Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:9][C:8]2([CH3:28])[CH3:27])=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[CH3:27][C:8]1([CH3:28])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 45.5 %

Procedure:
To a solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (100 mg, 0.3 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at 80° C. for 6 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL×3); and the combined organics were dried over anhydrous Na2SO4 The solvent was removed in vacuo and purified by preparative HPLC to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 52%) as a yellow foam. MS (ESI+) [(M+H)+] 367.2.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][NH:11][C:10](=[O:24])[CH2:9]1)=[O:7].[H-].[Na+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl>O1CCCC1.ClCCl.O>[F:29][C:28]([F:31])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:10](=[O:24])[CH2:9]1)=[O:7]
Reactant: O=C1CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)CN1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled solution of (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-5-(1H-indol-3-ylmethyl)piperazin-2-one (2.15 g) in tetrahydrofuran (43 ml) were added successively sodium hydride (60%) (0.37 g) and ethyl bromoacetate (0.56 ml) in a stream of nitrogen. The mixture was stirred for 55 minutes at the same temperature, and water (20 ml) and 0.5N hydrochloric acid (20 ml) were added successively to the mixture. After stirring for 10 minutes, dichloromethane (80 ml) was added into the mixture at room temperature and the organic layer was separated. The organic layer was washed with brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel (60 g) eluting with a mixture of dichloromethane-methanol (from 0% to 2% gradient solution) to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-(ethoxycarbonylmethyl)-5-(1H-indol-3-ylmethyl)piperazin-2-one (1.20 g) as an amorphous solid.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:45]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>CS(C)=O.O>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:45])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.5 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) in DMSO (5 mL) was added Boc anhydride (69 mg, 0.31 mmol) followed by pyridine (24 mg, 0.26 mmol) and stirred at room temperature for 5 min. Ammonium bicarbonate (62 mg, 0.78 mmol) was added and stirred for additional 1 h. Reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 59 mg (59%) of the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:6][C:3]=1[CH:4]=[O:5].C([OH:22])(C)(C)C.C(Cl)Cl.CC(=CC)C.[O-]Cl=O.[Na+]>O.CC#N.CC#N.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:6][C:3]=1[C:4]([OH:22])=[O:5]
Reactant: CC(C)(C)O
Reactant: COCCCOc1cc(C=O)c(Cl)cc1OC
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COCCCOc1cc(C(=O)O)c(Cl)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4-methoxy-5-(3-methoxy-propoxy)-benzaldehyde (1.08 g, 3.55 mmol) in a 3:1 mixture of tert-butanol/CH2Cl2 (20 mL) is added 2-methyl-2-butene (0.74 g, 5.32 mmol), followed by dropwise addition of a solution of NaClO2 (0.67g, 7.10 mmol) and NaH2PO4 (0.67 g, 4.26 mmol) in water (14 mL) over 15 min at room temperature, and stirring is continued overnight. The reaction mixture is poured into ice/saturated aqueous NaHCO3 solution, the water phase is washed with AcOEt. The ice-cold aqueous layer is acidified with HCl 37% to form a white precipitate which is filtered off, washed with ice-cold water and dried in vacuo. The compound is obtained as white solid. MS: 273.0 [M−H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.25 min. 1H-NMR (CDCl3): δ 1.96 (m, 2H), 3.25 (s, 3H), 3.47 (m, 2H), 3.85 (s, 3H), 4.03 (m, 2H), 7.10 (s, 1H), 7.39 (s, 1H) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16]C=[C:14]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:25])C.O=[O+][O-].[I-].[K+]>C(OCC)(=O)C.C(O)(=O)C.O>[NH2:16][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:25])[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=C(O)CCc1c[nH]c2c(C(=O)c3ccccc3)cccc12
Reactant: CCO
Agent: O=[O+][O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1c(C(=O)CCC(=O)O)cccc1C(=O)c1ccccc1
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 8.7 g (0.03 mole) of 7-benzoyl-1H-indole-3-propanoic acid in 300 ml of ethyl acetate and 100 ml of abs. ethanol was ozonized until ozone was present above the solution. The yellow solution was then treated with 16.6 g (0.1 mole) of potassium iodide in 30 ml of acetic acid and 30 ml of water. After stirring 1 hr, the liberated iodine was removed by washing with a 15% sodium thiosulfate solution and the yellow organic layer was concentrated. The residue was dissolved in 100 ml of ethanol and 20 ml of 6N hydrochloric acid and heated at reflux for 16 hr. The dark red solution was concentrated and the residue was partitioned between dil. sodium hydroxide and methylene chloride. The basic aqueous layer was made acidic and the pH was adjusted to 2-3 by the addition of dil. sodium hydroxide. The solid was collected and dried, then recrystallized from benzene isopropyl ether to give 5.9 g (67 %) of yellow powder, m.p. 161.0°-2.5° C.
Reaction SMILES: COS([O-])(=O)=O.[N+:7]([C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[CH3:20])([O-])=O.[H][H]>C(O)C.[Pt]>[NH2:7][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH3:20]
Reactant: C[n+]1ccccc1C=Cc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: CN1CCCCC1CCc1ccccc1N
Yield: 93.6 %

Procedure:
2-(2-Nitrostyrenyl)-1-methylpyridinium methyl sulfate (III; 25 g, 0.07 moles) and 10 g of 5% Pt on carbon (50% water wet) in 300 mL of 95% ethanol was put in a 2L Parr hydrogenation flask and hydrogenated at approximately 2 psi of hydrogen for 16 hours. The hydrogenation mixture rapidly turned orange and then slowly became colorless as the organic solid dissolved. Catalyst was removed by filtration and held for subsequent runs. The filtrate was concentrated in vacuo to an oil which was dissolved in 50 mL water and made basic (pH~11) with 50% sodium hydroxide solution. The basic aqueous phase was extracted with 50 and 25 mL portions of methylene chloride, the extracts were combined and dried (anhyd. K2CO3) , filtered and the solid removed in vacuo to yield 14.3 g (92%) of product II as an amber oil. This intermediate diamine oil (cf: U.S. 3,931,195; Example 1) was used directly in the next step of the process.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[C:19]([O:23][C:24]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]([C:29]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:30])[CH2:27][N:26]([CH:39]([CH3:40])[CH3:41])[C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:33][CH:34]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (0.5 g, 1.62 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.7 g, 2.05 mmol) in DCM (40 mL) were added HBTU (1.0 g, 2.64 mmol) and triethylamine (1.38 mL, 9.88 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (200 mL) and washed with brine (5×100 mL) and water (3×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (2:1-0:1) to give tert-butyl 2-(4-chlorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.63 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 8.50 (d, J=5.6 Hz, 1H), 7.31-7.23 (m, 4H), 4.76 (m, 1H), 4.18 (m, 3H), 4.92-3.25 (m, 10H), 1.48 (m, 12H), 0.99 (m, 3H), 0.69 (m, 3H). MS (APCI+) [M+H]+ 561.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[OH-].[Na+].[CH2:29]([OH:32])[CH2:30][CH3:31]>>[N:21]1([NH:20][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=[C:2]([O:32][CH2:29][CH2:30][CH3:31])[N:3]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCO
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1nc(NN2CCCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 37 %

Procedure:
2-Chloro-N-(1-piperidinyl)adenosine (0.50 g, 1.3 mmol) (Example 5) was dissolved in a solution of sodium hydroxide (0.51 g, 1.3 mmol) in 1-propanol (15 ml), and the solution was heated at reflux for 4.5 hours, after which time TLC investigation showed that the starting material had been consumed. The reaction mixture was evaporated and the resultant residue was dissolved in water. The solution was neutralized with 4N aqueous hydrochloric acid and extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and evaporated to an oil which was triturated with diethyl ether to afford a fawn foam. This foam was purified by column chromatography on silica gel (2×20 cm); elution with a mixture of dichloromethane/ethanol 25% aqueous ammonia solution (60/10/1) provided the title compound (0.20 g, 37%) as a semi-solid foam; 1H NMR (400 MHz, Me2SO-d6) δ3.54, 3.65 (2H, ABX, H-5'a and H-5'b), 3.92 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.60 (1H, q, H-2'), 5.80 (1H, d, H-1'), 8.16 (1H, s, H-8).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][CH3:26])[C:10]([N:12]1[C:20]2[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:22]([OH:24])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(OCC)C>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:22]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:25][CH3:26])=[O:24]
Reactant: NCC(F)(F)F
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2cccc(Cl)c2C[C@H]1C(=O)O
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2cccc(Cl)c2CC1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-4-chloroindoline-2(S)-carboxylic acid (0.2 g, 0.52 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.142 g, 1.0 mmol) were dissolved in dried dichloromethane (10 ml) under nitrogen at 0° C., and triethylamine (0.44 ml, 3 mmol) was added followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.265 g, 1.0 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was columned on silica gel using 95:5 dichloromethane: diethyl ether as eluent to provide a white solid as the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:12][CH2:11][Br:10])=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Br)ccc1OCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A mixture of the product 2-amino-4-bromophenol (500 mg, 2.66 mmol), 1,2-dibromoethane (2.5 g, 13.3 mmol) and K2CO3 (1.84 g, 13.3 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to give 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 37%) as a yellow solid. LCMS: 294 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 3.79 (t, J=6.0 Hz, 2H), 4.25 (t, J=5.6 Hz, 2H), 5.06 (s, 2H), 6.63 (dd, J1=2.4 Hz, J2=8.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)NN
Product: COC(=O)NNC(=O)c1ccc(Cl)cc1
Yield: 81.5 %

Procedure:
36.0 g. (0.4 moles) of methyl carbazate and 70.0 g. (0.4 moles) of p-chloro-benzoyl chloride are reacted in an analogous manner to Example 2. Thus 74.5 g. of the desired compound are obtained, yield 81.5%, m.p.: 160° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4].[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16].CCN(CC)CC>C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[C:16][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1Br
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Temperature: 70 °C
Yield: 46.3 %

Procedure:
A mixture of 2-bromo-5-fluoro-4-nitroaniline (9.0 g, 38.4 mmol), 3,3-dimethyl-but-1-yne (9.95 g, 121 mmol), CuI (0.5 g 2.6 mmol), Pd(PPh3)2Cl2 (3.4 g, 4.86 mmol) and Et3N (14 mL, 6.9 mmol) in toluene (100 mL) and water (50 mL) was heated at 70° C. for 4 h. The aqueous layer was separated and the organic layer was washed with water (80 mL×2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was recrystallized with ether to afford 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline (4.2 g, 46%). 1H-NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=8.4 Hz, 1H), 6.84 (brs, 2H), 6.54 (d, J=14.4 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CO[C:12](=[O:19])[C@H:13]([C@H:15]([CH2:17][CH3:18])[CH3:16])[NH2:14].Cl>C1COCC1.C(OCC)C.O>[NH2:14][C@@H:13]([C@H:15]([CH3:16])[CH2:17][CH3:18])[C:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:19]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@@H](C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 4.5 %

Procedure:
A 1 M solution of phenylmagnesium bromide (49.0 g, 0.27 mol) in THF was added dropwise to (S)-isoleucine methyl ester hydrochloride (9.8 g, 54.0 mmol) at 0° C. and then stirred for 17 h at room temperature. The reaction mixture was cooled to 0° C., quenched with dropwise addition of saturated NH4Cl and then diluted with AcOEt and water until partition occurred. Organic products were extracted into AcOEt (3×50 ml), dried over MgSO4/K2CO3 and concentrated to obtain a crude product. The crude product was dissolved in diethyl ether (150 ml), treated with concentrated HCl until all of the amine was converted to its HCl salt. The amine-HCl salt was stirred overnight, diluted with water until partition occured. The non-basic organics were extracted into diethyl ether (5×100 ml) and then the aqueous layer was made basic with NaOH pellets. After stirring for 4 h, organic products were extracted into AcOEt (4×75 ml) and dried over MgSO4/K2CO3. Concentration gave a crude product (6.1 g, 42%) as a pale yellow solid. This contaminated with the amino ester derived from the starting material, however was used for the next step without further purification. A small amount of the crude product (1.1 g) was purified over silica gel by means of dry-flash column chromatography, eluting first with CH2Cl2, then with a mixture of AcOEt and petrol, increasing from 40% up to 80%. From this, a pure amino alcohol 13 (654 mg, 60%) was obtained as a white amorphous solid. m.p. 128–129° C. (lit 135–136° C.). [α]D25=−128.17° (c, 4.26 in CHCl3) (lit: −124.1° (c, 1.23 in CHCl3)). δH 0.72 (3H, t, J=7.2 Hz, CH3), 0.94 (3H, d, J=6.9 Hz, CH3), 0.80–1.10 (1H, m, CH2), 1.40–1.60 (1H, m, CH), 1.76–1.94 (1H, m, CH2), 0.60–2.10 (3H, OH and NH2), 3.85 (1H, d, J=1.5 Hz, CH—NH2), 7.10–7.70 (10H, m, Ar—H). δC 12.1 (CH3—CH2), 18.7 (CH3—CH), 22.5 (CH2), 34.8 (CH—Me), 60.9 (CH—NH2), 79.6 (C), 125.5, 125.9, 126.1, 126.5, 127.8, 128.2, 144.9, 147.9 (Ar). νmax (cm−1): 3343, 3279 (N—H and O—H), 3085, 3023 (Ar C—H), 2959, 2926, 2873 (methyl and methylene C—H), 1589, 1491, 1447 (Ar C═C). m/e 270 (MH+, 4%), 252 (20%), 86 (100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([OH:30])[C:16]([NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCO)(CCO)CCO.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([OH:30])[CH2:16][NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: OCCN(CCO)CCO
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)C[C@@H](NC[C@@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Yield: 67.5 %

Procedure:
(2S)-2-(4-Benzyloxyphenyl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (2.50 g) was dissolved in tetrahydrofuran (31 ml), and borane-dimethyl-sulfide complex (1.76 ml) was added to the solution. After the mixture was heated under reflux for 4 hours, a solution of triethanolamine (4.62 g) in tetrahydrofuran (4.6 ml) was added to the reaction mixture and the mixture was heated under reflux for 11 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: ethyl acetate/ethanol=7/1) gave (1S)-1-(4-benzyloxy-phenyl)-2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]ethanol (1.63 g) as an amorphous.
Reaction SMILES: [CH2:1]([NH:8][CH2:9]C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O:21][CH3:22])(=[O:20])/[CH:14]=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].C=O.[CH3:25]CN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][C@H:15]([C:16]([O:18][CH3:19])=[O:17])[C@H:14]([C:13]([O:21][CH3:22])=[O:20])[CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CNCc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OC
Yield: 34.6 %

Procedure:
A solution of N-benzylglycine (12.39 g, 75 mmol), dimethyl maleate (6.26 g, 50 mmol), paraformaldehyde (4.5 g, 150 mmol) and DIEA (8.7 mL, 50 mmol) in toluene (100 mL) was stirred at reflux for 2 hours and concentrated. The residue was taken up in EtOAc. The solution was washed with brine 3×, dried (MgSO4) and concentrated. Column chromatography eluting with 50% EtOAc/hexanes provided dimethyl cis-1-benzyl-3,4-pyrrolidinedicarboxylate (4.8 g, 34%). MS (M+H)+=278.5.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:9](=[N:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: NCc1cccnc1
Solvent: ClCCl
Product: c1ccc(C(=NCc2cccnc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.7 ml of 3-(aminomethyl)pyridine are added to a solution of 2.8 ml of benzophenoneimine in 50 ml of DCM, and the mixture is stirred overnight at RT. A further 0.28 ml of benzophenoneimine is added and the mixture is stirred for 2 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 4.56 g of the expected product are obtained.