Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22](OC)=[O:23])[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([S:11]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[CH2:22][OH:23])[CH2:18][CH2:19]2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)N1CCC(c2ccccc2CO)CC1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Methyl 2-(1-(naphthalen-1-ylsulfonyl)piperidin-4-yl)benzoate (80 mg, 0.02 mmol) was dissolved in 1 mL of anhydrous THF under nitrogen protection. 0.4 mL of LiAlH4 (1.0M solution in THF) was added to the solution through a syringe at −78° C. After 30 minutes, the reaction mixture was quenched with MeOH, evaporated to dryness, and extracted with EtOAc and 0.1 N tartaric acid solution in water. The organic layer was then dried over Na2SO4, and the solvent was removed. The title compound was obtained in 60% yield after purification using preparative HPLC. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.58 (dd, J=12.38, 3.54 Hz, 2 H) 1.67-1.74 (m, 2 H) 2.52-2.61 (m, 2 H) 2.73-2.81 (m, 2 H) 3.88 (d, J=12.13 Hz, 2 H) 4.42 (d, J=3.79 Hz, 2 H) 4.96 (s, 1 H) 7.08-7.19 (m, 3 H) 7.24-7.29 (m, 1 H) 7.66-7.78 (m, 4 H) 8.13 (d, J=8.84 Hz, 1H) 8.17 (d, J=7.33 Hz, 1 H) 8.31 (d, J=8.08 Hz, 1 H) 8.75 (d, J=8.59 Hz, 1 H); ESI-MS: m/z 382.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[O:13][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:15][N:16]=2)=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([C:9]([NH:11][C:12]4[O:13][C:14]([C:17]5[O:18][CH:19]=[CH:20][CH:21]=5)=[N:15][N:16]=4)=[O:10])[CH:3]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(F)cc(Br)c1
Product: CCc1ccc(-c2ccc(-c3cc(F)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-5-fluoro-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 6 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: ClCCCOC1C=C[C:9]([C:12]2O[CH:14]=[C:15]([CH:17]=O)[N:16]=2)=CC=1.CN1N=NC(N)=N1.C([BH3-])#N.Cl[CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[O:41][CH:42]=[C:43]([CH2:45][NH:46][C:47]3[N:48]=[N:49][N:50]([CH3:52])[N:51]=3)[N:44]=2)=[CH:36][CH:35]=1.CC1CCCN1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O1CCCC1.C(#N)C.O.C(O)(=O)C>[CH3:52][N:50]1[N:49]=[N:48][C:47]([NH:46][CH2:45][C:43]2[N:44]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH2:32][CH2:31][CH2:30][N:16]4[CH2:12][CH2:9][CH2:17][CH:15]4[CH3:14])=[CH:35][CH:36]=3)[O:41][CH:42]=2)=[N:51]1
Reactant: O=Cc1coc(-c2ccc(OCCCCl)cc2)n1
Reactant: Cn1nnc(NCc2coc(-c3ccc(OCCCCl)cc3)n2)n1
Agent: CC1CCCN1
Agent: Cn1nnc(N)n1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1CCCN1CCCOc1ccc(-c2nc(CNc3nnn(C)n3)co2)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[4-(3-chloro-propoxy)-phenyl]-oxazole-4-carbaldehyde i100 (0.042 mmol), 2-methyl-2H-tetrazol-5-ylamine (4.16 mg, 0.042 mmol, 1 eq) and cyanoborohydride supported on polystyrene (26 mg, 0.1 mmol, 2.5 eq) is suspended in tetrahydrofuran (300 μl) containing 10% acetic acid and is stirred at 65° C. overnight. The polystyrene beads are then filtered off and the resulting solution is concentrated to dryness under a stream of nitrogen and taken up in dichloromethane (2 ml). The solution is washed with 1 M potassium hydrogenosulfate (1 ml) and concentrated under reduced pressure. The residue N-({2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}methyl)-2-methyl-2H-tetrazol-5-amine i101 is then treated with a solution of 2-methylpyrrolidine (4 mg, 1 eq) in acetonitrile (300 μl). Sodium carbonate (14 mg, 0.1 mmol, 2 eq) and sodium iodide (15 mg, 0.1 mmol, 2 eq) are added and the suspension is stirred overnight at 80° C. Water (1 ml) is then added and the mixture is extracted with dichloromethane (2×1 ml). The organic phases are concentrated and purified by preparative liquid chromatography (gradient: acetonitrile/water/hydrogen carbonate) to afford 2-methyl-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl]-2H-tetraazol-5-amine 139.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>[Pt]=O.CO>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: O=S(=O)(c1cccc(-c2ccncc2)c1F)C(F)(F)F
Agent: O=[Pt]
Solvent: CO
Product: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F

Procedure:
Preparation according to preparation 9: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-pyridine (0.16 g, 0.53 mmol), methanol (10 ml), platinum oxide (0.02 g). Yield: 0.11 g. MS m/z (relative intensity, 70 eV) 311 (M+, 2), 291 (47), 164 (92), 130 (62) 69 (bp).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(Cc2ccccc2)CC1
Yield: 103.9 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (34.5 g, 102 mmol), 4-amino-1-benzyl piperidine (21.4 g, 112 mmol), diisopropylethylamine (245 ml, 143 mmol) in propan-2-ol (1 L) was heated at reflux for 2 hours. The mixture was concentrated under vacuum and the residues partitioned between ethyl acetate and water. The organics were washed with water, dried with sodium sulfate and concentrated under vacuum affording 52.1 g of (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(1-benzyl-piperidin-4-yl)amine as an orange residue which was used for the next step without further purification. 1H NMR (400 MHz, DMSO) δ: 9.10 (s, 1H), 8.19 (m, 2H), 7.63-7.58 (m, 2H), 7.51 (t, 3H), 7.33 (d, 4H), 6.69 (d, 1H), 4.00 (s, 1H), 3.57 (br s, 2H), 2.84 (br s, 2H), 2.31 (br s, 2H), 2.11 (s, 3H), 2.04 (s, 1H).
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)(=O)[CH3:2].II.Br[CH:15]([F:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl.N1C=CC=CC=1.S(Cl)(Cl)=O>C1C=CC=CC=1.[Zn].C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)Cl>[CH2:10]([O:9][C:7]([C:4]1([C:1]([CH3:2])=[C:15]([F:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:6][CH2:5]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)C1(C(C)=O)CC1
Reactant: CCOC(=O)C(F)Br
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(F)=C(C)C1(C(=O)OCC)CC1
Reaction time: 1 h
Yield: 78479.6 %

Procedure:
To a solution (1500 ml) of ethyl 1-acetylcyclopropanecarboxylate (124.5 g, 0.797 mmol) in benzene was added zinc powder (156.4 g, 2.39 mmol). While heating under reflux, a catalytic amount of iodine was added thereto. Subsequently, a solution of ethyl bromofluoroacetate (94.23 ml, 0.797 mol) in benzene (200 ml) was added dropwise thereinto over a period of 1 hour followed by heating under reflux for 1 hour. Under ice cooling, 1 N hydrochloric acid (1000 ml) was added to the liquid reaction mixture and the mixture was stirred for 1 hour. The organic layer taken up by phase separation was washed successively with 1 N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in pyridine (387 ml, 4.78 mol). After adding thionyl chloride (69.8 ml, 0.957 mol) at -10° C., the resultant mixture was stirred under ice cooling for 3 hours. Under ice cooling, the liquid reaction mixture was poured into 1 N hydrochloric acid (2000 ml) and ethyl acetate (1500 ml) was added thereto. The organic layer taken up by phase separation was washed successively with 1 N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in dichloromethane (500 ml). Under ice cooling, 1,8-azabicyclo[5.4.0]-7-undecene (131 ml, 0.877 mol) was added dropwise thereinto and then the resultant mixture was stirred at room temperature for 17 hours. After adding 1 N hydrochloric acid (2000 ml) and chloroform (1000 ml), the organic layer taken up by phase separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue thus obtained was subjected to flash silica gel column chromatography (eluent:n-hexane:ethyl acetate=4:1) 152.78 g (78.5%) of the title compound as an oily substance. The compound thus obtained, which was a mixture of geometrical isomers (about 1:1), was not separated but employed in the subsequent reaction as such.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH3:19])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[C:29](ON1C(=O)C2C=CC=CC=2N=N1)(=[O:32])[CH2:30][CH3:31].C(O)(=O)CC>>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]([O:18][CH3:19])[C:29](=[O:32])[CH2:30][CH3:31])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CCC(=O)On1nnc2ccccc2c1=O
Reactant: CONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: CCC(=O)O
Product: CCC(=O)N(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)OC
Yield: 31 %

Procedure:
The title compound was prepared by a procedure similar to that in Example 41. Namely, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide obtained in Example 15 was reacted with 4-oxo-4H-benzo[d][1,2,3]triazin-3-yl propionate prepared from propionic acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-propionyl-amino)-methyl]-benzamide (35.0 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([N:24]([CH2:26][C:27](O)=[O:28])[CH3:25])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(N[C@H](C(NCC(N[C@H](C(O)=O)C)=O)=O)CC1C=CC(O)=CC=1)=O)(C)(C)C.C(OC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1C=CC=CC=1)N)C1C=CC=CC=1>>[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[NH:43][C:27](=[O:28])[CH2:26][N:24]([C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH3:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(CC(=O)O)C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN(C)C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-L-tyrosylglycylsarcosine and L-phenylalanyl-L-methionine benzyl ester are substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine and the L-phenylalanyl-L-leucine benzyl ester, respectively, of Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosylglycylsarcosyl-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[N:9]=2)=[CH:4][C:3]=1[CH3:19].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:19])[CH:4]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: Cc1cc(-c2cc(C(F)(F)F)[nH]c(=O)n2)ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1Cl

Procedure:
The title compound was prepared from 4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (9.07 g, 31.4 mmol) and phosphoryl chloride (100 mL) according to the general procedure I. Obtained as a white solid (8.68 g, 99%). MS (EI) 306.1 [(M)+]; mp 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:14][CH2:13][C:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][S:10][C:11]=1[C:15]([F:16])([F:18])[F:17])(=[O:29])=[O:28]
Reactant: OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (80 mg, 0.27 mmol, 1.00 equiv), dichloromethane (2.0 mL), triethylamine (83 mg, 0.82 mmol, 3.01 equiv). This was followed by the addition of MsCl (62 mg, 0.54 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 30° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.12 g of [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a yellow solid. This crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C12H9ClF3NO3S2, 372.0 (M+H). found 372.0.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:47][NH2:48]>ClCCl.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:48][OH:47])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A solution (3R)-6-cyclohexyl-3-(3-{[[3-(dimethylamino)propyl](methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 84) (566 mg, 0.88 mmol) and N-methylmorpholine (390 μl, 3.52 mmol) in dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (340 μl, 2.64 mmol) and stirred under an argon atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (540 μl, 4.40 mmol) was added and the mixture was stirred for 4.5 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (2.5 ml) and stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (20 ml), dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of 97:3:0.3 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound (150 mg).
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])=[O:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH3:29])[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:29][C:21]1[C:22]([C:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[O:15][CH3:16])=[O:4])=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)ccc3ccccc23)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5B (2.02 g, 10 mmol), 3,4,5-trimethoxytoluene (1.82 g; 10 mmol), P2O5 (10.0 g) and dichloromethane is stirred at room temperature for 16 hours. Subsequently, the dichloromethane is distilled off and the residue is diluted with ethyl acetate. The organic phase is washed with water and concentrated. The residue is purified by column chromatography (petrol ethers:ethyl acetate, 8:2 v/v) and recrystallized from petrol ether:diisopropylether (1:1 v/v). The solid material is collected by vacuum filtration, washed with cold petrol ether:diisopropylether (1:1 v/v) and dried, yielding white crystals, 0.9 g, (24.6%) mp 72° C.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Cl:8][C:9]1[CH:17]=C[C:12]([C:13]([OH:15])=[O:14])=[C:11](C)[CH:10]=1.CI>O1CCCC1.C([Li])CCC.CCCCCC>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[C:7]([CH2:5][CH3:6])[CH:17]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(Cl)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The starting material is prepared as follows: To the ice-cooled, stirred solution of 9.6 ml of diisopropylamine in 200 ml of tetrahydrofuran, 42 ml of 1.6 molar butyl lithium in hexane are slowly added, followed by the solution of 5.1 g of 4-chloro-2-methylbenzoic acid in 60 ml of tetrahydrofuran. The mixture is stirred for 15 minutes at 0°, then cooled to -70° and 7.5 ml of methyl iodide are slowly added. It is allowed to warm to 0°, quenched with water, the aqueous layer separated and acidified with concentrated hydrochloric acid. It is extracted with methylene chloride, the extract dried and evaporated, to yield the 4-chloro-2-ethylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[CH:13]([CH3:16])[C:12]3=[N:17][N:18]=[C:19]([CH3:20])[N:11]3[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH:13]([CH3:16])[C:12]3=[N:17][N:18]=[C:19]([CH3:20])[N:11]3[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)=[CH:6][CH:7]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2C
Agent: B
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)CC2C
Yield: 7.7 %

Procedure:
To a solution of 6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (40.0 mg, 0.12 mmol) in THF (5 ml) was added BH3-THF solution (1 mL, 1M in THF) slowly, the resulting mixture was stirred under reflux overnight, concentrated, the residue was purified by Prep-HPLC (column: Gemini 5u C18 250*21.5 mm; mobile: H2O (0.1% TFA)-ACN(0.1% TFA)) to give 6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as an off-white solid (3.0 mg, 7.8%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: COc1cccc(B(O)O)c1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cccc(OC)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-methoxy-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.82 min; Mass spectrum (ESI+): m/z=487 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([O:36][CH2:37][CH3:38])[CH:27]=2)[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].CO>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[C:28]([O:36][CH2:37][CH3:38])[CH:27]=2)[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 141E (4.64 g, 8.9 mmol) in THF (20 mL) was added lithium hydroxide (17.8 mL, 1M, 17.8 mmol) then methanol (5 mL). After stirring for 2 h at rt, the reaction was concentrated and redissolved in ethyl acetate. The aqueous layer was neutralized and acidified to pH 3-4 using 10% citric acid. The product was extracted with ethyl acetate (3×) and washed with brine and dried over sodium sulfate. The solvent was removed to give 3.6 g of 2-(4-(N-(benzyloxycarbonyl)carbamimidoyl)phenylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetic acid as a yellow solid (80% yield). LC-MS: 506.11 (M+H)+. The enantiomers were separated using a semi-preparative HPLC equipped with an Astex Chirobiotic T column (20 mm×500 mm). The separation was performed using an isocratic method of methanol with 0.1% triethylamine plus 0.2% acetic acid to provide 141F.