Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccccc2)C1
Agent: Cl
Product: O=C(Nc1ccccc1)C1CCCNC1
Yield: 54.3 %

Procedure:
A solution of 1-t-butoxycarbonyl-3-piperidinecarboxanilide (437 mg, 1.43 mmol) and hydrochloride (1 ml, 4.00 mmol, 4N ethyl acetate) was stirred for several hours. Filtration of the precipitate gave 3-piperidinecarboxanilide hydrochloride (187 mg, 55%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][CH2:13][C:14]([OH:16])=[O:15].Cl>O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCBr
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cccc(F)c1

Procedure:
A solution of sodium hydroxide (6.7 gm, 167 mmol) in water (20 mL) was added slowly to a neat mixture of 3-fluorophenol (8.9 gm, 79.5 mmol) and 3-bromopropionic acid (12.26 gm,80 mmol) as the reaction became exothermic. The mixture was refluxed gently for two hours and then allowed to cool and become semi-solid. Water was added to dissolve the semi-solid and then was acidified with concentrated HCl. The product was extracted into diethyl ether and the ethereal extract was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was slurried in 4:1 hexanetbenzene to give crystalline 3-(3-fluorophenoxy) propionic acid. m.p.: 90-91° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19](OC)(OC)[CH:20]([CH3:22])[CH3:21]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:19]([O:18][CH3:17])[CH:20]([CH3:22])[CH3:21])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: COC(OC)(OC)C(C)C
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: COC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)C(C)C

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 1.1.1-trimethoxy-2-methylpropane
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@H:24]([C:33]([NH:35][C@H:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>C(OCC)(=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:2][C:3]([NH:23][C@H:24]([C:33]([NH:35][C@H:36]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:5]
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 87 %

Procedure:
By coupling Z-Gly-OSu and H-Asp(OtBu)-Val-OtBu there is obtained Z-Gly-Asp(OtBu)-Val-OtBu, m.p.132° C. (ethyl acetate), yield: 87%.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:39]([O:40][CH3:41])=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[C:25]([F:42])[CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:39]([O:40][CH3:41])=[CH:38][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]5)=[O:28])=[C:25]([F:42])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2cc(OC)c(N)cc2F)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: CO
Solvent: O
Product: CCN1CCC(NC(=O)c2cc(OC)c(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2F)CC1
Temperature: 160 °C
Yield: 39 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 121 mg, 0.39 mmol) and 4-amino-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 116 mg, 0.39 mmol) were taken up in 4-methyl-2-pentanol (4 mL) and p-toluenesulphonic acid monohydrate (150 mg, 0.79 mmol) added. The reaction mixture was heated at 160° C. by microwave irradiation for 1 hour. The cooled reaction mixture was poured into a mixture of methanol & water (5:2 v/v, 7 mL) and the resultant solution loaded onto an SCX-3 cartridge (5 g), which had been pre-wet with methanol. The cartridge was washed through with methanol (40 mL) and eluted with 2M ammonia in methanol (30 mL). The ammoniacal solution was evaporated to give an amber gum afforded which was purified by base modified reverse phase preparative HPLC which was re-purified by flash chromatography on a silica column eluting with 2.5-10% ammonia/methanol in DCM. Product containing fractions were combined and evaporated and the residue triturated with diethyl ether and resultant solid dried under vacuum, at 60° C., for 3 hours to yield the title compound as a flocculent white solid (86 mg, 39%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1cccc(F)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(F)c4)cc23)CC1
Yield: 67.2 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.15 mMol) 3-fluorobenzoic acid, 11.8 mg (67%) of the title compound were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.I[C:17]1[C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=[CH:19][N:18]=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:17]3[C:22]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[CH:21][CH:20]=[CH:19][N:18]=3)[C:9](=[O:15])[C:10]2([CH3:13])[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cccnc2I)cc1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cccnc2C2Cc3ccc(OC)cc3C(C)(C)C2=O)cc1
Temperature: 80 °C
Yield: 44.1 %

Procedure:
Toluene (0.5 ml) was added to 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 36 mg), 2-iodo-3-(4-methoxy-benzyloxy)-pyridine (Compound GT15-1, 50 mg), sodium t-butoxide (35.3 mg), Pd2dba3 (13.5 mg) and Xantphos (17 mg), and the mixture was stirred and heated at 80° C. for 2.5 hrs under nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate and subjected to Celite filtration. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (27 mg, 44%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[CH3:26])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: NCC(O)c1cccc(Br)c1
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2cccc(Br)c2)cc1
Yield: 38.3 %

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(3-bromophenyl) ethanamine (2.16 g) and 4-{(E)-2-carbomethoxyethenyl}phenylpropan-2-one (2.18 g). Elution with 1% methanolchloroform on Kieselgel 60 gave the title compound as a solid 1.6 g (benzene-petrol 80-100) m.p. 105°-111° C. as a 42:58 mixture of diastereoisomers. τ(CDCl3) 8.95 (3H, d, J=6 Hz), 6.9-7.7 (7H, m, 2H disappears with D2O), 6.2 (3H, s), 5.5 (1H, m), 3.6 (aH, d, J=16 Hz) 2.55 (8H, m), 2.35 (1H, d, J=16 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([O:39]C)=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CCC[C@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@@H]2CCC[C@@H]2C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
To a mixture of methyl (1S,2R)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.25 g), THF (2.0 ml), and methanol (2.0 ml) was added a 1 M aqueous sodium hydroxide solution (2.0 ml) under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture was added 1 M hydrochloric acid (2.0 ml) under ice-cooling, followed by stirring at room temperature. The solid precipitated was collected by filtration and washed with water to obtain (1S,2R)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylic acid (0.22 g).
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([CH:21]([CH2:24][CH3:25])[CH2:22][OH:23])[CH3:20]>>[CH2:1]([Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([O:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:23][CH2:22][CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCC(CC)CO
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Product: CCCCCCCC[Sn](CCCCCCCC)(OCC(CC)CC)O[Sn](CCCCCCCC)(CCCCCCCC)OCC(CC)CC
Reaction time: 0.67 h
Yield: 99 %

Procedure:
700 g (1.94 mol) of dioctyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 1600 g (15.7 mol) of 2-ethyl-1-butanol (made by Chisso Corporation, Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 157° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational agitation and heating were carried out for approximately 40 minutes at normal pressure, and then the purge valve was closed, and the pressure in the system was gradually reduced, and water-containing 2-ethyl-1-butanol was distilled off with the pressure in the system at from 84 to 65 kPa. This state was maintained for 7 hours, and then the pressure in the system was further reduced, and excess 2-ethyl-1-butanol was distilled off. Once the distillate stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 883 g of reaction liquid was obtained in the flask. According to 119Sn-, 1H-, and 13C-NMR analysis results, the product 1,1,3,3-tetraoctyl-1,3-bis(2-ethylbutyloxy)-distannoxane was obtained at a yield of 99% based on the dioctyltin oxide. The same procedure was repeated twelve times, thus obtaining a total of 10600 g of 1,1,3,3-tetraoctyl-1,3-bis(2-ethylbutyloxy)-distannoxane.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([C:14]2[N:15]=[C:16]([C:26](O)=[O:27])[N:17]([CH3:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:1]1([NH:7][C:26]([C:16]2[N:17]([CH3:25])[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:15]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Reactant: NC1CCCCC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
Using essentially the same procedure as Example 4, Step B, but using cyclohexylamine (0.025 mL), 4,5-diphenyl-1-methylimidazole-2-carboxylic acid (30 mg, 0.10 mmol) from Example 4, Step A was converted to the title compound.
Reaction SMILES: [N+]([C:4]1[C:5]([N+:11]([O-])=O)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO[CH:16](OC)[N:17](C)C.N1CCCC1>>[NH:17]1[C:7]2[C:6](=[C:5]([NH2:11])[CH:4]=[CH:9][CH:8]=2)[CH:10]=[CH:16]1
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: C1CCNC1
Product: Nc1cccc2[nH]ccc12

Procedure:
Scheme 4 illustrates the production of a compound of Formula (In) in which R99 is an indole compound and R7, R8, R9, R10, R11, R12, R28, R29 and R30 are defined as above for Formula (III). A piperidin-4-one compound of Formula (XIVa) is produced as described above in Scheme 3. A dinitro-toluene compound of Formula (XVI) is reacted with N,N-dimethylformamide dimethyl acetal and pyrrolidine under conditions effective to bring about cyclization, thereby providing an indol-4-ylamine compound of Formula (XVII). The compound of Formula (XVII) is then reacted with a bis(2-chloroethyl)-benzylamine under conditions effective to produce the compound of Formula (XVIII). The compound of Formula (XVIII) is then reacted under conditions effective to remove the benzyl protecting group to produce a 4-piperazin-1-yl-indole of Formula (XIX). The piperazin-1-yl-indole compound of Formula (XIX) is then reacted with the piperidin-4-one compound of Formula (XIVa) as described above in Scheme 1 to produce the piperazine-piperidine compound of Formula (XX), which is a compound of Formula (III).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]([NH:13][CH2:14][CH2:15][C:16]#[N:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[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.C[Si]([N:63]=[N+:64]=[N-:65])(C)C>C(#N)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]1[N:13]([CH2:14][CH2:15][C:16]#[N:17])[N:65]=[N:64][N:63]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)NCCC#N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 410 mg of tert-butyl {(2S)-3-(benzyloxy)-1-[(2-cyanoethyl)amino]-1-oxopropan-2-yl}carbamate, 400 mg of triphenylphosphine, and 10 ml of acetonitrile were added 310 μl of diisopropyl azodicarboxylate and 210 μl of trimethylsilyl azide under ice-cooling, followed by stirring at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 280 mg of tert-butyl {(1R)-2-(benzyloxy)-1-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]ethyl}carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1cccc(Br)c1
Reaction time: 48 h

Procedure:
A magnetically stirred solution of 3-bromobenzaldehyde (86.5 g, 0.468 mol) and malonic acid (107 g, 1.03 mol) in pyridine (200 ml) was treated with piperidine (4.0 ml, 40.45 mmol) and heated at ~90° C. for 90 min then under reflux for 30 min. The cooled mixture was poured onto ice (200 g) and water (300 ml) then acidified to pH=1 with conc. hydrochloric acid. Filtration afforded a white solid which was washed with water (4×200 ml), dried by suction and placed in an oven at 70° C. for 48 h until constant weight was obtained (96.02 g, 90%); νmax (nujol)/cm-1 3400-2000 (br. OH), 1684.5, 1631.5, 1587.0; δH (270 MHz) 6.45 (1H, d, 2-H, 3J2,3 =16,2 Hz); 7.28 (1H, t, 5'-H, Jo =7.8 Hz); 7.48 (1-H, dt, 4'-H, Jo =7.9, Jm =1.3 Hz); 7.54 (1-H, dt, 6'-H, Jo =7.9, Jm =1.0 Hz); 7.70 (1-H, t, 2'-H, Jm =1.8 Hz); 7.71 (1H, d, 3-H, 3J3,2 =15.8 Hz).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].C(=O)=O.CC(C)=O.[CH2:19]([O:26][C@@H:27]([CH3:31])[CH:28]1[O:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.[Cu](Cl)Cl>[CH2:19]([O:26][C@H:27]([CH:28]([OH:30])[CH2:29][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](OCc1ccccc1)C1CO1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Cu]Cl
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)C(O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
A solution of 2.0M benzylmagnesium chloride in tetrahydrofuran (2.38 ml) was added dropwise to a stirred mixture of lithium chloride (20.2 mg) and copper(II) chloride (32 mg) in tetrahydrofuran (10 ml) at −78° C. (dry-ice/acetone) for a period of 10 minutes under nitrogen atmosphere. A solution of (3S)-3-benzyloxy-1,2-epoxybutane (obtained in Preparation 9) (425 mg) in tetrahydrofuran (10 ml) was added dropwise to this mixture at −78° C. over 10 minutes. The resulting mixture was stirred at −78° C. for 2.5 hours and then allowed to warm to room temperature, and stirred overnight. The reaction mixture was treated with saturated ammonium chloride solution (20 ml) at an ice-bath temperature, and then diluted with ethyl acetate (100 ml). The organic layer was washed with H2O (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (10:1) to give (2S)-2-benzyloxy-5-phenylpentan-3-ol (620 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH3:10])[C:6]=2[CH:11]=1.[Li+].CC([N-]C(C)C)C.[I:20]CCI.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([I:20])[N:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: ICCI
Reactant: Cn1cnc2ccc(Cl)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(I)nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flask charged with a solution of 6-chloro-1-methyl-1H-benzo[d]imidazole (2 g, 12 mmol) in THF (100 mL) was cooled to −78° C. and 1.8M LDA in THF/hexanes/ethylbenzene (9.34 mL, 16.81 mmol) was added dropwise, and the mixture was stirred at −78° C. for 1 h. A solution of 1,2-diiodoethane (3.72 g, 13.2 mmol) in THF (50 mL) was added dropwise and the mixture was stirred at −78° C. for 1 h. Water (0.3 mL) was added followed by silica gel (20 g) and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with EtOAc in heptane (v/v, 10 to 50%) to give 6-chloro-2-iodo-1-methyl-1H-benzo[d]imidazole. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 7.19 (dd, J=8.59, 2.02 Hz, 1H) 7.58 (d, J=8.59 Hz, 1H) 7.78 (d, J=2.02 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.Cl.[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][NH:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][N:24]2[C:3]1[C:2]([F:1])=[CH:15][C:14]2[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]3[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=23
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CC2CNC1CN2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1COc2c(N3CC4CCC3CN4)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 26.8 %

Procedure:
A solution of 0.56 g (2.0 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 0.41 g (2.2 mmol) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 25 ml of acetonitrile was heated under reflux for 18 hours. The solution was evaporated to dryness and the residue was triturated with methanol and filtered to give 0.20 g of the title compound, 260°-265° C.