Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:9]2[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][CH:6]=[C:5]([CH:10]=2)[C:3]([OH:2])=[O:4])=[C:21]([F:28])[CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1

Procedure:
The title compound was synthesized in analogy to Examples BI to BJ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (CAN 1211589-51-3) and B-(4-chloro-2-fluorophenyl)-boronic acid, (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 348.0061 (M−H)−.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:29])[CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]([OH:29])[CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of zinc chloride (7.06 g, 51.8 mmol) in *diethyl ether (100 ml) was added sodium borohydride (3.92 g, 103.5 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(2,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (10 g, 25.9 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid as added to the reaction solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (8.23 g, 82%) as a colorless oil.
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.[N:8]1([CH2:13][CH2:14][C:15]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16]=2[C:24]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)(O)[CH3:25])[CH2:12][CH2:11][CH2:10][CH2:9]1.S([O-])([O-])(=O)=S.[Na+].[Na+].[NH4+].[OH-]>C(#N)C.ClCCl>[N:8]1([CH2:13][CH2:14][C:15]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16]=2[C:24]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)=[CH2:25])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(O)(c1cscn1)c1c(CCN2CCCC2)sc2ccccc12
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: C=C(c1cscn1)c1c(CCN2CCCC2)sc2ccccc12
Temperature: 100 °C

Procedure:
NaI was taken up in acetonitrile (30 mL) under N2 and trimethylsilyl chloride was slowly added (2.97 mL, 24 mmol). The mixture was stirred for 15 min after which a solution of 1-[2-(2-pyrrolidin-1-yl-ethyl)-benzo[b]thiophen-3-yl]-1-thiazol-4-yl-ethanol (1.4 g, 3.91 mmol) in acetonitrile (30 mL) and dichloromethane (10 mL) was added. The reaction was heated in a closed vessel to 100° C. for 3 hrs. After cooling to room temperature 1M sodium thiosulfate was added followed by NH4OH until pH ˜9. After extraction with EtOAc, drying (MgSO4), filtering, concentration in vacuo and subsequently purification by mass triggered preparative HPLC, 4-{1-[2-(2-pyrrolidin-1-yl-ethyl)-benzo[b]thiophen-3-yl]-vinyl}-thiazole (Compound 19-3) was isolated MH+=341.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[S:12][CH2:13][CH3:14].[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[S:12]([CH2:13][CH3:14])=[O:15]
Reactant: OO
Reactant: CCSc1c(Cl)ccc(C(=O)O)c1C
Solvent: CC(=O)O
Product: CCS(=O)c1c(Cl)ccc(C(=O)O)c1C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
1.15 g (4.98 mmol) of 4-chloro-3-ethylthio-2-methylbenzoic acid in 10 ml of glacial acetic acid were heated to a temperature of 50° C.-60° C. At this temperature, 484 mg (35% strength, 4.98 mmol) of an aqueous hydrogen peroxide solution were added dropwise. The mixture was stirred at this temperature for 5 h. The reaction mixture was cooled, washed with an aqueous saturated sodium bisulfite solution and, after analytical proof of absence of peroxides, freed from the solvents. Water was added to the residue, and the mixture was acidified with 6M HCl. The mixture was extracted with ethyl acetate, and the combined organic phases were dried, filtered and, under reduced pressure, freed from the solvent. 1.24 g of the product (purify about 95% by weight) were isolated.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.Br.Br.[CH2:49]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH2:50][CH3:51].CCN(C(C)C)C(C)C.Cl>CN(C=O)C.O>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:55]3[CH2:56][CH2:57][N:52]([CH2:49][CH2:50][CH3:51])[CH2:53][CH2:54]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: CCCN1CCNCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (0.5 g, 1.561 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.449 g, 2.342 mmol), HOBT (0.359 g, 2.342 mmol) and 1-propylpiperazine dihydrobromide (0.543 g, 1.873 mmol) in DMF (1.56 mL) and added DIPEA (1.09 mL, 6.24 mmol) to give an orange solution. After stirring for 20 minutes the reaction mixture was heated to 60° C. for 3 hours, then was diluted with water (5 mL) and acidified with 6N aqueous hydrochloric acid to pH 6 and stirred at ambient temperature for 30 minutes to give a solid. The solid was collected by filtration, washed with water (3 mL) and suspended in ACN (10 mL). The suspension was treated with 1N aqueous hydrochloric acid (2 mL) and heated to 40° C. Ethyl ether was then added until the mixture became slightly cloudy (˜8 mL) and then allowed to cool to ambient temperature to give a solid, and then cooled in an ice bath for 30 minutes. The solid was collected by filtration and dried in vacuum at 80° C. for 1.5 hour to give the title compound as a hydrochloride salt (81.3 mg, 0.174 mmol, 11.15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.45 Hz, 3 H) 1.64-1.79 (m, 2 H) 2.43 (s, 3 H) 2.81-3.20 (m, 4 H) 3.21-4.90 (m, 6 H) 7.67 (d, J=7.58 Hz, 1 H) 7.71-7.91 (m, 2 H) 7.93-8.74 (m, 4 H) 10.75 (br. s., 1 H) 13.23 (br. s., 1 H); [M+H]+ 431.
Reaction SMILES: Cl.[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:20]([O:19][C@H:12]1[C@H:13]([NH:18][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH2:14][C@H:15]([CH2:16][OH:17])[C@H:11]1[O:10][C:2](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diyl dibenzoate hydrochloride (150. mg, 0.380 mmol) in DCM (10.0 mL) at 0° C. was treated with Et3N (0.170 mL, 1.22 mmol) and stirred for 20 min. Isonicotinoyl chloride (88.0 mg, 0.490 mmol) was then added and the mixture was stirred for 2 h. The reaction was treated with saturated aqueous solution of ammonium chloride (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (100. mg, 60%). LC/MS: Rt=1.49 min, ES+ 461 (FA standard).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][N:11]([C@H:19]([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:42]([C:45]1[S:49][CH:48]=[C:47]([C:50]([N:52]2[CH2:57][C:56]3([CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)[O:55][CH2:54][CH2:53]2)=[O:51])[CH:46]=1)([CH3:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O.C(O)(=O)C.CN1CCCC1=O>[Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][N:11]([C@H:19]([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:60]2[CH2:59][CH2:58][C:56]3([O:55][CH2:54][CH2:53][N:52]([C:50]([C:47]4[CH:46]=[C:45]([CH:42]([CH3:44])[CH3:43])[S:49][CH:48]=4)=[O:51])[CH2:57]3)[CH2:62][CH2:61]2)[CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](Cc1cccc(C=O)c1)N(C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)C(=O)OC(C)(C)C
Reactant: CC(C)c1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(C[C@@H](C)N(C[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)C(=O)OC(C)(C)C)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (R)-2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl((R)-1-(3-formylphenyl)propan-2-yl)carbamate (Example 276, step i) (0.476 g) was treated with (5-isopropylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (Example 275, step i) (0.296 g), N-methyl-2-pyrrolidinone (20 mL), acetic acid (0.052 mL) and sodium triacetoxyborohydride (0.294 g), and the mixture was stirred at room temperature overnight. The solution was poured into a mixture of saturated sodium bicarbonate solution and water and extracted three times with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo, then purified by flash chromatography on silica eluted with 1:5:94 NEt3:MeOH:DCM to afford the subtitled compound. Yield 0.471 g.
Reaction SMILES: C1(O[N:8]=[C:9]([C:11]2[N:12]=[CH:13][N:14]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:15]=2[NH2:16])[NH2:10])CCCCC1.CN(C)C=O.[C:31](=S)=[S:32]>>[CH:13]1[N:14]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:15]2[C:11](=[C:9]([NH2:10])[NH:8][C:31]([N:16]=2)=[S:32])[N:12]=1
Reactant: NC(=NOC1CCCCC1)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: S=C=S
Solvent: CN(C)C=O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 76 %

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-cyclohexyl-oxime was dissolved in 4 ml of an aqueous solution containing 3 ml of N,N-dimethylformamide, and 1 ml of carbon disulfide was added to the solution. The resulting mixture was allowed to react in an autoclave at 125° C for 5 hours under autogenous pressure (about 10 Kg/cm2), and the reaction product was worked up in the same manner as described in Example 1 to obtain 0.305 g of 2-thioadenosine having a melting point of 197° C (with decomposition) in 76% yield.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH2:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][NH:17][CH2:16]1.[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28].CO>C(OCC)(=O)C>[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:17]3[CH2:16][CH2:15][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc2c(c1)CCNCC2
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCc2ccccc2CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=336 (M+ of free base). α[D]589 =-14.17 (c=0.61, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12].C(N(CC)CC)C.[C:28](C1NC=CN=1)(C1NC=CN=1)=[S:29]>O1CCCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([OH:12])=[C:5]([N:4]2[C:3]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:18])[F:19])=[CH:16][C:2]=3[NH:1][C:28]2=[S:29])[CH:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1cc(Cl)ccc1O
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Oc1ccc(Cl)cc1-n1c(=S)[nH]c2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h

Procedure:
2-amino-N-(5-chloro-2-hydroxyphenyl)-4-trifluoromethyl-aniline (0.51 g, 1 5 mmol), triethylamine (0.28 ml, 2 mmol) and thiocarbonyl diimidazol (0.36 g, 2 mmol) was dissolved in dry tetrahydrofuran (15 ml) and the mixture was stirred for 30 minutes. The reaction mixture was evaporated in vacuo. The residue was redissolved in ethanol and water and light petroleum were added. The precipitate was isolated and was purified by column chromatography on silica gel with ether/light petroleum (2:1) as eluent. Yield of title compound was 200 mg, M.p. 248°-250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:34]2[CH2:35][CH2:36][N:31]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH2:32][CH2:33]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COc1ccccc1CNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1ccccc1CNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-2-methoxy-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C@H:13]([N:18]([CH2:29][C@H:30]2[C@@H:34]([F:35])[CH2:33][N:32](C(OCC3C=CC=CC=3)=O)[CH2:31]2)[C:19]([N:21]2[CH2:26][C@@H:25]([CH3:27])[O:24][C@@H:23]([CH3:28])[CH2:22]2)=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:46]2[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=2[F:53])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[C:12]([C@H:13]([N:18]([CH2:29][C@H:30]2[C@@H:34]([F:35])[CH2:33][NH:32][CH2:31]2)[C:19]([N:21]2[CH2:22][C@@H:23]([CH3:28])[O:24][C@@H:25]([CH3:27])[CH2:26]2)=[O:20])[C:14]([CH3:15])([CH3:16])[CH3:17])=[N:11][C:10]([C:46]2[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=2[F:53])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(C(=O)N(C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2F)[C@@H](c2nc(-c3cc(F)ccc3F)nn2Cc2ccccc2)C(C)(C)C)C[C@H](C)O1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(C(=O)N(C[C@@H]2CNC[C@@H]2F)[C@@H](c2nc(-c3cc(F)ccc3F)nn2Cc2ccccc2)C(C)(C)C)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((2S,6R)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (91 mg, 0.124 mmol) in degassed ethanol (12 mL, 0.1 M solution) was added Pd/C (2.64 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for 45 min. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude product, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (2S,6R)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamide was obtained in 94% yield (70 mg) as a free amine 1H NMR (CD3Cl, 300 MHz): δ 7.83 (1H, m), 7.52 (2H, m), 7.34-7.27 (3H, m), 7.08 (1H, m), 7.04 (1H, m), 5.94 (2H, m), 5.41 (1H, s), 3.92-3.62 (3H, m), 3.60-3.45 (3H, m), 3.17-2.58 (3H, m), 2.57-2.37 (1H, m), 2.35-2.04 (2H, m), 1.85 (2H, m), 1.20 (6H, s), 0.9 (1H, m), 0.8 (9H, s). LC/MS (uplc): MH+ 599.5, 1.06 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][C:10]=1[CH3:18].C(Cl)(=O)C(Cl)=O.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[C:10]([CH3:18])[CH:11]=3)=[O:17])[CH2:30][C:29]=12
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a stirred solution of 2′-methoxy-2-methyl-biphenyl-4-carboxylic acid (0.250 g; 1.032 mmol) in dichloromethane (20 mL) was added one drop of N,N-dimethylformamide followed by dropwise addition of oxalyl chloride (0.144 mL; 1.65 mmol). After stirring for one hour, the mixture was thoroughly evaporated to give the crude acid chloride as a brown oil. The acid chloride then was dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo [2,1-c][1,4] benzodiazepine (0.57 g, 3.10 mmol) and N,N-diisopropylethyl amine (0.79 mL, 4.53 mmol) in dichloromethane (15 mL). After stirring for 1 hour, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 5 to 15% ethyl acetate in hexane yielded a white foam which crystallized upon sonication in ethanol/hexane to give 0.42 g of the desired title product as a white solid, m.p. 133-135° C. MS [(+)ESI, m/z]: 409 [M+H]+. Anal. Calcd. for C27H24N2O2: C, 79.39; H, 5.92; N, 6.86. Found: C, 79.16; H, 5.87; N, 6.90.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:25][CH:18]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: CC(C)CCCC(C)CCBr
Reactant: O=c1ccc2cc(O)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCOc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (114 mg, 0.7 mmol) and 4 mL of anhydrous N,N-dimethylformamide (DMF) were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask at which point the solution turned color from yellow to orange. The solution was kept stirring at 0° C. for 30 minutes. 1-Bromo-3,7-dimethyloctane (344.4 μL, 1.66 mmol) in 1 mL of DMF was cooled to 0° C. and added drop-wise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen to warm back to room temperature over 14 hours. The desired product was obtained through preparatory thin layer chromatography using a 7:3 Hexanes:Ethyl acetate solvent system. The purified product was verified by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). 1H-NMR (300 MHz, CD3COCD3): δ 0.95-1.86 (19H), 4.08 (t, 2H), 6.40 (d, 1H, J=9 Hz), 7.17 (m, 2H), 7.27 (s, 1H), 7.92 (d, 1H, J=9 Hz); 13C-NMR (75 Hz, CD3COCD3): δ 19.91, 22.87, 22.97, 25.13, 25.37, 36.60, 37.92, 39.93, 67.54, 111.97, 117.58, 118.47, 120.28, 120.56, 129.10, 144.35, 149.19, 156.44, 160.77. FIRMS (EI) Calcd. for C19H26O3: 302.18820. found: 302.18871.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].C(=O)(O)[O-].[Na+].[Br-].[K+].S(=O)(O)[O-].[Na+]>O.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: OCCCCCCCCCBr
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: O=CCCCCCCCCBr
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a 100-mL round-bottomed flask equipped with a magnetic stirrer, addition funnel and temperature controller, under nitrogen, was added 9-bromononanol (8.92 g, 40 mmol) and dichloromethane (30 mL). The resulting mixture was cooled to 5° C. and a solution of sodium bicarbonate (0.47 g, 5.6 mmol) and potassium bromide (0.48 g, 4 mmol) in water (10 mL) was added. 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical (TEMPO) (63 mg, 0.4 mmol) was added and then a 10 to 13% bleach solution (27 mL) was added dropwise through the addition funnel at a rate such that the temperature was maintained at about 8° C. (+/−2° C.) with an ice cold bath (over about 40 min.). After addition of the bleach was complete, the mixture was stirred for 30 min. while maintaining the temperature at about 0° C. A solution of sodium bisulfite (1.54 g) in water (10 mL) was added and the resulting mixture was stirred at room temperature for 30 min. The layers of the mixture were then separated, and the milky aqueous layer was extracted with dichloromethane (1×20 mL). The combined dichloromethane layers were then washed with water (1×30 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (8.3 g, 94% yield), which was used without further purification in the next step.