][O:29][C:30]1[C:31]2[N:32]([CH:36]=[C:37]([CH3:39])[N:38]=2)[CH:33]=[CH:34][CH:35]=1>CN1CCCC1=O>[C:8]([N:11]([CH2:13][C:14]([NH:24][C:25]1[C:26]([Cl:44])=[C:27]([C:40]([Cl:43])=[CH:41][CH:42]=1)[CH2:28][O:29][C:30]1[C:31]2[N:32]([CH:36]=[C:37]([CH3:39])[N:38]=2)[CH:33]=[CH:34][CH:35]=1)=[O:16])[CH3:12])(=[O:10])[CH3:9]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: Cc1cn2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Agent: CC(C)(C)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(=O)N(C)CC(=O)Nc1ccc(Cl)c(COc2cccn3cc(C)nc23)c1Cl
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
Pivaloyl chloride (0.22 ml) was added dropwise to a mixture of acetylsarcosine (264 mg), N-methylmorpholine (0.22 ml) and N-methylpyrrolidone (30 ml) under a dry ice-tetrachloromethane bath cooling. This mixture was stirred for 10 minutes under ice-cooling, and 8-[3-amino-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (500 mg) was added thereto under a dry ice-tetrachloromethane bath cooling. The mixture was stirred for 22 hours at ambient temperature. The mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo, and the residue was purified by flash column chromatography (methylene chloride:methanol=50:1, V/V) to give 8-[3-(acetylsarcosylamino)-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (260 mg).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.21 (2H, s), 6.72 (1H, d, J=2.0 Hz), 7.26 (1H, s), 7.37-7.47 (4H, m), 7.56 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.8 Hz) [M+H] Calc'd for C16H11ClN4O, 311. Found, 311.
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].Br[CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Ca+2]>C(O)C>[C:16]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:17]
Reactant: CCOC(=O)C(Br)C#N
Reactant: CC(C)=CC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Yield: 56.5 %

Procedure:
A mixture of 1,1-dichloro-4-methylpenta-1,3-diene (30.2 parts) and ethyl bromocyanoacetate (19.2 parts) is heated in ethanol (100 parts by volume) at 77°-80° C. for 6 hours in the presence of cupric chloride (1.34 parts) and calcium carbonate (10 parts). The crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate is isolated as described in Examples 13-24. The product has a strength of 61.0% and a cis-cyano/trans-cyano ratio of 85.2:14.8. The yield is 56.5%.