Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41]([N:45]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]([NH:52]C(=O)OC(C)(C)C)[C:46]1=[O:60])[CH:42]([CH3:44])[CH3:43]>>[CH2:34]([C@H:14]([CH2:13][CH2:12][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:52][C@H:47]1[CH2:48][CH2:49][CH2:50][CH2:51][N:45]([CH2:41][CH:42]([CH3:43])[CH3:44])[C:46]1=[O:60])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][CH:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: CC(C)CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Product: COC(=O)[C@@H]1CCCC2SCC[C@H](NC(=O)[C@@H](CC[C@@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(CC(C)C)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S)-Methyl 4-((2S,5S)-2,5-dibenzyl-6-((S)-1-isobutyl-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (40 mg, 0.070 mmol) and Intermediate 80 (26 mg, 0.088 mmol) to give a white solid (40 mg, 77% yield). Anal. Calcd. for C41H56N4O6S m/z 732.4. found: 733.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (d, J=7.3 Hz, 2H), 7.67 (d, J=6.8 Hz, 1H), 7.18 (m, 10H), 6.96 (m, 1H), 6.48 (m, 1H), 5.62 (m, 1H), 5.15 (m, 1H), 5.02 (m, 1H), 4.45 (m, 1H), 3.75 (m, 1H), 3.57 (s, 3H), 3.49 (m, 2H), 3.20-3.00 (m, 2H), 2.79 (m, 3H), 2.63 (m, 4H), 2.80-2.57 (m, 4H), 1.82-1.59 (m, 13H), 1.26 (m, 1H), 0.81 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.O=[C:13]1[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][C:21]#[N:22])[CH2:15][CH2:14]1>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH:13]2[CH2:18][CH2:17][N:16]([C@H:19]([CH3:23])[CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: COC(=O)c1ccc(NC2CCN([C@H](C)CCN)CC2)cc1

Procedure:
Using general procedure A with methyl 4-aminobenzoate (507 mg, 3.35 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (669 mg, 4.03 mmol) followed by general procedure J afforded 4-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-benzoic acid methyl ester as a white foam (390 mg, 38% over 2 steps).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:21][C:20]3[CH:19]=[C:18]([CH2:22][CH2:23][CH2:24][OH:25])[C:17]([OH:26])=[CH:16][C:15]=3[CH:14]3[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.CNC1C=CC=C(NC)N=1>O.C(OCC)(=O)C.C(Cl)Cl>[CH3:27][S:28]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:21][C:20]3[CH:19]=[C:18]([CH2:22][CH2:23][CH2:24][O:25][S:28]([CH3:27])(=[O:30])=[O:29])[C:17]([O:26][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:16][C:15]=3[CH:14]3[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1)(=[O:30])=[O:29]
Reactant: OCCCc1cc2c(cc1O)C1CCCCC1C(c1ccc(O)cc1)C2
Reactant: CS(=O)(=O)Cl
Agent: CNc1cccc(NC)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCCc1cc2c(cc1OS(C)(=O)=O)C1CCCCC1C(c1ccc(OS(C)(=O)=O)cc1)C2

Procedure:
Combine 9-(4-Hydroxy-phenyl)-2-(3-hydroxy-propyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-3-ol (0.1 g, 0.284 mmol), methanesulfonyl chloride (0.11 g, 0.94 mmol), triethylamine (0.19 g, 1.9 mmol), 2,6-dimethylaminopyridine (0.02 g, cat.) and methylene chloride (5 ml) and stir 15 hours. Remove solvent in vacuo and add ethyl acetate and water. Wash 1× with sodium bicarbonate solution solution followed by water. Dry over anhydrous sodium sulfate and remove solvent in vacuo to yield preparation 133 (0.16 g, g, 96%). 1H NMR (CDCl3): 7.34 (d, J=8.8 Hz, 2H), 7.28 (d, J=8 Hz, 2H), 7.26 (s, 1H), 7.09 (s, 1H), 4.28 (t, J=7.1 and 6.2 Hz, 2H), 3.24 (m, 6H), 3.16 (s, 3H), 3.03 (s, 3H), 2.9 (d, J=11.9 Hz, 1H), 2.82 (t, J=7.5 and 8.4 Hz, 3H), 2.45 (d, J=13.7 Hz, 1H), 2.1 (m, 3H), 1.8-1.0 (m, 6H).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:32][CH3:33])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1)[CH3:21].C(OCC)(=O)C.N>ClCCl.C(OCC)(=O)C.C1CCCCC1.CO>[CH2:32]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:33]
Reactant: CCN(CC)CCCC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: N
Solvent: CO
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCN(CC)CCCC1CCCCN1C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 70 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-(diethylamino)propyl]piperidine in a yield of 70% of theory. Colourless crystals, m.p. 125°-128° C. (ethyl acetate), Rf 0.15 (MachereyNagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 58/25/8/8/1, v/v/v/v/v)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH2:13][CH2:12]1)(=O)[NH2:8].[F-].[Na+].O>O1CCCC1>[NH2:8][CH2:7][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH2:13][CH2:12]1
Reactant: NC(=O)CN1CCn2nccc21
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCn2nccc21
Yield: 74 %

Procedure:
To a suspension of lithium aluminum hydride (2.84 g) in tetrahydrofuran (70 ml) was added dropwise a solution of 1-carbamoylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (6.2 g) in tetrahydrofuran (30 ml) at room temperature. The mixture was refluxed for 4 hours and cooled with ice-bath. Sodium fluoride (12.5 g) and water (4 ml) were added to the mixture under cooling. The insoluble material was filtered off and the filtrate was evaporated to give 1-(2-aminoethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (4.2 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ccc(CCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(CCCBr)cc1
Reaction time: 18 h
Yield: 89.4 %

Procedure:
Compound 96-1 (940 mg) was dissolved in methylene chloride (20 ml), triphenylphosphine (1.43 g) and N-bromosuccinimide (966 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 18 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (1.13 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:32]1[C:33]2[C:34]3[CH:47]=[CH:46][S:45][C:35]=3[C:36](=[O:44])[NH:37][C:38]=2[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]>>[CH:8]([NH:7][CH2:6][C:5]1[CH:11]=[CH:12][C:2]([C:32]2[C:33]3[C:34]4[CH:47]=[CH:46][S:45][C:35]=4[C:36](=[O:44])[NH:37][C:38]=3[CH:39]=[CH:40][C:41]=2[O:42][CH3:43])=[CH:3][CH:4]=1)([CH3:10])[CH3:9]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)NCc1ccc(Br)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(C)C)cc1
Yield: 57 %

Procedure:
Following General Procedure E, N-(4-bromobenzyl)propan-2-amine (200 mg, 0.88 mmol) was reacted with bis(pinacolato)diboron (240 mg, 0.96 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (270 mg, 0.88 mmol) to afford the desired product (190 mg, 57%) as a light brown solid: 1H NMR (500 MHz, CD3CD2OD) δ 7.68-7.63 (m, 2H), 7.56-7.49 (m, 2H), 7.41-7.34 (m, 3H), 6.04 (dd, J=5.4, 2.4 Hz, 1H), 4.33 (s, 2H), 3.72-3.67 (m, 3H), 3.56-3.50 (m, 1H), 1.45 (dd, J=6.6, 2.2 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:20]
Reactant: CN(C)C=O
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C=O)c1
Temperature: 25 °C

Procedure:
Under N2 in a flame-dried 3-neck round bottomed flask fitted with a reflux condenser and magnetic stirrer, a mixture of 5-bromo-2-(3,4-dichlorophenoxy)-benzaldehyde (3.0 g, 8.7 mmol), zinc (II) cyanide (1.5 g, 13 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.5 g, 1.3 mmol) in anhydrous DMF (145 ml) was stirred at room temperature while degassing with N2 for 5 min. After heating at approximately 80° C. for 90 min., the reaction was judged complete by thin layer chromatography (50% CH2Cl2:hexanes) and was allowed to cool to room temperature. The reaction mixture was then diluted with water and ethyl acetate (EA) and stirred another 10 min. The water layer was separated, extracted twice with EA and combined with the original EA layer, and washed with an aqueous solution of Rochelle salt (potassium sodium tartrate tetrahydrate) followed by aqueous NaCl. The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to an oil. The oil was flash chromatographed on a 15×5 cm column of silica gel, eluting with CH2Cl2:hexanes (1:1) to obtain the title product as a white solid, 1.5 g (60%), m.p. 122–126° C.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(Cc2ccccc2)Cc2ccccc2)O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N(Cc2ccccc2)Cc2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A solution of (4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide (10.0 g, 0.025 mol) in methanol (150 mL) containing anhydrous ammonia (2.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in a presence of a slurry of Raney nickel A-7000 (3.7 g). After 3 hours, uptake of hydrogen has ceased, the mixture is cooled to 20° C., the atmosphere is vented and exchanged for nitrogen, the slurry is filtered through celite, and concentrated at reduced pressure to give 9.4 g of (4R- cis)-6-(2-aminoethyl)-2,2 -dimethyl -N,N-bis(phenylmethyl)-1,3 -dioxane-4-acetamide as an oil;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:25][C:26]#[N:27])=[C:13]([CH:24]=1)[CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](=O)([O-])[O-].[K+].[K+].C=O.C(N(CCOCCOC)CCOCCOC)COCCOC>C1(C)C=CC=CC=1.CCOC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:25]([C:26]#[N:27])=[CH2:28])=[C:13]([CH:24]=1)[CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(NC(=O)OC(C)(C)C)ccc1CC#N)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C#N)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 10 h
Yield: 78.9 %

Procedure:
36E (0.344 g, 0.916 mmol) was dissolved in toluene (4 mL), and to the resulting solution were sequentially added potassium carbonate (0.253 g, 1.832 mmol), paraformaldehyde (0.275 g, 9.16 mmol) and tris(3,6-dioxaheptyl)amine (tda-1) (0.029 mL, 0.092 mmol). The reaction mixture was stirred at 85° C. for 10 h, then diluted with EtOAc (20 mL) and water (10 mL) and stirred for 15 min. The organic phase was separated, washed with water (3×10 mL), brine (1×10 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-40% EtOAc/hexanes) to give 36F (0.280 g, 0.723 mmol, 79% yield) as a colorless syrup, which solidified upon standing. MS (ESI) m/z: 388.3 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.48 (1H, d, J=16.56 Hz), 7.20 (1H, d, J=8.28 Hz), 7.05-7.16 (1H, m), 6.63 (1H, br. s.), 6.22 (1H, s), 5.91 (1H, s), 4.55 (2H, s), 2.82 (3H, br. s.), 1.38-1.57 (18H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:21])[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C)C=O.C(OCC)(=O)C>[CH3:21][N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=[O:14])=[O:13])[C:9]1[CH:10]=[C:2]([O:1][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2
Reactant: CN(c1cc(O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a solution of N-{5-hydroxy-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (800 mg) in N,N-dimethylformamide (10 mL) were added potassium carbonate (264 mg) and ethyl bromoacetate (0.18 mL), and the mixture was stirred at 50° C. for 6 hr. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=85:15-0:1) to give the title compound (724 mg, yield 76%) as a pale-yellow powder.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS[C:28]1[NH:29][CH2:30][C:31](=[O:33])[N:32]=1.C(N(CC)CC)C>C(O)C.CN(C=O)C>[C:1]1([CH:7]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:28]4[NH:29][CH2:30][C:31](=[O:33])[N:32]=4)=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC1=NC(=O)CN1
Reactant: NCCCOc1ccc2c(C(CC(=O)O)c3ccccc3)c[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)CC(c1ccccc1)c1c[nH]c2cc(OCCCNC3=NC(=O)CN3)ccc12

Procedure:
130 mg (0.29 mmol) of 36, prepared analogously to Example 14, are stirred for 24 hours at RT with 115 mg (0.87 mmol) of 2-methylsulfanyl-1,5-dihydroimidazol-4-one and 0.12 ml (0.87 mmol) of triethylamine in a mixture of 2 ml of ethanol and 1 ml of DMF, giving 3-phenyl-3-{6-[3-(1,5-dihydroimidazol-4-on-2-ylamino)propoxy]indol-3-yl}propionic acid. Purification by preparative HPLC on RP-18 gives 3-phenyl-3-{6-[3-(1,5-dihydroimidazol-4-on-2-ylamino)propoxy]indol-3-yl}propionic acid trifluoroacetate.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][CH2:10][CH2:11][NH2:12].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:8][O:9][CH2:10][CH2:11][NH:12][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: COCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCNC1CCCCC1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A solution of cyclohexanone (10 g, 0.10 mol) in Toluene (100 ml) was treated with 2-methoxy ethylamine (8.4 g, 0.11 mol) and refluxed at 110° C. for 3 h. The reaction mass was cooled and diluted with ethanol (50 ml) and sodium borohydride (5.8 g, 0.15 mol) was added in portions at 0° C. The reaction mass was stirred at RT for 12 h and concentrated under reduced pressure. The residue was dissolved in water (100 ml), extracted with DCM (2×100 ml), dried over sodium sulphate and evaporated. The crude material was purified by column chromatography by using DCM and methanol (98:2) as eluent to afford the title compound as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][OH:22]>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:20][CH2:21][OH:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OCCBr
Reactant: Nc1cc(O)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(OCCO)c2ccccc2n1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
To a mixture of 2-amino-4-hydroxyquinoline (0.505 g, 3.15 mmol) and K2CO3 (0.87 g, 6.3 mmol) in DMF (10 mL) was added of 2-bromoethanol (0.470 g, 3.78 mmol). The mixture was stirred at 150° C. for 7 h. The reaction mixture was concentrated and the residue purified by column chromatography on silica using MeOH/CHCl3 (1:9) as eluent. The resulting brown oil (0.30 g, 30%), which was used directly in the next step, contained 75% of the desired product and 25% of unreacted starting material. MS m/z 205 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([O:34][CH2:35][CH3:36])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([CH3:32])([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])[CH3:15])=[CH:9][C:8]=1[CH3:33])C.[Li+].[OH-]>>[CH2:35]([O:34][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([CH3:32])([C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])[CH3:15])=[CH:9][C:8]=1[CH3:33])[C:4]([OH:37])=[O:3])[CH3:36]
Reactant: CCOC(=O)C(Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid as colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[CH2:7]1)=[O:5])[CH3:2].C1COCC1>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Reaction time: 4 h
Yield: 99.3 %

Procedure:
The above (S)-3-(5-nitropyridine-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester (2.59 g, 9.25 mmol) was suspended in ethanol (50 mL) and THF (10 mL) was added. The mixture was gently heated to give a clear solution and 10% palladium on carbon (250 mg) was added. The mixture was hydrogenated at 45 psi for 4 hrs and then filtered. The filtrate was concentrated to give a purple solid as (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester (2.3 g, 100% yield). LCMS for C12H18N4O2 calcd (m/e) 250, obsd 251 (M+H).
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3][CH2:4][CH3:5].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3][CH2:4][CH3:5]
Reactant: Oc1ccccn1
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: CCOP(C)(=O)c1cc(Oc2ccccn2)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 17, ethyl P-methyl-2-nitro-5-chlorophenylphosphinate and 2-pyridyl alcohol are reacted together to give ethyl P-methyl-2-nitro-5-(2-pyridyloxy)phenylphosphinate.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[O:12]([CH2:30][CH2:31][C:32]1(CCO)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:41](O)(=[O:43])[CH3:42].C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[O:12]([CH2:30][CH2:31][C:32]1([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[Si:13]([C:26]([CH3:28])([CH3:27])[CH3:29])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: CC(=O)C1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 160.2 %

Procedure:
After adding 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (31 mg, 0.20 mmol) to a solution of 2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol (810 mg, 1.97 mmol) and iodobenzene diacetate (700 mg, 2.17 mmol) in methylene chloride (10 mL), the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine in that order and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (1.29 g). This was used without purification for the following step.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CC(O)=O.O=[Pt]=O>[C:1]1([C:11]([OH:13])=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ccccc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1CCCC2
Yield: 67 %

Procedure:
A solution of 10.0 9 (0.058 mol) of 1-naphthoic acid in 100 mL HOAc was treated with 0.5 g PtO2 and reduced at 29° C., 50 psi. When the required amount of H2 had been taken up, the mixture was filtered and the solvent removed under reduced pressure. The residue was recrystallized from EtOAc/hexane to give 6.84 g (67% yield) of the product. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([NH:7][CH:8]([C:15]([C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:16][C:15]([C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)=[C:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccoc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)c(Cl)c2)oc1-c1ccoc1
Yield: 46.6 %

Procedure:
10.0 g of ethyl 3-(3,4-dichlorobenzoylamino)-3-(3-furylcarbonyl)propionate, 50 ml of chloroform and 20.0 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 4.44 g of ethyl 2-[2-(3,4-dichlorophenyl)-5-(3-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 46.5%