Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].Br[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[O:34][C@@H:33]([C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[C@H:32]([C:42]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:43])[O:31]2)=[CH:26][CH:25]=1>CCCCCC.O1CCCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[O:34][C@@H:33]([C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[C@H:32]([C:42]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:43])[O:31]4)=[CH:26][CH:25]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: CCCCOC(=O)[C@@H]1OC(c2ccc(Br)cc2)O[C@H]1C(=O)OCCCC
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCC)CC2)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCOC(=O)[C@@H]1OC(c2ccc(C#Cc3ccc([C@H]4CC[C@H](CCC)CC4)cc3)cc2)O[C@H]1C(=O)OCCCC
Temperature: 60 °C

Procedure:
1.45 ml of an about 1.6M butyllithium solution in hexane were added dropwise at -50° C. to a solution of 0.5 g of 4-(trans-4-propylcyclohexyl)phenylacetylene in 5 ml of dry tetrahydrofuran and the mixture was left to react at this temperature for 30 min. Then, 4.4 ml of a 1M zinc chloride solution in ether were added dropwise, the cooling bath was removed and the mixture was left to react for 30 minutes. Thereupon, the mixture was cooled to 0° C. and at this temperature a solution of 0.95 g of dibutyl (4R,5R)-2-(4-bromophenyl)-1,3-dioxolane-4,5-dicarboxylate in 5 ml of dry tetrahydrofuran was added dropwise and thereafter 0.128 g of tetrakis(triphenylphosphine) palladium(O) was added. The reaction mixture was then heated to 60° C. for 15 hours., then cooled, partitioned between water and ether and the organic phase was separated and dried over magnesium sulfate. Thereupon, it was filtered over Celite, the solvent was evaporated and the residue was chromatographed on 100 g of silica gel with 5% ethyl acetate in cyclohexane. Further purification with active charcoal in isopropanol and two-fold crystallization from isopropanol gave 0.23 g of dibutyl (4R,5R)-2-{4-[4-(trans-4-propylcyclohexyl)phenylethynyl]phenyl}-1,3-dioxolane-4,5-dicarboxylate, m.p. (K-N*) 74.9° C., cl.p. (N*-I) 78.3° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br-].[K+]>[Cu].O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: Cc1cccc(Nc2cccc(C)n2)n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: Cc1cccc(N(c2ccccn2)c2cccc(C)n2)n1
Reaction time: 16 h

Procedure:
To a flask were added 2.0 g of 6-methyl-N-(6-methylpyridin-2-yl)pyridin-2-amine, 4.7 g of 2-bromopyridine, 1.6 g of sodium carbonate, 51 mg of copper bronze, 5 mg of potassium bromide, and 3 ml of mesytylene. After stirring under nitrogen at 160 C for 16 hours, the mixture was cooled to 22 C, and 35 ml of water was added and the product was extracted with 50 ml ethyl acetate. After washing twice with 20 ml of water, the solvent was removed, and the product was purified by silica gel chromatography using 60% ethyl acetate, 40% hexane, and 0.1% triethylamine resulting in 2.2 g of a yellow oil.
Reaction SMILES: ClCCl.[CH:4]1([C:10]2[CH:19]=[C:18]3[C:13]([C:14]([CH3:24])=[CH:15][C:16](=[O:23])[N:17]3[CH2:20][CH:21]=O)=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][N:36]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C>[CH:4]1([C:10]2[CH:19]=[C:18]3[C:13]([C:14]([CH3:24])=[CH:15][C:16](=[O:23])[N:17]3[CH2:20][CH2:21][N:47]3[CH2:48][CH2:49][CH:44]([N:36]([CH2:35][C:33]4[CH:32]=[CH:31][C:30]5[O:25][CH2:26][CH2:27][O:28][C:29]=5[CH:34]=4)[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:40])[CH3:41])[CH2:45][CH2:46]3)=[CH:12][CH:11]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Cc1cc(=O)n(CC=O)c2cc(C3CCCCC3)ccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C3CCCCC3)ccc12
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To 1.5 mL of dichloromethane solution containing 56 mg of (7-cyclohexyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde, 69 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 15 μL of acetic acid were added, and stirred for 5 min. To the reaction mixture, 63 mg of sodium triacetoxyborohydride was added, and stirred for 45 min. Water and chloroform were added, the organic layer was separated, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:2], to give 73 mg of tert-butyl (1-(2-(7-cyclohexyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.C(N(C(C)C)CC)(C)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:34]1([S:40]([NH:1][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCNS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 19 h
Yield: 75.1 %

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0403 g, 0.122 mmol) was dissolved in THF (2 mL) at rt under N2. Diisopropylethylamine (0.043 mL, 0.0316 g, 0.245 mmol, 2.00 equiv.) and benzenesulfonyl chloride (0.023 mL, 0.0324 g, 0.183 mmol, 1.50 equiv.) were added, then the reaction mixture was stirred for 19 h. Citric acid (10%) was added and the reaction mixture was stirred for 15 min. The reaction mixture was extracted with EtOAc, and the organic layer was washed sequentially with 10% citric acid, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (0.0649 g) was chromatographed (SiO2 25 g, eluted with 2:1 hexane:EtOAc) to give tert-butyl 6-{2-[(phenylsulfonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0430 g) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 1.46, 1.52, 2.95-3.02, 3.22-3.30, 3.63-3.75, 4.24-4.31, 4.63, 4.79, 7.09-7.26, 7.45-7.51, 7.48, 7.58, 7.79; MS (ESI+) for C25H31N3O4S m/z 470.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([CH3:28])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OC(=O)C)C>[CH3:28][C:19]1[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:26]([CH3:27])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(C)c(O)cc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(OS(=O)(=O)C(F)(F)F)cc1C
Temperature: 0 °C
Yield: 90.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.27 g) was added to an ice-cooled mixture of methyl 4-hydroxy-2,5-dimethylbenzoate (0.144 g) and pyridine (0.095 g) in methylene chloride (10 mL) with stirring. The mixture was stirred at room temperature for 30 min, and poured into a mixture of ethylacetate and 2 mol/L hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=10/1) to afford the title compound (0.226 g).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][OH:19]
Reactant: NO
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2sccc2Br)cc1
Reaction time: 8 h

Procedure:
A mixture of (3-bromothien-2-yl) (4-methoxyphenyl)methanone PG,47 (2.5 g) and hydroxylamine hydrochloride (1.5 g) and 15 ml of pyridine was stirred at room temperature overnight and then heated at 100°-115° C. for 4 hours. A thin layer chromatography analysis showed the reaction to be complete. The mixture was quenched with water and extracted with ether. The ether phase was washed with 3N hydrochloric acid and water and dried over anhydrous magnesium sulfate. Upon evaporation of the ether, an oil was obtained which crystallized upon standing overnight. The solid was recrystallized from ether/pentane to give a pure crystalline product (2.39 g, m.p. 110°-115° C.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]=[C:9]2[OH:12])=[CH:4][N:3]=1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([C:14]([F:13])([F:23])[F:24])[CH:16]=3)[C:9]2=[O:12])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Oc1nncc2cnc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ncc2cnn1Cc1cccc(C(F)(F)F)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-3,6-diazaisoquinoline (1.00 g, 4.46 mmol) using 3-trifluoromethyl-benzyl bromide (1.60 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 7-(3-phenylprop-1-ynyl)-2-(3-trifluoromethylbenzyl)-2H-3,6-diazaisoquinolin-1-one
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][CH:50]=[CH:49][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([O:42][CH2:43][CH2:44][C:45]([O:47]C)=[O:46])[CH:36]=2)=[CH:13][CH:12]=1.C(OC(C)C)(C)C.P([O-])([O-])([O-])=O>CS(C)=O>[C:45]([CH2:44][CH2:43][O:42][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[CH3:41])[CH2:34][O:33][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:49]=[CH:50][CH:51]=[CH:52][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:19]1)([OH:47])=[O:46]
Reactant: COC(=O)CCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc(C)c(OCCC(=O)O)c2)cc1
Temperature: 35 °C
Reaction time: 120 h

Procedure:
The mixture of 0.527 g of benzyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[3-(2-methoxycarbonylethoxy)-4-methylbenzyloxy]piperidine-1-carboxylate, 20 ml of diisopropyl ether, 0.20 ml of dimethyl sulphoxide and 100 ml of pH 7.0 phosphate buffer is admixed with 15 ml of Novozyme 398 (Novo Nordisk) and stirred at 35° C. over 120 hours. The reaction mixture is extracted repeatedly with tetrahydrofuran and the organic phases are concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (1:1 EtOAc-heptane); Rt=5.57.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[OH-].[Na+].Cl>CN(C=O)C.O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
To a mixture of hydroquinone(24 g, 0.22 mol) and ethyl bromoacetate(24 mL, 0.22 mol) in DMF(300 mL) was added 10 M aq. NaOH(22 mL, 0.22 mol). The mixture was stirred at 0° C. for 1 h, diluted with H2O, acidified with 6M aq. HCl and extracted with EtOAc. The EtOAc extract was dried(anhydrous MgSO4) and concentrated in vacuo. The residue was swished with Et2O to give ethyl 4-hydroxyphenoxy-acetate(5.8 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]CC)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113 %

Procedure:
To a solution of 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene 17a (5.0 g, 15.35 mmol, purchased from Shanghai Caerulum Pharma Discovery Co., Ltd.) in dichloromethane (50 mL) was added a solution of boron tribromide (1.7 mL, 16.89 mmol) in dichloromethane (10 mL) dropwise. The mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 7 and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 17b as a pale yellow solid (5.16 g, 100%). This material was not further purified.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14](OC)=[O:15])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][OH:23].[OH-].[K+]>C1COCC1.CO.CCOCC>[CH2:1]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:22][OH:23])=[O:15])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)c1ccccc1S(=O)(=O)NCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: O=C(NO)c1ccccc1S(=O)(=O)NCc1ccccc1
Temperature: 0 °C
Yield: 36.7 %

Procedure:
In a 50 mL round-bottomed flask was added methyl 2-(N-benzylsulfamoyl)benzoate 43 (49 mg, 0.160 mmol) in THF (321 μl) and MeOH (321 μl) and the solution was cooled to 0° C. Then, a 50% aqueous solution of hydroxylamine (530 mg, 8.02 mmol) was added, followed by a 4M aqueous solution of KOH (80 μl, 0.321 mmol) and the resulting colorless solution was stirred at 0° C., allowing to slowly warm to rt and stirred for 18 h. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc and combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide a colorless oil. A solid was obtained by successive dissolution in Et2O/Hex mixture and concentration which was triturated in Et2O to afford title compound 44 (18 mgs, 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.25 (s, 1H), 9.34 (s, 1H), 7.83 (dd, J=7.6, 1.2 Hz, 1H), 7.67 (td, J=7.4, 1.4 Hz, 1H), 7.61 (td, J=7.6, 1.6 Hz, 1H), 7.50 (dd, J=7.4, 1.6 Hz, 1H), 7.49 (bs, 1H), 7.27-7.18 (m, 5H), 4.05 (d, J=5.9 Hz, 2H). LRMS (ESI): (calc.) 306.34 (found) 307.14 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].C([O-])([O-])=[O:12].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]([NH2:6])=[O:12]
Reactant: N#Cc1ccc(I)c(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 251549.91 %

Procedure:
To a solution of 3-fluoro-4-iodobenzonitrile (2.7 g, 0.010 mmol) in DMSO (6.0 mL), K2CO3 (0.450 g, 0.003 mmol) and 30% H2O2 (2.4 mL) were added at 0-10° C. and the reaction mass was stirred at RT for 2 h. After completion of the reaction, the reaction mass was quenched in ice cold water. The obtained solid product was filtered off to afford 2.0 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 7.48-7.51 (In, 2H), 7.66 (br s, 1H), 7.69-7.70 (m, 1H), 8.09 (brs, 1H).
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[CH:17]=[C:16]([N:18]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:19](=O)[C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11]>ClCCl.O>[Cl:7][C:8]1[CH:17]=[C:16]([N:18]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH2:19][C:20]([F:22])([F:23])[F:21])[CH:15]=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1ccc(N(CC2CC2)C(=O)C(F)(F)F)cc1Cl
Agent: B
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(N(CC2CC2)CC(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
Borane-THF complex (1.0M solution in THF, 13.7 ml) was added under ice-cooling to a solution of methyl 2-chloro-4-[cyclopropylmethyl(2,2,2-trifluoroacetyl)amino]benzoate (500 mg) in dichloromethane (10 ml). The reaction mixture was then refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1Oc1cccc(C(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)O)c(Oc2cccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.7 %

Procedure:
A mixture of methyl 4-tert-butyl-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzoate (0.49 g, 1.4 mmol) and lithium hydroxide hydrate (0.12 g, 2.8 mmol) in THF (5 mL) and water (5 mL) was stirred at room temperature for two days. The reaction was made acidic with 1 M HCl(aq) and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and evaporated to give 4-tert-butyl-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzoic acid (0.45 g, 95% yield). LC/MS: m/z 340.5 (M+H)+ at 1.89 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=8.3 Hz, 1H), 7.85-7.81 (m, 1H), 7.36-7.33 (m, 2H), 7.26-7.24 (m, 1H), 7.09 (d, J=8.4 Hz, 1H) and 1.34 (s, 9H) ppm.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH2:16]([O:15][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][C:21]1[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=1[CH3:26])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:18])[CH3:17]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 64 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-phenyl-5-methyl-oxazole, the title compound was obtained in 64% yield as a colourless oil. MS: (M−H)− 403.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[NH2:33][C@@:34]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][C:38]2([CH2:40][CH2:39]2)[C@@H:37]2[C@H:35]1[C@H:36]2[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([NH:33][C@@:34]1([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:41][C:38]2([CH2:40][CH2:39]2)[C@@H:37]2[C@H:35]1[C@H:36]2[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)CC21CC1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)(C(=O)OCC)CC21CC1
Temperature: 22.5 °C
Yield: 100 %

Procedure:
Charge tetrahydrofuran (45 mL, 10 volumes) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (3.4 g, 1.2 equivalents) to a reactor followed by N-methylmorpholine (1.96 mL, 1.2 equivalents) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (3.12 g, 1.2 equivalents). Stir the resulting thin slurry between 20-25° C. for at least 3 hours until the reaction is complete by HPLC. Charge diethyl (1S,2S,5R,6S)-2-aminospiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate hydrochloride (4.55 g, 14.81 mmol) in one portion between 20-25° C. followed by N-methylmorpholine (1.63 mL, 1.0 equivalents) over at least 10 minutes keeping the temperature between 20-25° C. Stir the resulting slurry between 20-25° C. for at least 2 hours until the reaction is complete by HPLC. Filter the resulting solids and wash the wet cake with tetrahydrofuran (2×10 mL, 2.2 volumes) to provide the title compound assuming 100% yield. Use the pale amber tetrahydrofuran solution of the title compound without further purification assuming a 100% yield. 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (s, 1H), 6.72 (d, J=7.9, 1H), 4.08-3.92 (m, 5H), 2.42-2.37 (m, 1H), 1.81-1.64 (m, 3H), 1.47 (dd, J=6.6, 3.1, 1H), 1.34 (s, 9H), 1.18-1.08 (m, 9H), 0.66-0.59 (m, 1H), 0.57-0.52 (m, 1H), 0.46-0.36 (m, 2H).
Reaction SMILES: C(OC(N[C@@H](C(O)=O)C)=O)(C)(C)C.[N+](=C)=[N-].COC(=O)[C@@H](C)NC(OC(C)(C)C)=O.[H-].C([Al+]CC(C)C)C(C)C.C(OC(N[C@@H](C=O)C)=O)(C)(C)C.C(=C1C=CC=CC1[PH+](C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.[ClH:79].C(OC([NH:87][C@H:88]([CH3:97])[CH2:89][CH2:90][C:91]1[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1)=O)(C)(C)C>[Pd].O1CCOCC1.CO>[ClH:79].[CH3:97][C@@H:88]([NH2:87])[CH2:89][CH2:90][C:91]1[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1
Reactant: C[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: C1=CC(=Cc2ccccc2)C([PH+](c2ccccc2)c2ccccc2)C=C1
Agent: C=[N+]=[N-]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)CCc1ccccc1

Procedure:
(R)-1-Methyl-3-phenylpropanamine hydrochloride was prepared by first esterifying N-(tert-butyloxycarbonyl)-D-alanine with diazomethane, then reducing the resulting N-(tert-butyloxycarbonyl)-D-alanine methyl ester with diisobutylaluminum hydride, then condensing the resulting N-(tert-butyloxycarbonyl)-D-alaninal with benzylidenetriphenylphosphonium ylide, then hydrogenating over palladium catalyst the resulting [R-(E)]-N-(tert-butyloxycarbonyl)-1-methyl-3-phenyl-2-propenamine having m.r. 86°-88° C. and [α]D25 +54.0° (c=1, methanol), and finally deprotecting with hydrogen chloride in dioxane the resulting (R)-N-(tert-butyloxycarbonyl)-1-methyl-3-phenylpropanamine having m.r. 74°-76° C. and [α]D25 +7.2° (c=1, methanol). ##STR16##