Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:16]([N+:21]([O-])=O)[CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.ClCCl.[Ni](Cl)Cl>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:16]([NH2:21])[CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Yield: 89.8 %

Procedure:
Sodium borohydride (29.0 g, 0.767 mol) was added in small portions to a solution of nickel(II)chloride (22.8 g, 0.096 mol) in methanol (1.25 L). A solution of (7-benzyloxy-3-nitroquinolin-4-yl)-(2-methylpropyl)amine (67.4 g, 0.192 mol) in methanol (300 mL) and dichloromethane (300 mL) was added to the resulting mixture. A precipitate was present and was dissolved by the addition of dichloromethane (500 mL). Additional sodium borohydride (˜10 g) was added in small portions until the (7-benzyloxy-3-nitroquinolin-4-yl)-(2-methylpropyl)amine was consumed. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with 50:50 dichloromethane:methanol. The filtrate was concentrated under reduced pressure, and the black, oily residue was treated with water and dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was treated with activated charcoal, filtered, and concentrated under reduced pressure to yield 55.4 g of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine as an oily brown solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[OH:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[OH:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)NCCO)cc2)OC1(C)C
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Yield: 20.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (500 mg, 1.5 mmol) was reacted with N-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (450 mg, 1.5 mmol) to afford the desired product (130 mg, 20%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.78-7.74 (m, 2H), 7.58-7.42 (m, 4H), 5.74 (d, J=5.4 Hz, 1H), 4.78 (t, J=5.6 Hz, 1H), 3.71 (s, 3H), 3.45 (q, J=6.1 Hz, 2H), 2.93 (q, J=6.2 Hz, 2H).
Reaction SMILES: [H-].[Na+].C1(C(C2C=CC=CC=2)=[N:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])C=CC=CC=1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][N:25]=1.Cl>CN(C)C=O>[Cl:30][C:29]1[C:24]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:10])=[N:25][CH:26]=[C:27]([Cl:31])[CH:28]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(N)c1ncc(Cl)cc1Cl
Reaction time: 0.33 h

Procedure:
To a stirred solution of sodium hydride (0.445 g) in dry dimethylformamide (4 ml) at 0° C. was added ethyl N-(diphenylmethylene)glycinate (1.485 g) in dry dimethylformamide (3 ml) and stirring was continued for 20 minutes. 2,3,5-Trichloropyridine (1.58 g) in dry dimethylformamide (4 ml) was then added dropwise over 10 mins at 5° C. and the reaction mixture was stirred for 2 hours at room temperature. 2M hydrochloric acid (25 ml) was added and stirring continued for 2 hours. The solution was washed with diethyl ether and the layers were separated. The aqueous phase was neutralised with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine (×2), dried (MgSO4), filtered and the solvent removed to leave a residue which was purified by silica gel chromatography eluting with ethyl acetate/light petroleum (40-60° C.) to give the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.CS(C)=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](O)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[N:7][CH:6]=1
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(-c2ncc(Cl)cn2)c([N+](=O)[O-])c1

Procedure:
1.43 g of 2,5-dichloropyrimidine was dissolved in 20 mol of dimethyl sulfoxide. To this solution, a mixture of 1.50 g of 4-amino-2-nitrophenol and 5 ml of water, and 2.69 g of potassium carbonate were added, and the mixture was reacted in the atmosphere of nitrogen gas at a temperature of from 100° to 110° C. for 2 hours. After the completion of the reaction, the reaction product was poured into water, and extracted with methylene chloride. The extract layer was washed with brine and dried over anhydrous sodium sulfate, and purified by silica gel column chromatography, whereby 0.74 g of 4-(5-chloro-2-pyrimidinyl)-3-nitroaniline having a melting point of from 151° to 152° C., was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:15]/[OH:16])/[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:6]=1.Br[C:18]([CH3:29])([CH3:28])[C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:15][O:16][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])([CH3:29])[CH3:28])[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)/C(=N\O)c1csc(N)n1
Reactant: CC(C)(Br)C(=O)OCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(=NOC(C)(C)C(=O)OCC[Si](C)(C)C)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
24.9 g (102 mmol) of t-butyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate are dissolved in 400 ml of dimethylformamide. After the addition of 54.7 g (205 mmol) of 2-(trimethylsilyl)ethyl 2-bromo-2-methylpropionate, followed by 56.6 g (410 mmol) of finely ground potassium carbonate, the mixture is stirred at 25° C. for 4 hours in a nitrogen atmosphere. After the addition of 3 l of water, the mixture is extracted with 1.5 l of ethyl acetate. The organic phase is washed twice with 1.5 l of water. The aqueous phase is extracted with 1.5 l of ethyl acetate. The combined ethyl acetate solutions are dried over sodium sulphate and evaporated to dryness. The product is purified by flash chromatography on silica gel [hexane/ethyl acetate (2:1)] and crystallized from methanol/water. There are obtained 28.6 g (65.3%) of t-butyl 2-(2-amino-4-thiazolyl)-2-[(1-(2-(trimethylsilyl)ethoxycarbonyl)-1-methylethoxy]imino]-acetate of melting point 83° C.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([O:6][CH2:7][C@H:8]2[O:12][C@@H:11]([N:13]3[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]3=[O:15])[CH2:10][C@@H:9]2[OH:22])[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.[Si:29](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CN=C1>CN(C=O)C>[Si:29]([O:22][C@@H:9]1[C@@H:8]([CH2:7][O:6][N:5]2[C:4](=[O:23])[C:3]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]3[C:1]2=[O:28])[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A mixture of 5'-O-phthalimidothymidine (8.54 g, 22 mmol), t-butyldiphenylsilylchloride (6.9 ml, 26.5 mmol), imidazole (3.9 g, 57.3 mmol) and dry DMF (130 ml) was stirred at room temperature for 16 h under argon. The reaction mixture was poured into ice-water (600 ml) and the solution was extracted with CH2Cl2 (2×400 ml). The organic layer was washed with water (2×250 ml) and dried (MgSO4). The CH2Cl2 layer was concentrated to furnish a gummy residue which on purification by silica gel chromatography (eluted with EtOAc:Hexanes; 1:1, v/v) furnished 12.65 g (92%) of 3'-O-(t-butyldiphenylsilyl)-5'-O-phthalimidothymidine as crystalline material (mp 172°-173.5° C.). 1H NMR (DMSO-d6) δ 11.31 (s, 1, NH), 7.83 (m, 4, ArH), 7.59 (m, 4, TBDPhH), 7.51 (s, 1, C6H), 7.37-7.45 (m, 6, TBDPhH), 6.30 (dd, 1, H1', J1', 2' =8.8 Hz, J1',2" =5.6 Hz), 4.55 (m, 1, H4'), 4.15 (m, 1, H3'), 3.94-4.04 (m, 2, H5',5"), 2.06-2.13 (m, 2, H2',2"), 1.97 (s, 3, CH3), 1.03 (s, 9, C(CH3)3).
Reaction SMILES: C[O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([CH:20]([CH3:22])[CH3:21])[CH:11]=[C:12]([CH:17]([CH3:19])[CH3:18])[CH:13]=2)[N:8]=[CH:7]1.Cl>O>[CH:17]([C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([CH:20]([CH3:22])[CH3:21])[CH:11]=1)[N:8]=[CH:7][N:6](/[CH:5]=[CH:4]/[C:3]([OH:23])=[O:2])[C:15]2=[O:16])([CH3:18])[CH3:19]
Reactant: COC(=O)/C=C/n1cnc2c(C(C)C)cc(C(C)C)cc2c1=O
Agent: Cl
Solvent: O
Product: CC(C)c1cc(C(C)C)c2ncn(/C=C/C(=O)O)c(=O)c2c1
Temperature: 25 °C

Procedure:
A mixture of 1.15 g. of trans-3-(6,8-diisopropyl-4-oxo-4H-quinazolin-3-yl)-2-propenoic acid methyl ester and 50 ml. of 6 N hydrochloric acid was stirred and refluxed for 20 minutes. After cooling to room temperature, 100 ml. of water was added and the reaction mixture was cooled and filtered to yield 0.60 g, mp 181°-182° of pure trans-3-(6,8-diisopropyl-4-oxo-4H-quinazolin-3-yl)-2-propenoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23](=[O:25])[NH2:24])=O)(C)(C)C.O1CCOCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:23]([C@@H:9]1[CH2:10][C@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][NH:8]1)(=[O:25])[NH2:24]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
1.92 g of (2S, 4S)-1-(t-butoxycarbonyl)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (4) above] was dissolved in 25 ml of ethyl acetate, and 26.2 ml of a 4N dioxane solution of hydrogen chloride were added to the solution, whilst ice-cooling. The mixture was then stirred at 0° to 5° C. for 2 hours and at room temperature for 30 minutes. At the end of this time, it was poured into a saturated aqueous solution of sodium bicarbonate, to make it weakly basic, and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.36 g of the title compound as a powder, melting at 120°-121° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Product: c1cc(CN2CCCCC2)cc(OCCCNc2ccnc3ccccc23)c1
Temperature: 155 °C
Reaction time: 2 h

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (13.51 g) and 4-chloroquinoline (4.45 g) were heated with stirring at 155° C. for 21/2 hours. The cooled reaction mixture was dissolved in 2 Normal hydrochloric acid to pH 3-4 and the acidic solution was extracted with ethyl acetate. The aqueous solution was then basified to pH greater than 9 and was extracted with chloroform several times. The combined chloroform extracts were dried and evaporated to dryness to give the title compound as an oil. This was treated with maleic acid in ethanol to afford 4-[3-[3-(piperidinomethyl)phenoxy] propylamino]quinoline dimaleate (8.9 g), m.p. 127°-127.5° C. (recrystallised from isopropanol).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][S:27]([CH:24]5[CH2:26][CH2:25]5)(=[O:29])=[O:28])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Reactant: O=S(=O)(Cl)C1CC1
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4NS(=O)(=O)C3CC3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 4, reaction of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with cyclopropanesulfonyl chloride gave the title compound as colorless solid. MS: 412.5 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1>CC(O)C>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1cccc(N)c1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Cl)ncc1Cl
Solvent: CC(C)O
Product: CC(=O)c1cccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)c1
Temperature: 150 °C
Yield: 60.1 %

Procedure:
A solution of 2-(2-(2-(2,5-dichloropyrimidin-4-yl) ethyl)phenyl)acetamide (A139) (0.158 g, 0.509 mmol) in 2-propanol (2 mL) containing 1-(3-aminophenyl)ethanone (0.138 g, 1.01 mmol) was heated under microwave irradiation at 150° C. for 2 hours. The reaction mixture was adsorbed onto silica gel and the product was purified using silica gel column chromatography (CombiFlash Rf, 12 g SiO2 Cartridge, 10-65% EtOAc in cyclohexane) to give the title compound (A141) as a white solid (0.125 g, 60%). LCMS-B: rt 6.804 min; m/z 409 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:12]=1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[NH2:13][C:11]1[CH:12]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:23])[CH3:1])[CH:8]=[CH:9][C:10]=1[O:21][CH3:22]
Reactant: COc1ccc(NC(=O)CN(C)C)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(NC(=O)CN(C)C)cc1N
Yield: 95.5 %

Procedure:
A solution of 1,1-dimethylethyl [5-[(N,N-dimethylglycyl)amino]-2-(methyloxy)phenyl]carbamate (0.44 g, 1.36 mmol) and trifluoroacetic acid (1.55 g, 13.6 mmol, Aldrich) in dichloromethane (50 mL) was stirred overnight at room temperature. The crude reaction was diluted with dichloromethane (100 mL), washed with saturated NaHCO3 (100 mL), evaporated under reduced pressure, and dried under high vacuum to provide N1-[3-amino-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide (0.29 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (s, 6H) 2.99 (s, 2 H) 3.80 (s, 3 H) 5.29 (s, 2 H) 6.68-6.74 (m, 1 H) 7.03 (d, J=8.61 Hz, 1H) 7.22 (d, J=2.38 Hz, 1 H) 9.49 (s, 1 H). ESIMS (M+H)+=224.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23]([OH:25])=O)[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][C:30]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)([OH:33])[CH2:29][CH2:28]1>>[OH:33][C:30]1([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)[CH2:31][CH2:32][CH:27]([NH:26][C:23]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[C:14]([O:13][CH2:12][C:9]2[C:8]4[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=4[O:11][CH:10]=2)[CH:22]=[CH:21][CH:20]=3)=[O:25])[CH2:28][CH2:29]1
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 122) and amine 14.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH:22][CH2:35][C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1NCc1ccc2ccccc2c1
Yield: 79.8 %

Procedure:
The (2S)-(2-Amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (0.400 g, 0.972 mmol) was made according to the procedure for Example 282 and this was subjected to reductive amination with naphthalene-2-carbaldehyde (0.227 g, 1.45 mmol) and sodium triacetoxyborohydride (0.515 g, 2.43 mmol) as per general procedure E to yield the 3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (0.428 g, 80%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32](OC(F)(F)F)=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:40]C1C=C(B(O)O)C=CC=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:40])[CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2cccc(Cl)c2)CC1

Procedure:
(R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(3-chlorophenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one was synthesized as per (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 220) in 69% yield using 3-chlorophenylboronic acid as the reagent.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)(C)C>[CH2:11]([S:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][N:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Sc1nnc(S)s1
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCCCSc1nnc(SCCCCCC)s1
Yield: 70 %

Procedure:
2,5-bis(n-hexylthio)-1,3,4-thiadiazole was prepared in over 70% yield by reaction of 50 g. (0.32 mole) commercial 2,5-dimercapto-1,3,4-thiadiazole with 26.4 g (0.66 mole) sodium hydroxide in 400 ml refluxing isopropanol followed by the addition of 110 g (0.66 mole) 1-bromohexane. After removal of the solid precipitate (sodium bromide), 71.7 g of product was isolated by vacuum stripping. The product was used without further purification.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([CH3:11])[C@H:8]([CH2:12][N:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:7]1)(=O)=O.[C:19]([O-:22])(=[S:21])[CH3:20].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[C:19]([S:21][C@@H:6]1[CH2:10][N:9]([CH3:11])[C@H:8]([CH2:12][N:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:7]1)(=[O:22])[CH3:20]
Reactant: CC([O-])=S
Reactant: CN1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCNC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(=O)S[C@H]1C[C@@H](CN2CCNC2=O)N(C)C1
Yield: 79.3 %

Procedure:
A solution of (2S,4R)-4-methanesulfonyloxy-1-methyl-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (2.50 g) and tetra-n-butylammonium thioacetate (4.16 g) in acetonitrile (70 ml) was stirred at 50°-60° C. for 4 hours. The reaction mixture was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (200 g) eluting with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-methyl-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.84 g).
Reaction SMILES: Cl.[F:2][C:3]([F:35])([F:34])[C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:7][O:8][CH2:9][CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:11][NH:12][C:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:35][C:3]([F:34])([F:2])[C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=1)[CH2:7][O:8][CH2:9][CH:10]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:11][NH:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][CH2:16]1)=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(C(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.7 %

Procedure:
A mixture of Compound 4 produced in Example 32 (1.26 g, 2.4 mmol), tert-butyl bromoacetate (0.38 mL, 2.6 mmol), potassium carbonate (1.00 g, 7.2 mmol) and DMF (10 mL) was stirred for 20 hours at room temperature. Water was added to the reaction mixture followed by extracting with ethyl acetate. The organic layers were combined, washed with water and a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was evaporated therefrom in vacuo to give Compound 79 (1.34 g, 93%).
Reaction SMILES: O=[C:2]1[O:7][CH:6]=[C:5]([C:8]([O:10]C)=[O:9])[CH:4]=[CH:3]1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH2:19])[CH2:14]1.CO.[Li+].[OH-]>C1COCC1>[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:2](=[O:7])[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6]2)[CH2:14]1
Reactant: COC(=O)c1ccc(=O)oc1
Reactant: CC1CCCC(N)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCCC(n2cc(C(=O)O)ccc2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A solution of methyl 6-oxo-6H-pyran-3-carboxylate (620 mg, 4.0 mmol, Aldrich) and 3-methylcyclohexanamine (900 mg, 8.0 mmol, Pfaltz and Bauer) was heated in the Emry's optimizer microwave at 150° C. for 15 min. The resulting solution was transferred to a 50 mL round bottom flask with THF, then diluted with THF:MeOH to give approximately 40 mL of a 3:1 THF:MeOH solution. Add 1 M LiOH (6 mL, 6 mmol) and stir at RT overnight. The solution was concentrated in vacuo and the residue taken up in H2O. The aqueous solution was extracted with ether (30 mL). 2 N HCl was added to acidify the aqueous solution to pH 2. The aqueous solution was extracted with EtOAc (3×) and the combined EtOAc layers dried over MgSO4, and concentrated in vacuo to give 200 mg (21%) of the desired product as a light brown residue. MS m/z: 612.5(M+1).