Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:13][C:14]1[C:19]([Li])=[CH:18][CH:17]=[CH:16][N:15]=1.[Li+].CC([N-]C(C)C)C.ClC1C=CC=CN=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:19]1[C:14]([Cl:13])=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: [Li]c1cccnc1Cl
Agent: CC(C)[N-]C(C)C
Agent: Clc1ccccn1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(O)c1cccnc1Cl
Temperature: 25 °C

Procedure:
(Prepared similarly to literature procedure, Murtiashaw, C. W., et. al. J. Org. Chem., 1992, 57, 1930-1933). A solution of 3-(tert-butyldimethylsilyloxy)propanal (2.3 g, prepared from 3-(tert-butyldimethylsilyloxy)propan-1-ol via Swern oxidation as per Li, X.; Lantrip, D.; Fuchs, P. L. J. Am. Chem. Soc., 2003, 125, 14262-14263, Supporting information) in THF (10 mL) was slowly added via double ended needle to a solution of 2-chloro-3-lithiopyridine (prepared in turn from freshly prepared LDA (11.4 mM) and 2-chloropyridine (11.4 mM) (as per Gribble, G. W.; Saulnier, M. G. Tet. Lett. 1980, 21, 4137-4140) in THF (25 mL) at −78° C. The resulting mixture was allowed to slowly warm to RT over 15 hr, quenched via the addition of sat. NH4Cl (2 mL) and solvents reduced in vacuo. The resultant slurry was taken up in EtOAc, washed with brine, and purified via column chromatography (eluted with 15, 20 and 25% EtOAc/Hex) to yield the titled product (1.0 g), NMR CDCl3 1H δ 8.3 (dd, 1H), 8.0 (dd, 1H), 7.3 (dd, 1H), 5.2 (d, 1H), 4.5 (m, 1H), 4.0-3.8 (m, 2H), 2.1 (m, 1H), 1.8 (m, 1H) 0.9 (s, 9H), 0.1 (s, 6H); MH+=302/304.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:33])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[O:33])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared in Example 13, 300 mg, 0.65 mmol) in ethanol (20 mL) at 25° C. was treated with a solution of potassium hydroxide (109 mg, 1.94 mmol) in water (6 mL). This light yellow solution was stirred at 25° C. for 2 h and then concentrated in vacuo to remove ethanol. The resulting aqueous solution was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/80 hexanes/ethyl acetate plus 1% acetic acid) afforded 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid (226 mg, 80%) as a white solid: mp >200° C.; FAB-HRMS m/e calcd for C24H24N2O4S (M+H)+ 437.1535, found 437.1534.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C:33]([OH:36])(=[O:35])[CH3:34]>>[C:33]([O-:36])(=[O:35])[CH3:34].[C:27]1([N+:26]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccccc1
Reactant: O=C(C=C(CC(=O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(=O)O
Product: CC(=O)[O-]
Product: c1ccc(-c2cc(-c3ccccc3)[n+](-c3ccccc3)c(-c3ccccc3)c2)cc1
Reaction time: 2 h

Procedure:
In a suitable container (erlenmeyer flasks are suitable but any other vessel which may be heated could serve as well) place 33.33 g of recrystallized 1,3,5-triphenyl-2-penten-1,5-dione and 9.31 g of purified aniline. To this mixture add 37.5 ml of glacial acetic acid and heat on a steam bath or other suitable heating source for two hours. At the end of the heating period add 650 ml of distilled, deionized water and then add 6 N NaOH slowly with extremely rapid stirring. Discontinue the addition when the pH, indicated by a glass electrode, reaches 7.0. Allow any precipitate to settle, collect the supernate by filtration and retain this filtrate. Allow the filtrate to stand for a day, and then filter with 2 g of activated carbon by gravity through a tight filter paper to produce a decolorized filtrate. After determination of the 1,2,4,6-tetraphenylpyridinium acetate concentration (vide infra) dilute the solution to the desired concentration with distilled, deionized water. The 1,2,4,6-tetraphenylpyridinium cation is characterized through its perchlorate and perrhenate salts by elemental analysis.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2F)[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2].[OH-:22].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][OH:31])=[CH:28][CH:27]=1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:22][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[C:11]=2[O:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)cc2c1=O
Reactant: COc1ccc(CO)cc1
Reactant: [OH-]
Agent: [K+]
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 75 °C
Yield: 52.1 %

Procedure:
A mixture of ethyl 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (50 g, 167 mmol), KOH (94 g, 1671 mmol) and 4-methoxybenzyl alcohol (208 ml, 1671 mmol) was heated at 75° C. for 4 hours. LCMS showed completion of reaction. The solution was adjusted to pH 2 and was extracted with ethyl acetate. The organic layer was washed with water, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate, whereupon the crude product precipitated out as a solid substance. The precipitate was collected by filtration and washed with EA to afford 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (44 g, 87 mmol, 51.9% yield) as a yellow solid. LCMS: (M+H)+: 508.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)[CH:23]=[CH:24][CH:25]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:17])([F:32])[F:33])[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: OCCCC#Cc1cccc(OC(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3cccc(OC(F)(F)F)c3)cc21

Procedure:
In analogy to the procedure described for example 1 d], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) was reacted with 5-(3-trifluoromethoxy-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49](O)=[O:50])=[C:46]([CH3:48])[N:47]=3)[C:39]2=[O:52])=[CH:28]1.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][NH2:60])[CH:54]=1>>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49]([NH:60][CH2:59][C:55]4[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=4)=[O:50])=[C:46]([CH3:48])[N:47]=3)[C:39]2=[O:52])=[CH:28]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)sc1C(=O)NCc1cccnc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-(1H-indol-3-yl)ethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 36% yield: mp 198-201° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60-8.52 (m, 2H), 8.27 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.31-7.06 (m, 5H), 6.26-6.23 (m, 1H), 4.56 (d, J=5.4 Hz, 2H), 3.99 (t, J=7.8 Hz, 2H), 3.67 (t, J=6.8 Hz, 2H), 3.48 (t, J=7.8 Hz, 2H), 3.05 (t, J=6.9 Hz, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7, 155.4, 153.7, 149.0, 148.9, 148.6, 136.3, 135.9, 127.2, 122.2, 121.9, 119.5, 118.4, 116.6, 112.3, 111.3, 44.2, 42.5, 42.1, 41.3, 23.5, 17.3; MS (ES+) m/z 341.2 (M+1); MS (ES+) m/z 461.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[C:9]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])[CH3:10].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH:25]=O>C(O)C>[C:9]([O:12][CH2:13][C:14]1[NH:1][C:2]2[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]=2[CH:25]([C:24]2[CH:27]=[CH:28][C:29]([F:30])=[C:22]([Br:21])[CH:23]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])[CH3:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CCOC(=O)CCCOC(C)=O
Reactant: Cn1oc(=O)cc1N
Solvent: CCO
Product: CCOC(=O)C1=C(COC(C)=O)Nc2c(c(=O)on2C)C1c1ccc(F)c(Br)c1
Temperature: 80 °C
Yield: 28.4 %

Procedure:
The product from Example 45A (0.17 g, 1.5 mmol), ethyl 4-(acetyloxy)butanoate (0.28 g, 1.5 mmol), prepared as described in (Husband, et al., Tetrahedron (1995) 51(3), 865), and 3-bromo-4-fluorobenzaldehyde (0.3 g, 1.5 mmol) in ethyl alcohol (4 mL) were heated at 80° C. for 24 hours in a sealed tube. The reaction mixture was evaporated under reduced pressure and the residue chromatographed on silica gel eluting with 5% ethanol/methylene chloride to provide the title compound (0.2 g). 1H NMR (300 MHz, DMSO-d6) δ 1.03 (t, 3H), 2.1 (s, 3H), 3.23 (s, 3H), 3.82 (q, 2H), 4.8 (s, 1H), 5.12 (q, 2H), 7.25 (m, 1H), 7.3 (t, 1H), 7.48 (dd, 1H), 10.2 (s, 1H); MS (ESI−) m/z 467 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24](O)=[O:25])=[CH:10]2)=[O:5].N1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[CH:70]=[CH:69][C:63]([C:64]([N:66]([CH3:68])[CH3:67])=[O:65])=[CH:62][CH:61]=1>CN(C=O)C.O>[CH3:67][N:66]([CH3:68])[C:64]([C:63]1[CH:69]=[CH:70][C:60]([NH:59][C:24]([C:11]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:13]3[C:9]([CH:10]=2)=[CH:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:27])([CH3:1])[CH3:28])=[CH:15][CH:14]=3)=[O:25])=[CH:61][CH:62]=1)=[O:65]
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2Cc1ccccc1F
Reactant: CN(C)C(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)c2cc3cc(NC(=O)CC(C)(C)C)ccc3n2Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 200 mg (0.43 mmol) of 5-[(3,3-dimethylbutanoyl)amino]-1-(2-fluorobenzyl)-1H-indole-2-carboxylic acid (Example XXXIX) are dissolved in 2 ml of DMF, and 4 ml of pyridine are added. 489.2 mg (1.29 mmol) of HATU are added to this solution, 140.8 mg (0.86 mmol) of 4-amino-N,N-dimethylbenzamide are then slowly added dropwise and the reaction mixture is stirred at RT overnight. For work-up, water is added and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered, and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC. This gives 47.4 mg (15% of theory) of product.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([Cl:13])=[C:9]([NH:11]N)[CH:10]=1)([OH:4])=O.[CH3:14][O:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([CH:20]([CH2:24][CH3:25])C(O)=O)=O>>[Cl:13][C:8]1[C:9]2[NH:11][C:18]([C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[O:15][CH3:14])=[C:20]3[CH2:24][CH2:25][C:2](=[O:4])[C:5]([C:10]=23)=[CH:6][CH:7]=1
Reactant: NNc1cc(C(=O)O)ccc1Cl
Reactant: CCC(C(=O)O)C(=O)c1ccccc1OC
Agent: Cl
Product: COc1ccccc1-c1[nH]c2c(Cl)ccc3c2c1CCC3=O
Yield: 10.9 %

Procedure:
The procedure of Example 60, steps 1 to 3 was repeated using (5-carboxy-2-chlorophenyl)hydrazine hydrochloride (24.1 g) and (2-methoxybenzoyl)butyric acid (16 g) to yield 2.45 g (12%) of the titled compound as a yellow powder.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([I:14])=[C:10]([CH3:13])[CH:11]=2)[CH:6]=[N:5]1)(=O)C.N>CO.C1COCC1>[I:14][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[CH3:13])[NH:4][N:5]=[CH:6]2
Reactant: CC(=O)n1ncc2cc(I)c(C)cc21
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2[nH]ncc2cc1I
Yield: 100.8 %

Procedure:
1-Acetyl-5-iodo-6-methylindazole (1.5 g, 5.0 mmol) was stirred with ammonia (7 M in methanol, 4 mL) in methanol/THF (2/1, 15 mL) for 1 h. The solution was evaporated to give the subtitle compound (1.3 g, 100%) as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]2([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:9]2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: OC(c1ccc(Cl)cc1)C1CCCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1ccc(C2OC3(CCN(Cc4ccccc4)CC3)N3CCCCC23)cc1

Procedure:
A mixture of 17 g alpha-(4-chlorophenyl)-2-piperidinemethanol, 15 g of N-benzyl-4-piperidone, and 0.3 g of p-toluenesulfonic acid in 150 ml of xylene is stirred under reflux for 48 hours in a vessel provided with a Dean-Stark water separator. The cooled mixture is filtered and evaporated in vacuo. The residue is crystallized from methanol to provide the product, hexahydro-1'-benzyl-1-(4-chlorophenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 134°-136° C.
Reaction SMILES: [ClH:1].Cl.F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:10]([CH2:14][CH2:15][N:16]1[CH2:19][CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:17]1)[CH2:11][NH:12][CH3:13].[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Br:36])[CH:35]=1)[C:30]([OH:32])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)[F:64]>CN(C=O)C>[ClH:1].[ClH:1].[Br:36][C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([Br:26])[CH:35]=1)[C:30]([N:12]([CH2:11][C@H:10]([C:5]1[CH:6]=[CH:7][C:8]([F:64])=[CH:9][CH:4]=1)[CH2:14][CH2:15][N:16]1[CH2:19][CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:17]1)[CH3:13])=[O:32]
Reactant: CNC[C@@H](CCN1CC(N2CCOCC2)C1)c1ccccc1F
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: F[B-](F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CC(N2CCOCC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.7 %

Procedure:
[(2S)-2-(Fluorophenyl)-4-(3-morpholin-4-ylazetidin-1-yl)butyl]methylamine dihydrochloride (see Method 4; 292 mg, 0.68 mmol), 3,5-dibromobenzoic acid (215 mg, 0.77 mmol) and DIPEA (350 mg, 2.71 mmol) were dissolved in DMF (20 mL) and to the resultant solution was added TBTU (250 mg, 0.78 mmol) at 0° C. The mixture was stirred at RT for 2 h and then the solvent was removed by evaporation. The residue was diluted with ethyl acetate and then washed thrice with an aqueous solution of NaHCO3. The organic solution was combined with another preparation of the title compound (as free base) being prepared by a similar method (68 mg). The combined organic solutions were then dried over MgSO4 and the solvent was removed by evaporation to yield 344 mg. The product was purified by reversed phase chromatography using a mixture of acetonitrile and 0.1 M ammonium acetate aq. The collected fractions were freeze-dried and the residue was then dissolved in a mixture of water and acetonitrile. The solution was acidified with hydrochloric acid (2 M) and again freeze-dried. There was obtained 267 mg (55%) of the title compound as a grey solid. 1H NMR (500 MHz, CD3OD): 1.8-2.1 (cm, 2H), 2.7-4.8 (cm, 21H), 6.9-7.8 (cm, 7H); LCMS: m/z 584 (M+1)+.
Reaction SMILES: I[C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23]S(C)(=O)=O)=[CH:19][CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+].Cl>CN(C)C=O.O>[CH3:16][C:13]1[S:12][C:11]2[C:2]([S:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:3]3[C:8](=[C:9]([C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)[C:10]=2[C:14]=1[CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4]3
Reactant: Cc1sc2c(I)c3ccccc3c(-c3ccc(OS(C)(=O)=O)cc3)c2c1C
Reactant: Sc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3ccc(O)cc3)c2c1C
Temperature: 155 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a stirred suspension of methanesulfonic acid 4-(9-iodo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (0.620 g, 1.22 mmol), and copper I oxide (0.192 g, 1.34 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added thiophenol (0.270 mL, 2.68 mmol) and finely ground sodium hydroxide (0.107 g, 2.68 mmol) under a dry argon atmosphere. The vessel was sealed and heated at 155° C. for 9.5 hours. After stirring at ambient temperature for about 8 hours the reaction mixture was poured into water, acidified with hydrochloric acid and the organics were extracted into ether. The extracts were combined, filtered, washed with water and concentrated. The yellow solid residue was dissolved in dioxane (8 mL) and a 2.5 N soduim hydroxide solution (4.5 mL) was added. The vial was sealed and heated at 102° C. When the reaction was done (as indicated by thin layer chromatography) the mixture was cooled to room temperature, diluted with water, and acidified with hydrochloric acid. The organics were extracted with ether, combined with silica gel and the solvents were removed. The adsorbate was flash chromatographed (gradient 90/10-85/15 petroleum ether/ethyl acetate) and the solvents were chased with benzene and petroleum ether to give the tide compound as a white solid (0.426 g, 85%): NMR (DMSO-d6); δ 9.70 (s, 1H, OH), 8.40 (d, J=8 Hz, 1H), 7.56-7.51 (m, 2H), 7.44-7.40 (m, 1H), 7.25-7.12 (m, 5H), 7.02 (d, J=7 Hz, 2H), 6.93 (d, J=9 Hz, 2H), 3.67 (s, 3H), 1.62 (s, 3H); MS(EI): [M+] 412 (100%); Anal. calc. for C26H20OS2: C, 75.69, H, 4.89, N, 0.00. Found C, 74.98, H, 4.86, N, 0.13.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[S:8][C:9]([Cl:13])=[C:10]([Cl:12])[CH:11]=1)O)[CH3:2].C[C:16](C)(C)[C:17]([O-:20])([O-])[O-:18].[C:23](O)(=O)CCCCC>C1C2C(CCCC2)CCC1>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:7]1[S:8][C:9]([Cl:13])=[C:10]([Cl:12])[C:11]=1[CH2:16][C:17]([O:20][CH3:23])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(O)c1cc(Cl)c(Cl)s1
Reactant: CCCCCC(=O)O
Reactant: CC(C)(C)C([O-])([O-])[O-]
Solvent: C1CCC2CCCCC2C1
Product: CCOC(=O)Cc1sc(Cl)c(Cl)c1CC(=O)OC
Temperature: 180 °C
Yield: 29 %

Procedure:
A solution of the product from step (b) (12.2 g, 48.0 mmol) in decalin (145 ml) was treated with trimethylorthoacetate (24.5 ml, 192 mmol) and hexanoic acid (0.61 ml). The flask was equipped with a vigreux column and heated to 180° C. Additional hexanoic acid (3 ml) was periodically added over 6 h and the reaction was heated overnight. The reaction was concentrated on the rotavap and the residue was extracted with MeOH (100 ml ×2). The MeOH extracts were concentrated and purified by silica gel chromatography (EtOAc/Hexane-gradient) providing 4.36 g (29%) of the subtitle compound. MS: ESI (positive): 311, 313 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH:14]=[O:15])=[N:9]2)([O-:3])=[O:2].O1CCCC1.[BH4-].[Na+].O>CO>[OH:15][CH2:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: O=Cc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2nc(CO)ccc12
Reaction time: 5 h

Procedure:
700 mg (3.46 mmol) of 5-nitroquinoline-2-carbaldehyde are dissolved in 13 ml of methanol and 7.0 ml of tetrahydrofuran and mixed at 0° C. with 523 mg (13.9 mmol) of sodium borohydride. After 5 hours, the reaction is brought to a halt by adding water. The solvent is removed in a vacuum, the residue is taken up in dichloromethane and water, the aqueous phase is extracted with dichloromethane, and the combined organic phases are dried on sodium sulfate. After the solvent is removed, and after purification on silica gel with hexane-ethyl acetate (0-100%), 390 mg (55% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=O)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:23])C(Cl)=O.C(N(CC)CC)C.[CH3:32][OH:33]>CN(C=O)C>[CH3:32][O:33][C:19]([C:11]1[O:13][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:16][CH:15]=2)=[N:9][C:10]=1[CH3:14])=[O:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(NC(=O)c1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 2-(4-Trifluoromethyl-benzoylamino)-propionic acid (33.4 g, 128 mmol) is added oxalyl chloride (111 mL, 1.27 Mol) and 1 drop of DMF and the solution stirred overnight. The volatiles are removed in vacuo and toluene (20 mL) is added. The toluene is then removed in vacuo. To the resultant crude oil is dissolve in 50 mL methylene chloride, cooled to 0° C. and triethylamine (27 mL, 192 mmol) is added followed by methanol (50 mL). After 3 hrs the volatiles are removed in vacuo and the crude oil is purified by flash column chromatography (20%-50% ethyl acetate/hexanes) to provide 12.6 g (35%) of 4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methyl ester. This ester (2.0 g, 7.0 mmol) is reduced to the alcohol by dissolution in THF (50 mL) and adding 4 eq. LiBH4 (0.610 g, 28.0 mmol) to provide 1.8 g (100%) [4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol. MS M++1 258.