Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine (Aldrich) (1.45 g, 8.90 mmol), 4-methoxybenzylamine (Alfa Aesar) (1.278 mL, 9.78 mmol), and triethylamine (1.488 mL, 10.67 mmol) in DMF (10.0 mL) was stirred at 25° C. for 18 h. The resulting mixture was partitioned between EtOAc (300 mL) and half-saturated aqueous NaHCO3 (80 mL). The organic layer was separated, sequentially washed with water (2×80 mL) and brine (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 120 g, 0 to 100% EtOAc/Hexanes) furnished 6-chloro-N-(4-methoxybenzyl)-2-methylpyrimidin-4-amine (2.30 g, 8.72 mmol, 98% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.41 Hz, 2H); 6.89 (d, J=8.61 Hz, 2H); 6.18 (s, 1H); 4.42 (br. s., 2H); 3.81 (s, 3H); 2.50 (s, 3H). m/z (ESI, +ve ion) 264.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2-:11].[Na+].[OH-].[Na+]>CN(C=O)C>[C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: c1cc2c(cn1)CCCC2
Reactant: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1nccc2c1CCCC2
Temperature: 170 °C
Yield: 46.7 %

Procedure:
To a solution of 5,6,7,8-tetrahydroisoquinoline (5.0 g, 37.6 mmol) in DMF (8 mL) was added sodium amide (2.55 g, 63.9 mmol). The resulting mixture was heated to 170° C. for 16 h and cooled to room temperature. To the mixture was added aqueous 2 N NaOH (50 mL). The mixture was extracted with DCM (100 mL×3), and the combined organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 10:1) to give 5,6,7,8-tetrahydroisoquinolin-1-amine as a yellow solid (2.6 g, yield 46%). ESI MS: m/z 149 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J=5.2 Hz, 1H), 6.44 (d, J=5.2 Hz, 1H), 4.34 (br, 2H), 2.67 (t, J=12 Hz, 2H), 2.39 (t, J=12 Hz, 2H), 1.88 (m, 2H), 1.78 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](Cl)([Cl:16])=[O:15].CN(C)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:16][C:14]([O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[O:15]
Reactant: O=C(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,6-Diisopropylphenol (8.9 g; 0.05 mole) was dissolved in 35 mL benzene and cooled to -3° C. after which liquid phosgene (7.0 mL condensed at -70° C.) was added dropwise maintaining a temperature range of 0° to 3° C. N,N-dimethylaniline (6.0 g; 12.2 m mole) was added dropwise and stirred at 0° C. for 15 minutes. The yellow green suspension was quenched with 5 mL water and the layers were separated. The organic portion was washed with HCl (1N, 5 mL), saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated to dryness to give a green liquid which was distilled affording 2,6-diisopropylphenyl chloroformate as a yellow liquid. ##STR13##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1]
Reactant: BrCCCBr
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCBr)c(C)c1

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), K2CO3 (17.5 g, 144 mmol), and 1,3-dibromopropane (30 g, 144 mmol) in acetonitrile (400 ml) was heated at reflux for 6 hours. At the end of the reaction, the solvent was removed on a rotary evaporator, and the crude solid was extracted into dichloromethane (750 ml). The insoluble inorganics were filtered off. The dichloromethane solution was concentrated again to a crude oil (34.5 g). Purification was effected by flash chromatography over a silica gel column (SiO2, 150 g; eluted with 7:3 hexane:dichloromethane, 2 l; and dichloromethane 2 l). The material thus purified weighed 14.6 g (56%) and was recrystallized from ethanol. Recrystallization again from ethanol gave analytically pure 1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone, m.p.=59°-61° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) (0.72 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one (Compound 10), as a white solid (60% yield).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])[CH:2]=[CH2:3].ClC1C=C(C(OO)=[O:19])C=CC=1.S(=O)(O)[O-]>C(Cl)Cl>[O:19]1[CH2:3][CH:2]1[CH2:1][N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10]
Reactant: C=CCN1CC(=O)NC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Solvent: ClCCl
Product: O=C1CN(CC2CO2)C(=O)N1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A reaction solution of 1-(2-propenyl)-2,4-imidazolidinedione (0.036 mol) and 3-chloro-benzenecarboperoxoic acid (0.043 mol, 70.75%) in DCM (25 ml) was stirred for 2 hours at room temperature. An aqueous solution of bisulfite was added (to remove excess 3-chlorobenzenecarboperoxoic acid) and the mixture was stirred for 10 minutes. Na2CO3 was added and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent evaporated, yielding 5 g (89%) of (±)-1-(oxiranylmethyl)-2,4-imidazolidinedione (interm. 1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].CN(C)C=O.[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[Cl:11][CH2:10][CH2:9][CH2:8][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.7 %

Procedure:
A suspension of potassium carbonate (48.4 g) in a mixture of methyl 4-hydroxybenzoate (10.65 g), 1-bromo-3-chloropropane (55.1 g) and N,N-dimethylformamide (100 mL) is stirred at room temperature for 15 h. Solids are separated by filtration and washed three times with ethanol (30 mL). The combined filtrates are concentrated under reduced pressure, and then dissolved in ethyl acetate (200 mL). The organic layer is washed twice with water (50 mL), dried over magnesium sulphate and concentrated under reduced pressure to give 15 g of methyl 4-(3-chloropropoxy)benzoate used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].CCN(CC)CC>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a mixture of tert-butyl 4-amino-3-methylphenylacetate (1.88 g, 8.51 mmol), 2,6-dichlorophenyl isocyanate (1.60 g, 8.51 mmol) in THF (40 ml) was added Et3N (0.24 ml, 1.70 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methylphenylacetate (2.58 g, 74%) as a colorless powder. mp 243-244° C. (dec.); 1H-NMR (CDCl3) δ1.45 (s, 9H), 2.30 (s, 3H), 3.49 (s, 2H), 6.24 (s, 2H), 7.12-7.16 (m, 3H), 7.35 (d, J=8.3 Hz, 2H), 7.51 (d, J 7.8H, 1H).
Reaction SMILES: CO.[H-].[Na+].[C:5]([O:12][CH3:13])(=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=1[CH2:25]Br>CCOCC>[CH3:10][O:9][C:7]([C:6]1([C:5]([O:12][CH3:13])=[O:11])[CH2:25][C:17]2[C:16](=[CH:21][CH:20]=[CH:19][C:18]=2[N+:22]([O-:24])=[O:23])[CH2:15]1)=[O:8]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cccc(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
To a solution stirred under nitrogen at room temperature, to 5.0 mL methanol in 15.0 mL ether was added 60% sodium hydride (0.84 g, 0.021 mol) in small portions. After the addition was complete, the nearly clear and colorless solution was stirred for 5 minutes. To it was then added 1.3 g dimethyl malonate, giving a slightly cloudy colorless solution. To this was rapidly added a suspension of 3.1 g 1,2-bis(bromomethyl)3-nitrobenzene, which immediate gave a precipitate suspended in a dark green solution. This was removed by filtation and the filtrate was concentrated. The residue was purified on silica (20%-100% CH2Cl2 in hexanes) to give 1.93 g off-white solid (67%).
Reaction SMILES: [CH2:1]([CH:17]1[CH2:22][C:21](=[O:23])[O:20][C:18]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][NH2:44])=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25].C1(C)C=CC=CC=1>O>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][N:44]2[C:21](=[O:23])[CH2:22][CH:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]2=[O:20])=[O:42])[CH:29]=[C:28]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:33]=1[OH:34])([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
2-Hexadecylsuccinic anhydride (10.5 g, 31.3 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (9.2 g, 31.3 mmol) and 10 ml of toluene were combined and refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water. Solvent was then removed under vacuum as the mixture was warmed to about 130° C. After 20 minutes, the reaction mixture was cooled and the vacuum was removed. The resulting viscous yellow mass was further chilled in an acetone/dry ice bath causing the mass to harden for facile removal from the reaction vessel. About 19 g of a viscous yellow gum was obtained that solidified to a translucent white solid upon standing for several days at room temperature.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH2:13][C@H:14]([C:23](O)=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>O>[NH2:13][C@H:14]([C:23]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
Yield 175 mg, [α]D21 -17.4° (c=0.5, H2O); amino acid analysis (acid hydrolysis): Arg 1.00(1), Tyr 0.94(1); average recovery 86.5%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.12 g, 4.66 mol) in CH2Cl2 (10 ml), triethylamine (3.88 ml) and methanesulfonyl chloride (1.08 ml, 14 mmol) are added at 0° C. The reaction mixture is stirred for overnight, quenched with ice-water and extracted with dichloromethane. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give crude 8-methane sulfonyl-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.32 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[S:22][C:21]([S:23]([NH:1][C@H:2]([CH2:3][OH:4])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 45.2 %

Procedure:
To a reaction vessel was added a mixture of 3-pentanone (6.4 g), triethyl phosphonoacetate (34 g), NaH (3.6 g), and enough dry THF (250 mL), at 0° C. and maintained for 8 h to obtain α,β-unsaturated ester (ethyl 3-ethylpent-2-enoate) (2) (93%). This was followed by passing hydrogen gas (1 atm) over 10% Pd/C (250 mg), in MeOH (100 mL), for about 12 h at 25° C. To the reaction mixture was further added LiAlH4 (1.8 g), and dry THF (100 mL), at 0° C. for 12 h to obtain alcohol (3-ethylpentan-1-ol) (3) (83% for two steps). Alcohol (3) (6 g), was reacted with (o-iodoxy benzoic acid) (21.6 g), in dry DMSO (65 mL), at 25° C. for 2 h to yield aldehyde (3-ethylpentanal) (4). This is followed by addition of PhNO (nitrosobenzene)(5 g), L-proline (20 mol %)(1.3 g), in acetonitrile (250 mL), at −20° C. for 24 h and then added NaBH4 (7 g), in MeOH (100 mL). To the mixture is passed H2 gas (1 atm) over 10% Pd/C (250 mg), in MeOH (100 mL), for 12 h at 25° C., (77% over two steps) to obtain diol (3-ethylpentane-1,2-diol) (5). Then tert-butyl silylchloride (TBSCl) (7.5 g), in imidazole (4.5 g), and methylene chloride (200 mL), is added to the diol (5) at 0-25° C. (addition at 0° C. stirring at 25° C.) for 2 h to obtain (3-ethyl-2-hydroxy-pent-1-yloxy(tert-butyl)dimethylsilane) (6) (81%) followed by treatment with mesyl chloride (7.7 g), in triethyl amine (20 mL), for 45 min to yield (7). To the protected diol (3-ethyl-2-methansolphonyl-pent-1-yloxy(tert-butyl)dimethylsilane) (7) was added NaN3 (4 g), in dry DMF (100 mL), at 60° C. for 30 h, (78% for two steps) to obtain compound (2-azido-3-ethylpentyloxy tet-butyl dimethylsilane) (8). To the compound (8) was added LiAlH4 (2 g), in dry THF (100 mL), at 50° C. for 12 h to afford (S)-2-amino 3ethyl pentan-1-ol (9)(75%). A mixture of (S)-2-amino 3ethyl pentan-1-ol (9) (200 mg) and methylene chloride (20 mL) was placed under argon, and cooled to 0° C. Triethyl amine (484 mg) was added followed by the drop wise addition of 5-chlorothiophene-2-sulfonyl chloride (347.2) in methylene chloride (5 mL) for 30 min to obtain (S)—N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol (1A) (45.2% overall yield and 98% ee).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[NH:8][C:7]=1[CH3:14])=[O:5])C.[OH-].[K+].O>CO>[CH:12]([C:9]1[NH:8][C:7]([CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 8 °C
Yield: 93.5 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (806 g), potassium hydroxide (548 g), water (2400 mL) and methanol (300 mL) were refluxed for two hours with stirring and then cooled to 8° C. The mixture was extracted twice with dichloromethane. The aqueous layer was adjusted to pH 4 with 1000 mL of 10 N hydrochloric acid keeping the temperature under 15° C. Water was added to facilitate stirring. The solid was collected by vacuum filtration, washed three times with water and dried under vacuum at 50° C. to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic (645 g, 93.5% yield) acid as a yellow solid. NMR (DMSO-d6) δ2.40, 2.43 (2×s, 2×3H, 2×CH3), 9.57 (s, 1H, CHO), 12.07 (br s, 2H, NH+COOH). MS m/z 168 [M+1].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].Cl.N(CC)(CC)CC>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CCCCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCCCc1ccccc1

Procedure:
5-Phenylvaleric acid (2.67 g, 15 mmol) in distilled THF was reacted with CDI (15 mmol) followed by glycine ethyl ester.HCl (15 mmol) and (C2H5)3N (15 mmol) as described in Example 35 Part A. The crude material (3.25 g, 82%) was used without purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].O>O1CCOCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)c(F)cc2s1
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 5-bromo-6-fluoro-benzothiazol-2-ylamine (0.36 g, 1.45 mmol) in 1,4-dioxane (25.0 mL) was added ethyl isocyanate (0.69 mL, 8.74 mmol) and the resulting reaction mixture was heated at 80° C. for 15 h. After the completion of the reaction (TLC monitoring) the solvent was evaporated. The residue thus obtained was stirred with water at 60° C. for 5 h. The solution was then filtered and washed with ether to get the title compound (0.30 g, 69%). 1H-NMR (400 MHz, DMSO-d6): δ 1.08 (t, J=6.80 Hz, 3H), 3.17 (m, 2H), 6.69 (br s, 1H), 7.92 (d, J=6.40 Hz, 1H), 8.0 (d, J=8.40 Hz, 1H) and 10.86 (br s, 1H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:28])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:28])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
A mixture of 50 g of p-(tetradecyloxy)benzoic acid and 28.46 g of oxalyl chloride in 500 ml of chloroform containing 10 drops of N,N-dimethylformamide is stirred for 18 hours at ambient temperature. The solvent is evaporated and the residue dissolved in ether, filtered and evaporated to give 54 g of the desired product as a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12](C(C(O)=O)=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16]2)=[CH:11][CH:10]=1>ClCl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:1]([C:2]([Cl:4])=[O:3])=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(C(=O)O)cc(-c3ccccc3)nc2c1
Agent: ClCl
Product: COc1ccc2c(C(=O)Cl)cc(-c3ccccc3)nc2c1
Temperature: -10 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
2.8 ml (32.3 mmol) of oxalyl chloride were dissolved in 60 ml of CH2 Cl2. The solution was cooled at -10° C. and 6 g (19.0 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 7 g of the title compound, used without further purification.
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([NH2:71])[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:64])[CH3:63])=[O:58])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[C:73]1([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH:78]=[CH:77][C:76]([CH:79]2[CH2:83][CH:82](OC)O[CH:80]2OC)=[CH:75][CH:74]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([N:71]1[CH:82]=[CH:83][C:79]([C:76]2[CH:77]=[CH:78][C:73]([C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)=[CH:74][CH:75]=2)=[CH:80]1)[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:63])[CH3:64])=[O:58])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3(R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid.