Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:35]=[CH:36][CH:37]=4)[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:47][O:48][CH:49]([O:56][CH3:57])[CH2:50][NH:51][CH2:52][CH2:53][CH2:54][CH3:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O>[CH2:52]([N:51]([CH2:50][CH:49]([O:48][CH3:47])[O:56][CH3:57])[C:32](=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27][C:26]1[CH:35]=[CH:36][CH:37]=[C:24]([CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][C:15]3([O:14][CH2:13][CH2:12][N:11]([C:9]([C:7]4[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=4)=[O:10])[CH2:16]3)[CH2:17][CH2:18]2)[CH:25]=1)[CH2:53][CH2:54][CH3:55]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)O)c4)CC3)C2)cs1
Reactant: CCCCNCC(OC)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCCN(CC(OC)OC)C(=O)CCOCCc1cccc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(3-(2-(4-(2-Isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoic acid [Example 34, step c] (0.50 g), Hunig's base (0.58 mL), and N-(2,2-dimethoxyethyl)butan-1-amine [J. Am. Chem. Soc. 1949, 71(6), 2272] (0.12 g) were dissolved in dichloromethane (10 mL). HATU (0.33 g) was then added and the mixture was stirred at room temperature for 24 hours. The mixture was poured into water and extracted with dichloromethane. The organic extracts were combined and evaporated under reduced pressure to give the subtitled compound. Yield 0.45 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12](O)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12]([Cl:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 81 %

Procedure:
7-Benzyl-4-hydroxy-5,6,7,8-tetrahydro-1,3,7-triazanaphthalene [Ozdowska et al Rocz. Chem. Ann. Soc. Chim. Pol. 50, 1771 (1976)] 95.0 g, 15.9 mmol) was added to POCl3 and the mixture heated to 100° C. for 1 h. The reaction was cooled, concentrated under reduced pressure and the residue quenched with ice. After neutralising with K2CO3 the product was extracted with CH2Cl2, the organic layer washed with H2O, dried over MgSO4 and evaporated to give the subtitle compound as a brown oil (3.3 g, 81%). Rf 0.45 (CH2Cl2/MeOH/0.88NH3 92/7/1, v/v).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:65])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:24]([O:59][CH3:60])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:57][CH3:58])[C@@H:34]([CH3:56])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:98]=[C:99]1[CH:103]=[CH:102][C:101](=[O:104])[N:100]1[CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][C:110]([NH:112][NH2:113])=[O:111]>CN(C=O)C>[O:104]=[C:101]1[CH:102]=[CH:103][C:99](=[O:98])[N:100]1[CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][C:110]([NH:112][NH:113][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:65])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:24]([O:59][CH3:60])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:57][CH3:58])[C@@H:34]([CH3:56])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:111]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 mg (11 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 4000 μl of DMF and then admixed with 6.3 mg (33 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4.5 mg (33 μmol) of 1-hydroxy-1H-benzotriazole hydrate, 5.7 μl of N,N-diisopropylethylamine and with 11.5 mg (44 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT overnight and then concentrated under high vacuum. The remaining residue was purified by means of preparative HPLC. Thus, 2.6 mg (14% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:15]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=4[Cl:13])[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Br)ccc2n1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 6-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 15, Step 1; 0.582 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.548), triethylamine (Aldrich; 0.288 g), and THF (5 mL) is stirred at 80° C. for 6 h, at which time it is cooled and then partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. Chromatography of the residue on silica gel using methanol/dichloromethane (2/98) and crystallization gives 0.710 g of the title compound; mp 137-138° C.; MS m/z 438, 440; IR (mineral oil) 1479, 1341, 1058, 2810, 803 cm-1. 1H NMR (CDCl3) δ2.78, 3.09, 3.80, 6.96, 7.16-7.23, 7.35, 7.48, 7.55, 8.24.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]([CH3:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:16])[NH:9]2)[CH:2]=[CH2:3].[Br:17]N1C(=O)CCC1=O.O.O1CCCC1>C(Cl)(Cl)Cl>[Br:17][CH2:3][CH:2]1[O:14][C:13]2[C:4](=[C:5]3[C:10](=[C:11]([CH3:15])[CH:12]=2)[NH:9][C:8](=[O:16])[CH:7]=[CH:6]3)[CH2:1]1
Reactant: C=CCc1c(O)cc(C)c2[nH]c(=O)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)CC(CBr)O2
Yield: 38.3 %

Procedure:
5-Allyl-6-hydroxy-8-methylcarbostyril (9.36 g, 43.5 mmol) was dissolved in chloroform (11) with heat. To the obtained solution, N-bromosuccinimide (7.75 g, 43.5 mmol) was added, and the mixture was refluxed for 2 hours. After completion of the reaction, water was added to the reaction mixture, and unreacted 5-allyl-6-hydroxy-8-methylcarbostyril (2.2 g, 23.5%) was separated as an insoluble matter by filtration. The filtrate was washed with water, dried and condensed. The resultant residue was subjected to a recrystallizing procedure using tetrahydrofuran to obtain 4.90 g of 2-bromomethyl-5-methyl-1,2-dihydrofuro-[3,2-f]quinoline-7-one as pale yellow crystals (38.3%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH:6]([NH2:13])[C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:3].C(OC([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][C:23]1=[O:29])=O)(C)(C)C.C([O-])(=O)C.[Na+]>O.O1CCOCC1>[CH2:2]([O:4][C:5]([C:6]1[NH:13][C:25]2[CH2:26][CH2:27][NH:22][C:23](=[O:29])[C:24]=2[C:7]=1[C:8]([F:11])([F:10])[F:9])=[O:14])[CH3:3]
Reactant: CCOC(=O)C(N)C(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C(=O)NCC2
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A stirred mixture of 2-amino-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester hydrochloride (7.54 g, 32 mmol), 2,4-dioxo-piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 29.1 mmol) and sodium acetate (2.39 g, 29.1 mmol) in water (35 ml) and dioxane (35 ml) was heated to reflux for 2 hours. The mixture was cooled down to room temperature, and extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3), the combined organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents to give 3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (2.8 g, 35%) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[N:8][N:7]=1.C1[CH2:26][O:25][CH2:24]C1.C1CCN2C(=NCCC2)CC1.C[OH:39]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][O:25][C:26](=[O:39])[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][C:6]2[S:10][C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[N:8][N:7]=2)[CH:3]=1
Reactant: C1CCOC1
Reactant: CO
Reactant: N#Cc1ccc(-c2nnc(Cc3cccc(I)c3)s2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cccc(Cc2nnc(-c3ccc(C#N)cc3)s2)c1
Temperature: 100 °C
Yield: 60 %

Procedure:
Dissolve 4-[5-(3-iodo-benzyl)-[1,3,4]thiadiazol-2-yl]-benzonitrile (0.34 g, 0.75 mmol) into 8 mL of a 1:1 mixture of THF:MeOH in a microwave pressure tube. Add molybedinum hexacarbonyl (0.25 g, 0.95 mmol) and DBU (0.32 mL, 2.10 mmol) causing the solution to darken. Add palladium acetate (0.03 g, 0.11 mmol), seal the tube and heat at 100° C. in a microwave reactor for 10 min. Concentrate the mixture onto silica gel and purify by flash silica gel chromatography to provide (0.150 g, 60% yield of 3-[5-(4-cyano-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-benzoic acid methyl ester as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:23]=2)=[CH:15][CH:14]=1>>[CH3:31][C:21]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:8]=3)=[CH:14][CH:15]=2)=[N:23][C:22]=1[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3cccc(C#N)c3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 3-cyanobenzene boronic acid (219 mg, 1.49 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (100 mg, 0.30 mmol) to give 21 mg (20%). MS (m/e) 358.2 (M+1)
Reaction SMILES: Cl.Cl.[OH:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.CN(C)C=O.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:34])[C:32]=1F)[N:29]([CH2:35][CH2:36][F:37])[CH:28]=[C:27]([C:38]([OH:40])=[O:39])[C:26]2=[O:41]>C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:34])[C:32]=1[N:7]1[CH2:8][CH2:9][N:4]([OH:3])[CH2:5][CH2:6]1)[N:29]([CH2:35][CH2:36][F:37])[CH:28]=[C:27]([C:38]([OH:40])=[O:39])[C:26]2=[O:41]
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reactant: ON1CCNCC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(CCF)c2c(F)c(N3CCN(O)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 169.4 %

Procedure:
1-Hydroxypiperazine dihydrochloride (1.03 g), triethylamine (35.6 g) and dimethylformamide (85 ml) are added to 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (8.5 g), which is prepared by the procedure described in Japanese Patent First Publication No. 30964/1981, and the mixture is stirred for 1.5 hours at 100°-105° C. After cooling to room temperature, the reaction mixture is poured into ice-water (500 ml) and the pH is adjusted to 7.0 with 50% aqueous acetic acid. The resulting precipitate is filtered, washed with water and then recrystallized from dimethylformamide. Ethanol (100 ml) is added to the resulting pale yellow needles and the mixture is refluxed for 1.5 hours. After cooling the mixture to room temperature, the insoluble substance is filtered to yield 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (3.7 g) as pale yellow needles, m.p. 220°-229° C. (decomposition).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](=O)([O-])[O-].[K+].[K+].IC.Cl>O.CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Yield: 90 %

Procedure:
A 2 L flask equipped with a dropping funnel and mechanical stirrer was charged with crude 3-cyclohexyl-6-indole carboxylic acid (99.4 g, 0.409 mole) and anhydrous DMF (665 mL) was added followed by anhydrous potassium carbonate (78.13 g, 0.565 mole). Iodomethane (63.72 g, 0.449 mole) was added dropwise over 35 min with stirring to the slurry which was then stirred overnight at room temperature until complete disappearance of starting material (TLC). The resulting suspension was then poured into water (1350 mL) and acidified to pH 4 with 4N HCl (200 mL). The product was extracted into ether (3×1700 mL), washed with water and brine and dried (Na2SO4). Volatiles were removed under reduced pressure and the residue was triturated with hexane (700 mL). The beige solid was filtered and dried under vacuum (94.3 g, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C@@:23]23[C@H:18]([CH2:19][CH2:20][O:21][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH:14]13>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:14]2[C@:23]3([OH:13])[C@H:18]([CH2:19][CH2:20][O:21][CH2:22]3)[CH2:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: C1CC2O[C@@]23COCC[C@@H]3C1
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O[C@]12COCC[C@@H]1CCC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-fluoroaniline (0.721 g, 6.48 mmol) in CH2Cl2 (6 mL) at 0° C. was added trimethylaluminum (2M in toluene, 3.24 mL) dropwise. The mixture was warmed and stirred to rt for 30 min. (1aS,5aS)-hexahydro-4H-oxireno[i]isochromene (0.200 g, 1.30 mmol) in CH2Cl2 2 mL+0.5 mL rinse) was then added and the mixture was stirred at rt overnight. The reaction was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL) The mixture was diluted with more water and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.84-6.90 (m, 2H), 6.51-6.57 (m, 2H), 3.90-3.97 (m, 1H), 3.50-3.64 (m, 3H), 3.35-3.45 (m, 2H), 2.61 (s, 1H), 1.95-2.04 (m, 1H), 1.32-1.75 (m, 8H). HRMS (ES) m/z M+H cal'd: 266.1551. found: 266.1548.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=C=O.[NH2:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][NH:27][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([NH:19][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCCCCN=C=O
Reactant: NCCO
Product: CCCCCNC(=O)N1CC(=NOC)C[C@H]1C(=O)NCCO

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 2-aminoethanol the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=315.2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-2(1H)-one (Intermediate 1, crude, 60 mg, 0.20 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxy borohydride (127 mg, 0.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to a pH of 10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (8:1 to 4:1) gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of 1M HCl in ether (0.3 mL). The colorless precipitate was collected by filtration and gave 50 mg (48%) of the bis-hydrochloride salt of the product, mp 243° C.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:39]=[CH:38][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[CH:20][C:19]([CH2:32][C:33]([O:35]CC)=[O:34])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[CH:20][C:19]([CH2:32][C:33]([OH:35])=[O:34])=[CH:18][CH:17]=3)=[CH:38][CH:39]=2)=[O:10])=[CH:40][CH:41]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(CC(=O)O)ccc2Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4′-(methylsulfonyl)biphenyl-3-yl)acetate (20 mg, 0.0338 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.0676 ml, 0.338 mmol) and 300 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4′-(methylsulfonyl)biphenyl-3-yl)acetic acid (10 mg, 52.5% yield). (400 MHz, CD3Cl3, CD3OD) 7.90 (d, 2H), 7.70 (d, 2H), 7.60 (d, 2H), 7.40 (s, 1H), 7.35 (d, 1H), 7.25 (d, 2H), 7.15 (d, 2H), 7.05 (d, 1H), 6.85 (d, 2H), 6.55 (t, 1H), 3.63 (m, 4H), 3.05 (s, 3H), 2.90 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]([NH:20][NH2:21])=[O:19])=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.O.C1C[O:39][CH2:38]C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]1[O:19][C:38](=[O:39])[NH:21][N:20]=1)=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: NNC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2c(N3CCCCC3)nc3ccc(Cl)cc3c2-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-phenyl-2-piperidin-1-yl-quinoline-3-carboxylic acid hydrazide (30 mg, 70.9 μmol, Eq: 1.00) and N,N′-carbonyldiimidazole (13.8 mg, 85.1 μmol, Eq: 1.2) were dissolved in THF (1 ml). Then triethylamine (10.0 mg, 13.8 μL, 99.2 μmol, Eq: 1.4) was added and the reaction mixture was stirred for 2 h at RT. Water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 97:3) to afford the title compound as yellow solid (25 mg). MS (ESI): 407.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[C@@H:11]([CH3:13])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.C1COCC1>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C@@H:11]([CH3:13])[C:10]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a mixture of 1.00 g of 3-hydroxybenzaldehyde, 1.80 g of tert-butyl(R)-lactate, 2.58 g of triphenylphosphine, and 40 mL of THF was added 1.71 g of diethyl azodicarboxylate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with ethyl acetate, followed by washing with a 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.49 g of tert-butyl(2S)-2-(3-formylphenoxy)propanoate as a colorless oily substance.