Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:13]=[C:12]([C:22]([O:24]C)=[O:23])[CH:11]=1)#[N:2].[OH-].[Li+].[NH4+].[Cl-].CCOC(C)=O>O1CCOCC1.O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:21])[C:17]([F:18])([F:20])[F:19])[CH:13]=[C:12]([C:22]([OH:24])=[O:23])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2C#N)cc(C(O)C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)C(F)(F)F)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 2′-cyano-4′-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-3-carboxylate (250 mg, 0.72 mmol) in 1,4-dioxane (5 mL) and water (2.5 mL) was added lithium hydroxide (50 mg, 2.1 mmol). The reaction mixture was stirred at rt for 4 h, and then treated with aq. NH4Cl and EtOAc. The organic layer was separated, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel chromatography to afford the title compound. 1H NMR (CDCl3, 400 MHz): 8.27 (s, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.58 (s, 1H), 7.48 and 7.43 (AB, J=8.0 Hz, 2H), 5.17 (q, J=6.4 Hz, 1H), 2.43 (s, 3H).
Reaction SMILES: CN(C)CCCN=C=NCC.[Cl:12][C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][CH:26]3[CH2:28][CH2:27]3)[CH2:21][CH2:20]2)=[N:17][CH:18]=1.[CH3:29][C:30]1[N:31]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH:32]=[CH:33][N:34]=1.ON1C2C=CC=CC=2N=N1.C(#N)C.O.FC(F)(F)C(O)=O>CN(C)C=O.C(N(CC)CC)C>[Cl:12][C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]([CH:26]3[CH2:28][CH2:27]3)[C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N:31]4[CH:32]=[CH:33][N:34]=[C:30]4[CH3:29])=[CH:43][CH:42]=3)[CH2:21][CH2:20]2)=[N:17][CH:18]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reaction time: 18 h

Procedure:
1-(3-Dimethylamino-propyl)-3-ethyl-carbodiimide (EDC, 12 mg) in N,N-dimethylformamide (0.1 mL) is added to a solution of [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine (5 mg), 4-(2-methyl-imidazol-1-yl)-benzoic acid (6 mg), 1-hydroxy-benzo-triazole (3 mg), and triethylamine (15 μL) in N,N-dimethylformamide (0.4 mL) at room temperature. The solution is stirred for 18 h and then submitted to chromatography on reversed phase (HPLC, acetonitrile/water/trifluoroacetic acid) to give the pure title compound. LC (method 19): tR=3.97 min; Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:12](=[O:14])[C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from N-(3-nitro-phenyl)-oxalamic acid and 4-benzyl-piperidine according to the method described in Example 1c. Melting Point: 138-140° C. (diethylether)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[CH:16]([C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:12][CH:11]=[N:10][N:9]2[C:13]=1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=[O:17]
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Product: N#Cc1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 5e (162 mg, 0.698 mmol) was coupled with 4-bromobenzonitrile (190 mg, 1.04 mmol) using the procedures described in Example 20, Step A to afford compound 76a. Mass spectrum (LCMS, ESI pos.) Calcd. For C18H15N5O2: 334.1 (M+H). found 334.1.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[F:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1cc(F)ccc1F)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,5-difluorobenzoyl chloride, there is obtained ethyl N-(2,5-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 406 (4), 377 (18), 194 (100), 141 (49);
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Cl.[NH2:8][C@@H:9]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH3:13])=[O:11].O>C(N(C(C)C)CC)(C)C>[C:19]([O:18][C:16]([NH:15][CH2:14][C@H:9]([N:8]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:10]([O:12][CH3:13])=[O:11])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: ClCCOCCCl
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCOCC1
Temperature: 127 °C
Reaction time: 18 h
Yield: 24.3 %

Procedure:
2.8 g (20 mmol) of 1-chloro-2-(2-chloroethoxy)ethane are added to a solution of 5 g (20 mmol) of commercial methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate in 65 ml of diisopropylethylamine. The reaction mixture is stirred at 127° C. for 18 h. After the addition of water, the reaction medium is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 1.4 g (24%) of methyl(S)-3-tert-butoxycarbonylamino-2-morpholin-4-ylpropanoate are obtained in the form of an oil.
Reaction SMILES: F[C:2]1[C:3]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:20][NH2:21]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:8][C:6]1[CH:7]=[C:2]2[NH:21][N:20]=[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:3]2=[N:4][CH:5]=1
Reactant: O=C(Cc1ccccc1F)c1ncc(F)cc1F
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Fc1cnc2c(Cc3ccccc3F)n[nH]c2c1

Procedure:
9.07 g (32.4 mmol) of the compound from example 3A were initially charged in pyridine (84 ml). Subsequently, 8.10 g (162 mmol) of hydrazine hydrate and 19.8 mg (0.162 mmol) of 4-dimethylaminopyridine were added, and the mixture was heated at reflux for 30 min. The reaction mixture was diluted with ethyl acetate at RT and washed four times with 10% strength aqueous citric acid solution. The organic phase was subsequently washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. MTBE was added to the residue and the solids were filtered off. The latter were dried under high vacuum and gave 1.79 g (79% pure, 18% of theory) of the title compound. The filtrate was concentrated and gave a further 4.86 g (61% pure, 37% of theory) of the title compound. The two fractions were combined and reacted without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[O:15][C:16]([C:19](OC)=[O:20])=[CH:17][CH:18]=3)[N:13]=2)=[CH:5][C:4]=1[O:23][CH2:24][CH2:25][CH3:26].O1CCOCC1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH:18]=[CH:17][C:16](=[C:19]=[O:20])[O:15]3)[N:13]=2)=[CH:5][C:4]=1[O:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCOc1cc(-c2nc(-c3ccc(C(=O)OC)o3)cs2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCOc1cc(-c2nc(C3C=CC(=C=O)O3)cs2)ccc1OC
Yield: 47.1 %

Procedure:
To a suspension of 970 mg of 2-(4-methoxy-3-propoxyphenyl)-4-(5-methoxycarbonyl-2-furyl)thiazole in 30 ml of methanol was added 20 ml of 1,4-dioxane and 5 ml of a 5 N aqueous sodium hydroxide solution. The reaction mixture was refluxed for 3 hours, then concentrated approximately 1/10. Water was added to the residue, and washed with ethyl acetate. To the aqueous layer was acidified with 5 N hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried with magnesium sulfate. Evaporation the solution, the residue was recrystallized from ethyl acetate to obtain 420 mg of 2-(4-methoxy-3-propoxyphenyl)-4-(5-carbonyl-2-furyl)thiazole as a white powder. mp. 191.0-192.0° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=O)[C:5]2=[O:18].C1C=CC(OP(Cl)(OC2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[Cl:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH:49][C:15]([C:6]2[C:5](=[O:18])[C:4]3[C:9](=[N:10][C:11]([O:12][CH3:13])=[C:2]([I:1])[CH:3]=3)[N:8]([CH3:14])[CH:7]=2)=[O:17])=[CH:46][CH:45]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1nc2c(cc1I)c(=O)c(C(=O)O)cn2C
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc2c(cc1I)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
6-Iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (1.50 g) is dissolved in CH2Cl2 (0.5 L). To this is added diphenyl chloridophosphate (1.5 mL) and triethyl amine (1.7 mL). The resulting mixture is stirred at room temperature for 2 h, followed by the addition of 4-chlorobenzyl amine (1.2 mL). The reaction is stirred for additional 3 h, then washed with 1N HCl, 1N NaOH, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc 4/1, 1/1, CH2Cl2/MeOH 19/1) and the product is then triturated with MeOH to afford 592 mg (29%) of N-(4-chlorobenzyl)-6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide. Physical characteristics are as follows: 1H NMR (CDCl3) δ 10.20, 9.01, 8.81, 7.32-7.27, 4.62, 4.13, 3.96; 13C NMR (CDCl3) δ 175.24, 164.41, 162.95, 159.66, 148.69, 147.78, 147.69, 137.26, 132.85, 128.93, 128.69, 118.76, 113.68, 55.77, 42.58, 39.12; IR (diffuse reflectance) 2296, 1908, 1665, 1613, 1593, 1570, 1544, 1507, 1491, 1460, 1447, 1386, 1286, 1278, 809, cm−1; MS (FAB) m/z 484 (MH+), 486, 485, 484, 344, 343, 217, 133, 127, 125, 55; Anal. calcd for C18H15ClIN3O3: C, 44.70; H, 3.13; N, 8.69. Found: C, 44.38; H, 3.17; N, 8.62.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:12]([NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:27]3[CH2:33][CH2:32][NH:31][CH2:30][C:28]=3[N:29]=2)=[CH:20][CH:19]=1)=[O:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:27]3[CH2:33][CH2:32][N:31]([C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[N:10][C:2]=4[CH3:1])[CH2:30][C:28]=3[N:29]=2)=[CH:22][CH:23]=1)=[O:16])[CH3:13]
Reactant: Cc1ncccc1C(=O)O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cccnc2C)C3)cc1
Yield: 58 %

Procedure:
The compound oy was obtained following the general procedure in Example 213, substituting 3-methyloxetane-3-carboxylic acid for 2-methylnicotinic acid and substituting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt (jk) for 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt (bf). The desired product oy (74 mg, 58% yield) was obtained as white solid: 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.20 (m, 2H), 7.42 (m, 2H), 6.15 (m, 1H), 4.61 (m, 2H), 3.82 (m, 1H), 3.73 (m, 4H), 3.49 (m, 5H), 3.20-3.04 (m, 2H), 2.76 (m, 2H), 2.53 (s, 3H, overlapping with DMSO peak), 1.06 (t, J=7.1 Hz, 3H); LC-MS m/z=502 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:2]1.C[Si]([N:34]=[C:35]=[O:36])(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:29][C:22]1[C:23]([F:28])=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[CH:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][N:1]([C:35]([NH2:34])=[O:36])[CH2:4]4)[CH:9]=3)[CH:11]=2)[NH:16][CH:17]=1)[CH3:20]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CN(C(N)=O)C4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(1-azetidin-3-yl-1H-pyrazol-4-yl)-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (6.0 mg, 0.014 mmol), trimethylsilyl isocyanate (5.0 μL, 0.037 mmol), DIPEA (0.02 mL, 0.09 mmol) and DCM (2 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.89 (d, J=7.1 Hz, 3 H), 4.29-4.36 (m, 2 H), 4.42 (t, J=8.5 Hz, 2 H), 5.20-5.34 (m, 2 H), 7.14-7.23 (m, 1 H), 7.37 (d, J=1.3 Hz, 1 H), 7.39-7.52 (m, 2 H), 7.69 (s, 1 H), 7.94 (s, 1 H), 8.33 (s, 1 H). MS (ES+): m/z 473.11 (100) [MH+]. HPLC: tR=2.86 min (ZQ3, polar—5 min).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:21](=[O:38])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:21]([OH:38])[CH:22]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)([OH:30])[CH2:28][CH2:29]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:12]([CH3:13])[CH3:14])([CH:15]([CH3:17])[CH3:16])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C(O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of sodium borohydride (0.032 g, 0.85 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (0.454 g, 0.850 mmol in 10 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The white precipitate which formed was collected by filtration to afford 0.245 g (54%) of (1R*, 2R*)-1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which had: NMR δ7.39 (ABq, Δv1-3=35.2 Hz, J=8.5 Hz, 4 H), 7.06 (dd, J=2, 11.5 Hz, 1 H), 6.96-6.82 (m, 2 H), 5.15 (s, 1 H), 4.18 (d, J=9.5 Hz, 1 H), 3.04 (dt, J=2.5, 11.5 Hz, 1 H), 2.78-2.67 (m, 1 H), 2.67-2.52 (m, 3 H), 2.12 (sym m, 2 H), 1.80 (distorted d, J=14 Hz, 2 H), 1.54 (s, 1 H), 1.36-1.19 (m, 3 H), 1.08 (d, J=7 Hz, 18 H), 0.80 (d, J=6.5 Hz, 3 H). The product also contained about 8% of the erythro diastereomer but was suitable for use without additional purification.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].C[N:38]1[CH2:43][CH2:42][O:41]C[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:34])([F:36])[F:35])[O:19][N:18]=2)=[CH:15][CH:16]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:38]1[CH2:43][CH:42]([OH:41])[CH2:39]1)=[O:10])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCC(=O)N1CC(O)C1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 26 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), azetidin-3-ol, HCl (5.45 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (Sun Fire C18 5u19×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, product retention=11.15 min (20 mL/min, 220 nM) to provide (R/S)-2-hydroxy-N-(3-(3-hydroxyazetidin-1-yl)-3-oxopropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.013 mmol, 26.2% yield): LCMS=558.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, d, J=8.36 Hz), 7.52-7.78 (7 H, m), 5.11 (1 H, s), 4.40-4.57(1 H, m), 4.10-4.38(2 H, m), 3.89(1 H, ddd, J=9.52, 4.24, 1.21 Hz), 3.68-3.80 (1 H, m), 3.49 (2 H, t, J=6.27 Hz), 2.27-2.46 (2 H, m); HPLC peak RT=8.1 min (Method A).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][N:13](C)C=O>C(OCC)(=O)C.[C-]#N.[C-]#N.[Zn+2]>[CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:12]#[N:13])[C:3]=2[CH:4]=[CH:5][N:6]=1
Reactant: Brc1cccc2cnccc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cccc2cnccc12
Temperature: 25 °C
Yield: 97 %

Procedure:
5-Bromoisoquinoline (8 g, 38.65 mmol) and dimethyl formamide (100 mL) were mixed and stirred. The reaction solution was added with Zn(CN)2 (2.72 g, 23.19 mmol) and Ph(PPH)4 (1.78 g, 1.55 mmol), followed by stirring for about 4 hours at 100° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (5.8 g, 97%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
To a solution of 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (8.45 9, 18.2 mmol, 1 equiv) in MeOH (85 mL) and THF (85 mL) was added 1 N NaOH (91 mL, 91 mmol, 5 equiv). The solution was stirred at room temperature for 4 hours. The organic layer was removed in vacuo and the aqueous layer was washed with EtOAc (100 mL). The aqueous layer was then acidified to a pH of about 4 with concentrated HCl and a precipitate formed. The mixture was stirred for 48 hours and the solids collected by filtration to provide 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (4.5 g, 57% over two steps) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH:8]=[C:9]([C:11]([OH:13])=O)[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl.Cl.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:11]([C:9]1[O:10][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=3[CH:8]=1)=[O:13])[CH2:20]2
Reactant: O=C(O)c1cc2ccc([N+](=O)[O-])cc2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc([N+](=O)[O-])cc2o1
Reaction time: 0.67 h

Procedure:
1040 mg (5.02 mmol) of 6-nitrobenzofuran-2-carboxylic acid, 1000 mg (5.02 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 2290 mg (6.03 mmol) of HATU, 2250 mg (18.08 mmol) of N,N-diisopropylethylamine and 15 ml of DMF are reacted according to the general procedure (variant B). DMF is removed under reduced pressure. The product is taken up in 100 ml of 1N aqueous sodium hydroxide solution and extracted three times with in each case 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure using a rotary evaporator. The reaction mixture is taken up in methanol and, together with acidic ion exchange resin (Dowex WX2-200), stirred for about 40 min. The loaded ion exchange is washed six times with in each case 100 ml of methanol. The product is then eluted with methanol/triethylamine 99:1 to 90:10. The solvent is removed under reduced pressure. The product is dried over magnesium sulfate. 1.75 g (99% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc(C(=O)O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.1 %

Procedure:
To a solution of 5-ethoxy-isophthalic acid dimethyl ester (D43) (22 g, 92.4 mmol, 1 equiv) in MeOH (440 ml) was added 1N aqueous NaOH solution (87.8 ml, 87.8 mmol, 0.95 equiv) and the resulting solution was stirred at room temperature for 17 h. Most of the MeOH was removed in vacuo and the residue was partitioned between AcOEt and 1N aqueous NaOH solution. The aqueous layer was extracted with AcOEt, acidified to pH 1 and re-extracted with AcOEt. The second organic extract was dried over MgSO4 and concentrated in vacuo to give 5-ethoxy-isophthalic acid monomethyl ester (D45) (17 g, 82%) as a white solid. [M+H+ NH3]+=242.0, RT=2.79 min