Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:16][CH:17]=O)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:19]=1.B#B.Cl.[OH-].[Na+]>O1CCCC1.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:16][CH3:17])[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:19]=1
Reactant: CCCC(COc1noc2ccc(Cl)cc12)NC=O
Agent: B#B
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(COc1noc2ccc(Cl)cc12)NC
Reaction time: 1 h

Procedure:
To a solution of 1 g of 5-chloro-3-(2-formylaminopentyloxy)-1,2-benzoisoxazole in 10 ml of tetrahydrofuran is dropwise added 10.1 ml of a tetrahydrofuran solution (1.0M) of diborane with ice-cooling over ten minutes, and they are further subjected to reaction at room temperature for one hour. Subsequently, 5 ml of methanol is added with ice-cooling, and thereafter, 10 ml of 6N hydrochloric acid is added thereto, and after stirring for one hour, the solvent is removed by distillation under reduced pressure. Ethyl acetate and water are added to the residue obtained, the pH is adjusted to 8 with a 10% (w/w) aqueous sodium hydroxide solution, and the organic layer is separated. The separated organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and thereafter concentrated to about 20 ml under reduced pressure. Thereto is added 5 ml of a dioxane solution (2.2N) of hydrogen chloride, and the crystals precipitated are collected by filtration, to obtain 0.6 g of colorless, crystalline 5-chloro-3-(2-methylaminopentyloxy)-1,2-benzoisoxazole hydrochloride having a melting point of 152.9°-154.8° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:19])[C:11]2[C:16]([CH2:17]/1)=[CH:15][C:14]([CH3:18])=[CH:13][CH:12]=2>CCO.[Pt]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:19]
Reactant: Cc1ccc2c(c1)C/C(=C\c1ccncc1Br)C2=O
Agent: [Pt]
Solvent: CCO
Product: Cc1ccc2c(c1)CC(Cc1ccncc1Br)C2=O
Reaction time: 3 h
Yield: 59.3 %

Procedure:
Pt/C (5 wt % loading, 125 mg) was added to a stirred solution of the compound 90 (1.24 g, 4 mmol) in EtOH (40 mL) at room temperature. The resulting suspension was stirred for 3 hours under H2 atmosphere (1 atm) then filtered over Celite, rinsed with dichloromethane and concentrated to dryness. The crude residue was purified by column chromatography on SiO2 (gradient of EtOAc in petroleum ether) to afford the title compound 105 as a white solid (Yield 0.75 g, 59%).
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[C:15]2=[O:21])[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH:26]=[CH:27][C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:28]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH2:7][CH2:8][C@H:9]([CH3:10])[C@H:4]([OH:3])[CH2:5]3)[C:15](=[O:21])[CH:16]2[CH3:20])=[O:29])[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CC[C@H](C)[C@H](O)C2)CCN1C(=O)/C=C/c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 41; 0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3-chloro-cinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=434.3 (M+H)+.
Reaction SMILES: OC1[O:6][CH:5]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([N:16]4[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]4=[O:24])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:4][CH2:3]1.Cl.[NH2:26][OH:27]>N1C=CC=CC=1>[OH:6][CH:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]3=[O:24])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH:3]=[N:26][OH:27]
Reactant: NO
Reactant: COCC1CN(c2ccc3nc(C4CCC(O)O4)sc3c2)C(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: COCC1CN(c2ccc3nc(C(O)CC=NO)sc3c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
72 g of the 3-[2-(5-hydroxytetrahydrofuran-2-yl)-benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone obtained in the Example 7 was dissolved in 150 ml of pyridine. 18.6 g of hydroxylamine hydrochloride was added to the solution at room temperature and the mixture was stirred for 10 min and then poured into ice/water. After extraction with ethyl acetate followed by washing with dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and an aqueous common salt solution, the product was dried over magnesium sulfate. After concentration under reduced pressure, the obtained solid was recrystallized from acetone/diisopropyl ether to give 73 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[N:9][NH:8][C:7](=[O:11])[CH:6]=1.C[O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:21][CH:20]([N:8]2[C:7](=[O:11])[CH:6]=[C:5]([O:4][C:3]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:2]=3[Cl:1])[CH:10]=[N:9]2)[C:19]([OH:28])=[O:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1cc(Oc2cccc(Cl)c2Cl)cn[nH]1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Cl)c2Cl)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 19 steps 4-5, starting from 5-(2,3-dichloro-phenoxy)-2H-pyridazin-3-one alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,3-dichloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (12 g, 78% for the final step); LC-MS: 307 [M+1]+, tR=2.50 min. HPLC: 30.31% at 214 nm, 90.71% at 254 nm, tR=3.81 min. 1H NMR (300 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.63 (d, 1H, J=2.1 Hz), 5.79 (d, 1H, J=10.2 Hz), 3.95 (d, 1H, J=12.3 Hz), 3.58 (d, 1H, J=3.3 Hz), 2.04˜1.91 (m, 2H), 1.64˜1.49 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH:5]=[CH:6][C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[CH2:7][OH:8])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COC(=O)C=Cc1ccc(OCCN(C)c2ccccn2)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CN(CCOc1ccc(/C=C/CO)cc1F)c1ccccn1

Procedure:
In substantially the same manner as in Reference Example 58, methyl 3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamate was subjected to reduction reaction with diisobutylaluminum hydride to yield (E)-3-(3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]-2-propen-1-ol. The product was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.80-81° C.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[C:35]([CH2:39][C:40](Cl)=[O:41])([CH3:38])([CH3:37])[CH3:36].O>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[C:40](=[O:41])[CH2:39][C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)CC(C)(C)C)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 14 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added thereto, and the mixture was stirred at −78° C. for 20 min. Tert-butylacetyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (15 mg, yield 14%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](OC4C=CC=CC=4)=[O:29])=[CH:23][C:22]=3[O:37][CH3:38])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[C:41]([NH2:45])([CH3:44])([CH3:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:45][C:28](=[O:29])[NH:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:8]2[C:7]3[CH:39]=[CH:40][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]2=[O:17])(=[O:19])=[O:20])=[C:22]([O:37][CH3:38])[CH:23]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1OC
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)NC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.7 g of the compound obtained in EXAMPLE 16 step A), 1 ml of tert-butylamine and 25 ml of DCM is stirred for 48 hours at RT. The solvent is evaporated off under vacuum and the residue is chromatographed on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 0.41 g of the expected product after crystallization from an AcOEt/iso ether mixture (50/50; v/v). M.p.=237° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[CH3:24][O:23][N:22]([CH3:21])[C:17]([CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:19]
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Yield: 87.1 %

Procedure:
1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid (5.86 g, 22.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.55 g, 36.4 mmol) in tetrahydrofuran (60 mL) was stirred with triethylamine (5.50 mL, 39.5 mmol), 1-hydroxybenzotriazole (1.17 g, 8.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.18 g, 37.4 mmol) at room temperature for one day. After addition of water, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a colorless oil (5.95 g, yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[NH2:14].N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCOC(C)=O>ClCCl>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([NH:14][S:22]([CH3:21])(=[O:24])=[O:23])[CH:5]=[C:6]([C:10]([F:12])([F:11])[F:13])[CH:7]=1
Reactant: COc1c(N)cc(C(F)(F)F)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1c(N)cc(C(F)(F)F)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
2-Methoxy-5-trifluoromethylbenzene-1,3-diamine (2.32 g, 11.3 mmol) was dissolved in 50 mL anhydrous dichloromethane. The solution was cooled to 0° C., and pyridine (3.64 mL, 45.0 mmol) and methane sulfonyl chloride (0.89 mL, 11.5 mmol) were added. The reaction was left to stir overnight at room temperature. A few more drops (˜0.1 mL) of methane sulfonyl chloride were added and the reaction stirred an extra day. Then 200 mL EtOAc, was added and the solution washed once with 100 mL water, twice with 15 mL saturated aqueous NH4Cl solution and finally with brine. The organic solution was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/hexanes eluent mixtures, providing N-(3-amino-2-methoxy-5-trifluoromethyl-phenyl)-methanesulfonamide (1870 mg, 6.58 mmol, 58% yield) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
4-Bromobenzenesulfonyl chloride (256 mg, 1 mmol) was added dropwise to a solution of 1,1-dimethylethyl (2-aminoethyl)carbamate (197 mg, 1 mmol) and triethylamine (0.42 mL, 3 mmol) in CH2Cl2 (5 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The mixture was then concentrated, and the crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 362 mg (96%) of 1,1-dimethylethyl (2-{[(4-bromophenyl)sulfonyl]amino}ethyl)carbamate as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.75-7.68 (m, 2H), 7.67-7.61 (m, 2H), 5.28 (bs, 1H), 4.78 (bs, 1H), 3.26-3.20 (m, 2H), 3.11-3.03 (m, 2H), 1.43 (s, 9H); LRMS (ESI), m/z 379/381 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])(C)([CH3:3])[CH3:2].C(N)(C)C.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>>[CH:1]([NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)N
Product: CC(C)NC(=O)C(C)(C)C
Yield: 96 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of isopropylamine (9.0 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with pivaloyl chloride (8.9 mL, 100 mmol) afforded LtBu,iPrH as white crystalline solid (13.75 g, 96%) upon sublimation at 55° C./0.05 Torr: mp 106-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:34][CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C)[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1([N:16]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:34][CH2:35][CH2:36][OH:37])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1(N(CCCO)S(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a solution of the crude 1{[3-(tert-butyl-dimethylsilanyloxy)-propyl]-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester (279 grams) in methylene chloride (1 L) at room temperature was added boron trifluoride etherate (103 mL, 0.84 mole). After 1 hour, the reaction was quenched by sequential addition of saturated ammonium chloride solution and water. The organic phase was separated, washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent under vacuum provided crude 1-[[4-(4-fluorophenoxy)benzenesulfonyl]-(3-hydroxypropyl)amino]cyclopentanecarboxylic acid benzyl ester as an amber oil (235 grams).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[CH3:9][C:10]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:16][CH2:17][CH:18]=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O.C(O)C>[OH:8][N:7]=[CH:18][CH2:17][CH2:16][C:10]([CH3:9])([S:20]([CH3:23])(=[O:22])=[O:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: NO
Reactant: CCOC(=O)C(C)(CCC=O)S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(CCC=NO)S(C)(=O)=O
Reaction time: 15 h
Yield: 98 %

Procedure:
Sodium bicarbonate (2.29 g, 27.3 mmol, 1.05 equiv) was added to a solution of hydroxylamine hydrochloride (1.94 g, 27.3 mmol, 1.05 equiv) in water (100 mL) at room temperature. After the evolution of gas ceased (approx. 30 min), a solution of ethyl 2-methyl-2-(methylsulfonyl)-5-oxopentanoate (6.14 g, 26.0 mmol, 1.0 equiv) in ethanol (100 mL) was added dropwise over 30 min, and the reaction was allowed to stir overnight (approx. 15 h). The reaction mixture was concentrated under reduced pressure to half the volume (approx. 100 mL) and partitioned between dichloromethane (200 mL) and water (100 mL). The aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the title compound (6.4 g, 97%, approx. 1:1 mixture of E/Z isomers). MS (LCMS) m/z 252.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ1.34 (td, J=7.12, 1.17 Hz, 6H) 1.56-1.72 (m, 6H) 2.11-2.19 (m, 2H) 2.19-2.29 (m, 1H) 2.44 (d, J=3.71 Hz, 4H) 2.51-2.63 (m, 1H) 3.06 (d, J=2.93 Hz, 6H) 4.30 (qd, J=7.12, 3.22 Hz, 4H) 6.66-6.88 (m, 1H) 7.43 (d, J=5.07 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21]Br)[CH:9]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(CBr)cc2C1=O
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(CN3CCOCC3)cc2C1=O
Reaction time: 2 h
Yield: 16.1 %

Procedure:
6-Bromomethyl-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (1.1 g, 2.96 mmol) was dissolved in N,N-dimethylformamide. Pyridine (264 μl, 3.26 mmol) and morpholine (284 μl, 3.26 mmol) were added thereto and the mixture was stirred for 2 hours. After the reaction was completed, the organic layer was extracted with ethyl acetate/ammonium chloride/saturated sodium chloride, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 180 mg of 6-(morpholine-4-yl methyl)-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (180 mg, yield 16.1%) as red oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][NH2:4].CC(C[AlH]CC(C)C)C.[C:16]([O:20][C:21]([N:23]1[CH2:29][CH2:28][C:27]2[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([S:43][CH2:44][C:45](OC)=[O:46])=[CH:39][CH:38]=3)=[C:31]([Cl:34])[CH:32]=[CH:33][C:26]=2[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1.CCOC(C)=O>[C:16]([O:20][C:21]([N:23]1[CH2:29][CH2:28][C:27]2[C:30]([NH:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([S:43][CH2:44][C:45](=[O:46])[NH:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[CH:41][CH:42]=3)=[C:31]([Cl:34])[CH:32]=[CH:33][C:26]=2[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CN
Reactant: COC(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)CNC(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
Dissolve 2,2-dimethyl-propylamine (0.1 mL, 0.84 mmol) in anhydrous THF (0.6 mL) under nitrogen. Cool the solution at 0° C. and add DIBAL-H (0.79 mL, 0.79 mmol, 1M solution in toluene). Allow the mixture warm up to room temperature and stir for 2 h. Add this complex to a solution of 3-(tert-butoxycarbonyl)-7-chloro-6-(4-methoxycarbonylmethylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.14 mmol) in THF (0.3 mL) and stir at room temperature overnight. Dilute with EtOAc and quench with 5% aqueous KHSO4. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as an oil (51 mg, 65%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[C-]#N.[K+].[C:17](#[N:19])C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:11]1([C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][C:17]#[N:19])=[CH:4][CH:5]=2)=[O:10])[CH2:13][CH2:12]1
Reactant: O=C(c1ccc(CBr)cc1)C1CC1
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [C-]#N
Solvent: O
Product: N#CCc1ccc(C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Mix (4-bromomethyl-phenyl)-cyclopropyl-methanone (5.0 g, 21 mmol), potassium cyanide (2.0 g, 30 mmol), tetrabutylammonium bromide (150 mg), water (5 mL) and acetonitrile (50 mL). Mechanically stir at room temperature for 3 hours, pour into water (450 mL) and stir overnight. Collect by filtration and recrystallize (hexane) to give the title compound as a white crystalline solid; mp 86-87° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH3:6].C(O)(=O)C>C(O)C>[CH2:3]([CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[CH:32][C:33]([CH2:36][OH:37])=[CH:34][CH:35]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C=O)cc3)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(CO)cc3)cc2)cc1)C(=O)O
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
Sodium borohydride (95%, 34 mg) was added to a solution of 2-butyl-3-[4-[2-(4′-formylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid (366 mg) in ethanol (10 ml) at ambient temperature. The mixture was stirred for 1.5 hours. At the end of this time 50% acetic acid was added to the reaction mixture. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Diisopropyl ether was added to the residue to give the title compound (331 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[NH2:37][CH2:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:37][CH2:38][C:39](=[O:40])[NH:41][CH2:42][CH3:43])=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CCNC(=O)CN
Product: CCNC(=O)CNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-N-ethyl-acetamide.