Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:26]([F:25])[CH:27]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Product: Cc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)cc1F
Yield: 1.9 %

Procedure:
The title compound (0.002 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-fluoro-4-methylbenzyl bromide (0.09 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14. found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.43 (m, 4H), 7.19 (t, J=7.9 Hz, 1H), 6.88-6.80 (m, 2H), 5.34 (s, 2H), 3.88 (s, 2H), 3.16-3.13 (m, 2H), 2.87-2.85 (m, 2H), 2.23 (d, J=1.5 Hz, 3H), 1.81-1.78 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:3]1.[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH:18]=O.[BH4-].[Na+]>CO.ClCCl>[NH3:1].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: N#Cc1ccc(N2CCC(N)C2)nc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N
Product: N#Cc1ccc(N2CCC(NCc3ccc(Cl)cc3Cl)C2)nc1
Reaction time: 2 h
Yield: 29.9 %

Procedure:
Stir a solution of 6-(3-aminopyrrolidin-1-yl)-nicotinonitrile (200 mg, 1.06 mmol) and 2,4-dichlorobenzaldehyde (371 mg, 2.12 mmol) in methanol (10 mL) for 1 hour. Add 10% sodium borohydride on alumina (400 mg) in one portion and stir for 2 hours. Dilute with dichloromethane (50 mL) and filter through a pad of Celite®. Concentrate to give a residue. Dissolve the residue in 5:95 methanol:dichloromethane and filter through a plug of silica gel. Concentrate to a residue and chromatograph by reverse phase chromatography, eluting with acetonitrile (0.1% trifluoroacetic acid):water (0.1% trifluoroacetic acid). Chromatograph on a SCX column eluting with methanol and then a 1:1 solution of 2.0 M ammonia in methanol:dichloromethane to give the title compound (55 mg, 15%). 1H NMR (400 MHz, CDCl3) δ 8.39 (d, 1H, J=1.8 Hz), 7.57-7.54 (m, 1H), 7.38-7.33 (m, 2H), 7.23-7.20 (m, 1H), 6.32 (d, 1H, J=8.8 Hz), 3.90 (s, 2H), 3.80-3.25 (m, 4H), 2.30-2.19 (m, 1H), 2.05-1.90 (m, 1H), 1.76 (br s, 1H); MS (ES): m/z=347.1, 349.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:7]=1.[OH-].[NH4+:14]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH2:14])[CH:5]=[N:4][CH:3]=1
Reactant: ClCCCOc1cncc(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCCCOc1cncc(Cl)c1
Temperature: 100 °C
Yield: 63.4 %

Procedure:
The 3-chloro-5-(3-chloropropoxy)pyridine (5.74 g, 28.0 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 3.30 g (63.4%) of an oil.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25]>CO.O1CCCC1.C(O)=O>[Cl:20][CH2:21][CH2:22][NH:23][C:24]([N:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:25]
Reactant: NC1CCCCC1
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCCl)N(C1CCCCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 43.7 %

Procedure:
A mixture of 3.6 g of D-galactose, 10 g of cyclohexylamine and 20 ml of methanol is heated at 60° C. for one hour under stirring. After the reaction, the reaction mixture is condensed to dryness under reduced pressure and the residue is washed with ether, whereby 5.2 g of 1-cyclohexylamino-b 1-deoxy-D-galactose are obtained as a crude product. 5.2 g of said crude product are dissolved in 50 ml of methanol, and a solution of 2.3 g of 2-chloroethyl isocyanate in 10 ml of tetrahydrofuran is added dropwise thereto at 0° to 5° C. The solution is stirred at room temperature for one hour. Then, the reaction solution is condensed under reduced pressure, and the residue obtained is dissolved in 20 ml of formic acid. The formic acid solution is allowed to stand at room temperature for 20 minutes, and 150 ml of ether-n-hexane (3:1) are added thereto. The resultant oil is purified by silica gel chromatography (Solvent:chloroform-ethyl acetatemethanol (3:1:1)). 3.2 g of 1-(2-chloroethyl)-3-cyclohexyl-3 -(D-galactopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([Br:10])[CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Br)cc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (0.308 g, 1.0 mmol), benzylamine (0.218 mL, 2.0 mmol), and K2CO3 (0.553 g, 4.0 mmol) in toluene (6 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-5-bromo-2,3-dihydro-isoindol-1-one (0.150 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 4.76 (s, 2H), 7.21-7.38 (m, 5H), 7.52 (s, 1H), 7.61 (d, 1H), 7.76 (d, 1H). GC-MS: m/z 302 (M)+, 226 (M−76)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>>[ClH:1].[CH:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=[CH:21][C:12]=1[C:4]1[CH:3]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1cc(-c2ccc3c(c2)CCCC3)nc2ccccc12
Reactant: NCCO
Product: Cl
Product: OCCNc1cc(-c2ccc3c(c2)CCCC3)nc2ccccc12

Procedure:
The title compound, m.p. 250-252° C. and MS: m/e=319.4 (M+H+), was prepared from 4-chloro-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-quinoline and ethanolamine.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(CO)ccc1NC1CCCCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-cyclohexylamino-3-nitrobenzyl alcohol (21.0 g, 83 mmol) in DCM (300 mL) was added powdered 4 Å molecular sieves (15 g) and N-methyl morpholine-N-oxide monohydrate (10.8 g, 92.2 mmol). Tetra-n-propylammonium perruthenate (VII) (2.91 g, 8.28 mmol) was then added in a single portion. An initial exotherm was controlled using an ice bath, and then the reaction mixture was stirred at room temperature for 18 hr. The mixture was then reduced to ˜100 mL by evaporation, and loaded onto a column of silica (400 g). The column was eluted with acetone:hexane 1:3 and the spot at 0.30 was collected, affording 4-cyclohexylamino-3-nitrobenzaldehyde as a yellow solid. (11.0 g, 44.3 mmol): 1H NMR (CDCl3, 300 MHz) δ 9.60 (s, 1 H), 8.32 (s, 1 H), 7.71 (d, J=10 Hz,1 H), 6.73 (d, J=10 Hz, 1 H) 3.46–3.32 (m, 1 H), 1.90–1.15 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)nnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccccc2)nnc1Cl
Temperature: 80 °C

Procedure:
3,6-Dichloro-4-methylpyridazine (1.00 g, 6.1 mmol) was mostly dissolved in dioxane (22.5 mL) then added phenylboronic acid (0.82 g, 6.7 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.25 g, 0.31 mmol) and a solution of cesium carbonate (6.0 g, 18 mmol) in water (7.5 mL). The reaction mixture was heated at 80° C. for 6 hours. The reaction mixture was concentrated under vacuum and the remaining solid was triturated with water. The solid was collected on a glass frit, washing well with water. The sample was purified by flash chromatography eluting with 1:4 ethyl acetate/hexane to afford 3-chloro-4-methyl-6-phenylpyridazine as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][NH2:14])=[CH:9][CH:8]=2)[N:6]=1.[C:17]([NH:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].C(N(C(C)C)CC)(C)C>CS(C)=O>[C:44]([Si:41]([CH3:43])([CH3:42])[O:40][C@H:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[N:26][CH:25]=1)[CH2:28][NH:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:8][CH:9]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(=O)Nc1ccc(C(COS(=O)(=O)c2ccc(C)cc2)O[Si](C)(C)C(C)(C)C)cn1
Reactant: Cc1nc(-c2ccc(OCCN)cc2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc([C@H](CNCCOc2ccc(-c3csc(C)n3)cc2)O[Si](C)(C)C(C)(C)C)cn1
Temperature: 80 °C
Yield: 44.6 %

Procedure:
In a round-bottomed flask, 2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamine (175 mg, 0.747 mmol) and toluene-4-sulfonic acid 2-(6-acetylamino-pyridin-3-yl)-2-(tert-butyl-dimethyl-silanyloxy)-ethyl ester (231 mg, 0.498 mmol) were dissolved in dimethylsulfoxide (0.50 mL), and diisopropyl ethyl amine (0.105 mL, 0.600 mmol) was added in one portion. The resulting mixture was heated to about 80° C. for about sixteen hours, and was then partitioned between diethyl ether and water. The aqueous phase was extracted with diethyl ether four times, and the combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting white solid was purified by column chromatography (methylene chloride to 10% methanol/methylene chloride) to afford 117 mg (45%) of the desired product. LRMS ([M+1]+): 527.1.
Reaction SMILES: [ClH:1].FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C(NC[C@H]3CCNC3)=O)SC=12.[F:41][C:42]1[CH:71]=[C:70]([NH:72][C:73]([NH:75][C:76](=[O:84])[CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[S:74])[CH:69]=[CH:68][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]([NH:56][CH2:57][CH2:58][N:59](C)[C:60](=O)OC(C)(C)C)=[O:55])[S:53][C:46]=12>>[ClH:1].[F:41][C:42]1[CH:71]=[C:70]([NH:72][C:73]([NH:75][C:76](=[O:84])[CH2:77][C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)=[S:74])[CH:69]=[CH:68][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]([NH:56][CH2:57][CH2:58][NH:59][CH3:60])=[O:55])[S:53][C:46]=12.[ClH:1]
Reactant: CN(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)NC[C@H]4CCNC4)sc23)c(F)c1
Product: CNCCNC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1

Procedure:
Following the procedure described above for the synthesis of 137a but replacing compound 135b with compound 138, title compound 137b was obtained as an HCl salt in 65% yield 1H NMR (400 MHz, DMSO-d6 ppm: 12.49(s, 1H), 11.83(s, 1H), 9.39(t, J=5.2Hz, 1H), 8.80(bs, 1H), 8.62(d, J=5.6 Hz, 1H), 8.39(s, 1H), 8.04(d, J=11.6 Hz, 1H), 7.97(bs, 1H), 7.58-7.50(m, 2H), 7.37-7.31(m, 4H), 7.31-7.24(m, 1H), 6.80(d, J=5.6 Hz, 1H), 3.78-3.71(m, 0.5H), 3.61(q, J=6.0 Hz, 1H), 3.21-3.24(m, 0.5H), 3.18-3.04(m, 2H), 2.60 (t, J=4.8 Hz, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(O)(C)C>ClCCl>[CH3:24][S:25]([O:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:27])=[O:26]
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 73.3 %

Procedure:
3,3-diphenyl-1-propanol (1000 g, 4.7 mol) was dissolved in 3 L dichloromethane. To the mixture was added triethylamine (712 g, 7.05 mol). After stirring at 0° C. for half an hour, to the resulting mixture was slowly added MsCl (645 g, 5.64 mol) dropwisely. The reaction was conducted at 25° C. After the completion of reaction monitored by TLC, the reaction solution was washed with water thrice. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce an oily crude product. To the crude product was added isopropanol. The resulting mixture was filtered by suction to produce 3,3-diphenylpropyl methanesulfonate as a solid (1000 g) in a yield of 73% (two steps together).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]2[NH:9][C:10]([C:12](Cl)(Cl)Cl)=[N:11][C:7]=2[CH:6]=1)=[O:4].Cl.Cl.[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:22])[CH3:21].C([O-])(O)=[O:31].[Na+]>C1COCC1.O.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]2[NH:9][C:10]([C:12](=[O:31])[NH:29][CH:26]3[CH2:27][CH2:28][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]3)=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Reactant: O=C([O-])O
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg (1.7 mmol) Methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylate were added to a mixture of 548 mg (1.8 equiv.) 1-isopropyl-piperidine-4-ylamine-dihydrochloride and 1.43 g (10 equiv.) NaHCO3 in 15 mL THF and 7.5 mL H2O and stirred vigorously for 4 h at room temperature. The reaction mixture was diluted with dichloromethane and washed with a saturated NaHCO3-solution and brine. The organic layer was dried over MgSO4 and concentrated. Preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:34])=[C:17](F)[C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[CH:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OCC)(=O)C.Cl>CN(C)C=O.O>[CH2:35]([NH:42][C:17]1[C:18]2[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]3[CH:21]([CH3:25])[CH2:22][O:23][C:24]([C:19]=23)=[C:15]([C:12]2([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:14][CH2:13]2)[C:16]=1[F:34])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)c(NCc3ccccc3)c3c(=O)c(C(=O)O)cn1c23
Reaction time: 4.5 h
Yield: 46.4 %

Procedure:
In 2 ml of N,N-dimethylformamide was dissolved 200 mg of 10-(1-benzyloxycarbonylaminocyclopropyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. To the resulting solution was added 319 mg of benzylamine. The resulting mixture was stirred at 90°-100° C. for 4.5 hours. The reaction mixture was added to a mixture of 5 ml of ethyl acetate and 5 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained and the resulting crystals were collected by filtration to obtain 110 mg (yield: 46.4%) of 8-benzylamino-10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro- 3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C@H:10]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:11][C:12](=[O:29])[CH:13]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[CH:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:40])[C@H:10]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:11][C:12](=[O:29])[CH:13]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[CH:14]([O:19][C:47](=[O:49])[CH3:48])[CH2:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(O)C(C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)c1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(OC(C)=O)C(C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Nα-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan benzyl ester (255 mg) in dichloromethane (5 ml) were added pyridine (74 mg), acetic anhydride (72 mg) and 4-(dimethylamino)pyridine (11 mg) at 5° C. and the mixture was stirred at ambient temperature for 18 hours. The mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.5N hydrochloric acid (20 ml×2), saturated sodium bicarbonate aqueous solution (20 ml×2) and brine (20 ml) successively and the organic layer was dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give Nα-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-acetoxyheptanoyl]-L-tryptophan benzyl ester as an oil.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CC2C=CC(C[CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=CC=2)C=CC=CC=1.O=[C:45]1[CH2:50][CH2:49][CH2:48][N:47]([CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:46]1.[OH2:60]>>[C:26]1([CH2:25][CH2:24][CH2:23][O:60][C:29]2[CH:30]=[CH:31][C:26]([CH:25]=[C:45]3[CH2:50][CH2:49][CH2:48][N:47]([CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:46]3)=[CH:27][CH:28]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CCCCc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: CC(C)(C)OC(=O)CCN1CCCC(=O)C1
Reactant: O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCN1CCCC(=Cc2ccc(OCCCc3ccccc3)cc2)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Sodium hydride (60% in-oil dispersion, 800 mg) was added at room temperature to dimethyl sulfoxide (20 mL) under an argon gas atmosphere. The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled at room temperature. From the total obtained solution, 1.3 mL was added at room temperature to a dimethyl sulfoxide solution (2.0 mL) of triphenyl[4-(4-phenylbutyl)benzyl]phosphonium bromide salt (830 mg). The reaction mixture was stirred at room temperature for 30 minutes, and added with a dimethyl sulfoxide (2.0 mL) solution of the compound (830 mg) prepared in Example 24. The reaction mixture was stirred at 50° C. for 18 hours. The mixture was added with water (10 mL), and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1), to thereby obtain the title compound (112 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:18])[CH3:2].Cl[CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[N:9]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:18])[CH3:2]
Reactant: ClCc1cccc2ccccc12
Reactant: CCOC(=O)CCn1c(=O)[nH]c2ccc(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccc(C#N)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of 3-(6-Cyano-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid ethyl ester (0.1 g, 0.39 mmol) in DMA (3 mL) were added 1-(chloromethyl)naphthalene (0.1 g, 0.58 mmol) and K2CO3 (0.11 g, 0.81 mmol). The reaction mixture was stirred at 65° C. for 16 h. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 20 mg (13%) of the desired product.