Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH2:23][CH2:24][OH:25]>>[OH:25][CH2:24][CH2:23][NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: NCCO
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCO)cc2c1=O
Yield: 59 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-ethanol according to the GPA affording 20 mg (59%) of a red powder. Rt=2.86 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[N:19]=[CH:20][O:21][C:22]=2[C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)=[O:17])[CH:12]=[N:11]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[N:19]=[CH:20][O:21][C:22]=2[C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)=[O:17])[CH:12]=[N:11]1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCNC(=O)OC(C)(C)C)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCN)c2)c1
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl(2-(4-(5-(m-tolyl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)ethyl)carbamate (4.29 g, 10.426 mmol) in DCM (60 mL), TFA (12 mL, 156.39 mmol) was added at 0° C. After strring for 1 h at rt, the reaction mixture was concentrated. The residue was dissolved in DCM and 2 N aq. NaOH-solution was added. The org. layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were dried (MgSO4), filtered and the solvent removed to yield the title compound as a white solid, which was used in the next step without further purification. LC-MS conditions B: tR=0.54 min, [M+H]+=312.31.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C@:13]([N:19]([CH3:29])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)=[O:21])([CH3:18])[C:14]([NH:16][CH3:17])=[O:15])([OH:12])=O.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][NH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.O.CN(C=O)C>[I:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:19]([CH3:29])[C@:13]([CH3:18])([C:10]([NH:37][O:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)=[O:12])[C:14]([NH:16][CH3:17])=[O:15])=[O:21])=[CH:23][CH:24]=1
Reactant: CNC(=O)[C@@](C)(C(=O)O)N(C)C(=O)c1ccc(I)cc1
Reactant: NOC1CCCCO1
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: CCOC(C)=O
Solvent: O
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Reaction time: 2 h
Yield: 25.9 %

Procedure:
DIPEA (5.3 mL) was added to a DMF (16 mL) solution of 1-{[(2S)-2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 14, 4.0 g) and O-(tetrahydropyran-2-yl)hydroxylamine (1.6 g), and HATU (5.9 g) was added under water cooling. The mixture was stirred for 2 hours under ice cooling, and then stirred for 1 hour at room temperature. Water and ethyl acetate were sequentially added, and the organic layer was isolated. The extract was washed sequentially with water and brine, and dried over anhydrous sodium sulfate. OH type silica gel (4.0 g) was added, and the mixture was filtered for 10 minutes at room temperature. Then, the silica gel was filtered out, and the solvent was distilled off under reduced pressure. A mixed solvent (IPE:ethyl acetate=10:1) was added to the resulting residue, and the supernatant was removed. This procedure was repeated twice, and then a solvent mixture of ethyl acetate (6.0 mL) and IPA (6.0 mL) was added to the resulting residue. The solids were collected by filtration to obtain (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, white solid) (1.3 g, 26%). Moreover, the residue obtained from the filtrate was purified by OH type silica gel column chromatography (ethyl acetate/hexane=50/50→gradient elution with chloroform/acetone=100/0→85/15) to obtain (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, white solid) (1.7 g, 34%).
Reaction SMILES: [Cl:1][C:2]1[C:18]([OH:19])=[CH:17][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Cl:20].[N+]([O-])(O)=[O:22]>C(O)(=O)C>[C:9]([C:6]1[C:5]2[C:17](=[O:22])[C:18](=[O:19])[C:2]([Cl:1])=[C:3]([Cl:20])[C:4]=2[O:8][CH:7]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1coc2c(Cl)c(Cl)c(O)cc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C1C(=O)c2c(C(=O)c3ccccc3)coc2C(Cl)=C1Cl
Temperature: 60 °C

Procedure:
To a solution of compound 4 (100 mg, 0.32 mmol) in glacial acetic acid (2 mL) at room temperature was added nitric acid (0.1 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 60° C. for 3 h, allowed to cool to room temperature, and poured over crushed ice. The resulting precipitate was filtered, dried, and recrystallized (CH2Cl2-pet. ether) to afford compound SKC-BF-09 (40 mg, 40%) as brick red solid. TLC Rf=0.5 (petroleum ether-EtOAc, 7:3); 1H NMR (CDCl3) δ 7.93 (s, 1H), 7.86 (d, J=6.9 Hz, 2H), 7.64 (app t, 1H), 7.50 (d, J=7.6 Hz, 2H); MS (ES) m/z 321 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21]>CCOCC>[OH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21]
Reactant: COc1ccc([C@H]2Cc3ccccc3NC(=O)[C@H]2O)cc1
Solvent: CCOCC
Product: COc1ccc([C@@H]2Cc3ccccc3NC(=O)[C@H]2O)cc1

Procedure:
Flash chromatography (LPS-1 silica gel, 70:30 hexanes-ethyl acetate) of the mother liquor resulting from the trituration from ether of the crude (cis)-3-hydroxy-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (see example 2E) afforded the title trans isomer, melting point 168°-170° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N+:19](=[CH:21][C:22](=[O:38])[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:27]([F:37])[CH:26]=1)[CH3:24])=[N-:20]>CCOCC>[CH2:16]([O:15][P:11]([C:9]1([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][C:21]([C:22](=[O:38])[CH:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:27]([F:37])[CH:26]=2)[CH3:24])=[N:19][NH:20]1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: CC(C(=O)C=[N+]=[N-])c1ccc(-c2ccccc2)c(F)c1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)CC(C(=O)C(C)c2ccc(-c3ccccc3)c(F)c2)=NN1

Procedure:
Ethenylidene bisphosphonic acid tetraethyl ester (II, PREPARATION 1, 11.1 g) and 1-diazo-3-[2-fluoro(1,1'-biphenyl)-4-yl]-butan-2-one (I, PREPARATION 3, 10.0 g) are stirred for 18 hrs in ether (40 ml). A seed crystal from an earlier reaction is added to the mixture, whereupon the reaction sets up into a solid mass. The precipitate is filtered, then recrystallized from methylene chloride/hexane (45/55) to give the title compound, mp 109°-110°; MS (m/e) 568, 431, 403, 385, 341, 313, 301 and 199; IR (mineral oil mull) 3179, 1656, 1557, 1265, 1246, 1033, 1009, 993, 976 and 965 cm-1 ; NMR (CDCl3) 7.4, 7.2, 6.91, 4.81, 4.4, 4.05, 3.4, 1.49, 1.34, 1.16 and 1.08 δ; CMR (CDCl3) 195.1, 162, 158, 149, 142, 136, 130.7, 128.8, 128.5, 127.6, 123.9, 115.8, 115.6, 64.3, 63.6, 46.1, 36.4, 17.7, 16.5, 16.2 and 16.1 δ.
Reaction SMILES: [CH2:1](Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(O)=O.[NH:18]([C:20]1[N:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[C:23]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:24]([C:30]1[CH:35]=[CH:34][C:33]([C:36]3([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=1)=[N:25]2)[NH2:19]>C(OCC)(=O)C.CN1C(=O)CCC1.C(Cl)Cl>[C:48]1([C:23]2[C:24]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)=[N:25][C:26]3[CH:27]=[CH:28][N:29]4[CH:1]=[N:19][N:18]=[C:20]4[C:21]=3[CH:22]=2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O=CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5cnnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added EDC (569 mg, 2.97 mmol), HOBt (401 mg, 10.6 mmol), formic acid (248 mg, 5.40 mmol), DCM (20 mL), & NMP (2.5 mL). The reaction mixture was then stirred at room temperature under an atmosphere of nitrogen for 30 minutes. Then added tert-butyl {1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (1.30 g, 2.70 mmol). The reaction mixture was then permitted to stir overnight at room temperature under an atmosphere of nitrogen. The reaction mixture was then suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography 50-90% EtOAc/DCM, then 1-15% IPA/DCM. The appropriate fractions were combined and the solvent was removed in vacuo to give tert-butyl {1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6b) as a tan solid. MS (M+H)+: observed=492.2, calculated=492.6.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([O:19][CH2:18][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: OCc1cc2cc(Br)ccc2n1Cc1ccccc1
Product: CC(=O)OCc1cc2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from (1-benzyl-5-bromo-1H-indol-2-yl)methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a semi-solid. Mass spectrum (ESI, [M−H]−) m/z 356. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, 1H, J=2.13 Hz), 7.38 (d, 1H, J=8.86 Hz), 7.29-7.20 (m, 4H), 6.94 (d, 2H, J=7.17 Hz), 6.64 (s, 1H), 5.47 (s, 2H), 5.21 (s, 2H), and 1.79 ppm (s, 3H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[C:15]3[C:30](F)(F)F)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].COC(C1CN(CC2C=C(C)C3C(=CC=C(O[C@H]4CC[C@H](C(C)(C)C)CC4)C=3)N=2)C1)=O>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH:25]([C:27]([OH:29])=[O:28])[CH2:26]2)[CH:16]=[C:15]3[CH3:30])[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(CN4CC(C(=O)O)C4)cc(C(F)(F)F)c3c2)CC1
Agent: COC(=O)C1CN(Cc2cc(C)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Product: Cc1cc(CN2CC(C(=O)O)C2)nc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc12

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid using 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-methyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester as starting material. ESI-MS (M+H+): 411.30; 1H NMR (400 MHz, METHANOL-d4) Shift 7.97 (d, J=9.29 Hz, 1H), 7.41 (dd, J=2.64, 9.16 Hz, 1H), 7.36 (d, J=2.51 Hz, 1H), 7.27 (s, 1H), 4.73 (s, 2H), 4.45-4.59 (m, 4H), 4.36-4.45 (m, 1H), 3.71-3.86 (m, 1H), 2.69 (s, 3H), 2.28 (d, J=11.29 Hz, 2H), 1.92 (d, J=10.79 Hz, 2H), 1.37-1.52 (m, 2H), 1.19-1.36 (m, 2H), 1.06-1.19 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([C:16](OC)=[O:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=1
Reactant: COC(=O)c1c(CCc2c(Cl)cccc2Cl)noc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A solution of methyl 3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolecarboxylate (0.900 g, 2.63 mmol) in THF (7.3 mL) was stirred at 0° C. as a 1.5M solution of diisobutylaluminum hydride in toluene (3.7 mL, 5.6 mmol) was added. The solution was allowed to warm to room temperature and stir overnight. Additional diisobutylaluminum hydride in toluene (1.8 mL, 2.7 mmol) was added and the solution was allowed to stir for another 3 hours. Methanol was added followed by a saturated aqueous solution of Rochelle's salt. The solution was stirred for two hours then was partitioned between ethyl acetate and brine. The organic layer was dried with magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-60% ethyl acetate in hexane) to provide the title compound (0.80 g, 51.6% as 0.25EtOAc). 1H NMR (DMSO-d6): δ 7.45 (d, J=8 Hz, 2H), 7.28 (t, J=8 Hz, 1H), 4.89 (t, J=5 Hz, 1H), 4.26 (d, J=5 Hz, 2H), 3.31-3.18 (m, 3H), 2.83-2.79 (m, 2H), 1.21 (d, J=7 Hz, 6H).
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH2:22])=[CH:16][C:17]=2Cl)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)=[CH:16][C:15]([NH2:22])=[CH:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Cl)c2c(c1)CN(Cc1ccccc1)CC2
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1cc2c(c(Nc3ccc(C(F)(F)F)cc3)c1)CCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 79.1 %

Procedure:
Sodium iodide (252 mg, 1.68 mmol) and hydriodic acid (1 mL, 47% aqueous solution) were added to the solution of 2-benzyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-amine (380 mg, 1.4 mmol) and 4-aminobenzotrifluoride (446 mg, 2.8 mmol) in dioxane (10 mL) and the reaction solution was stirred at 100° C. over night before solvent was removed in vacuo. Residue was dissolved in ethyl acetate, washed by water, brine, dried over sodium sulfate and was purified by column chromatography. Product was obtained as brown oil (440 mg, 79%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4].CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1.CCOC(C)=O>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[C@H:2]([NH:1][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COc1ccccc1[C@@H](O)[C@H](N)CN1CCCC1
Reactant: CCCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@H](O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a 0° C. solution of (1R,2R)-2-amino-1-(2-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-ol (0.1 g, 0.40 mmol) (compound 6) in THF (5 ml) was added Hunig's Base (0.07 g, 0.52 mmol), followed by the dropwise addition of octanoyl chloride (0.07 g, 0.40 mmol). The resulting mixture was allowed to stir overnight at room temperature, diluted with EtOAc, and washed with satd. aq. NaHCO3, satd. aq. NaCl, and dried over MgSO4. Purified by flash silica chromatography (MeOH/CH2Cl2) to give a yellow oil (0.03 g, 0.09 mmol, 22% yield). HPLC purity 93% (tR=5.3 min) NMR (500 MHz, CDCl3) δ 7.4 (m, 1H), 7.2-7.3 (m, 1H), 6.9-7.0 (m, 1H), 6.8-6.9 (m, 1H), 6.0-6.1 (m, 1H), 5.3 (d, 1H), 4.2-4.3 (m, 1H), 3.8 (s, 3H), 2.9-3.0 (m, 3H), 2.5-2.7 (m, 4H), 2.0-2.1 (m, 2H), 1.7-1.8 (m, 4H), 1.9-2.0 (m, 2H), 1.2-1.4 (m, 6H), 0.8-0.9 (t, 3H). ESI-MS m/z 377.2 (M+H +).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1Cl
Temperature: 70 °C
Yield: 53.3 %

Procedure:
Sodium hydroxide (40 mg) was added to a solution of ethyl 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D108) (300 mg) in iPrOH (10 mL) and water (10 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E81) (150 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.61 (2H, t), 2.97 (2H, t), 5.46 (1H, m), 7.34 (1H, d), 7.71 (2H, m), 8.12 (1H, s), 8.54 (1H, s), 8.92 (1H, s), 11.18 (1H, s), 12.05 (1H, br s). MS (ES): C21H19ClN4O4 requires 426; found 427.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=[O:14])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25]CC2C=CC(OC)=CC=2)[N:3]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH:5]=[C:6]([C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3cccc(C(=O)O)c3)c(C#N)c(N)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O
Product: N#Cc1c(-c2cccc(C(=O)O)c2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A mixture of 3-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)benzoic acid (starting compound 5, 0.16 g, 0.36 mmol), trifluoroacetic acid (3.0 mL), anisole (0.50 mL), and water (0.50 mL) was stirred at room temperature overnight. The reaction mixture was diluted with toluene and concentrated under reduced pressure. The residue was dissolved in THF and then crystallized with hexane. The resulting precipitate was collected by filtration and washed with hexane, and then dried under reduced pressure to give 2-amino-6-(2-hydroxyphenyl)-4-(3-hydroxycarbonylphenyl)nicotinonitrile (0.12 g, yield 74%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:7](=[NH:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:23][C:19]=1[C:20](O)=[O:21].CCN(CC)CC.C(P(=O)(OCC)OCC)#N>C1COCC1>[NH2:28][S:27]([C:24]1[CH:25]=[CH:26][C:18]([F:17])=[C:19]([CH:23]=1)[C:20](/[N:16]=[C:7]1/[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15]2)[N:9]([CH3:10])[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]/1)=[O:21])(=[O:30])=[O:29]
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CCC1
Reactant: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(S(N)(=O)=O)ccc2F)n1CC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To a solution of Example 113C (0.43 g, 1.9 mmol) and 2-fluoro-5-sulfamoylbenzoic acid (Enamine, 0.47 g, 2.1 mmol) in THF (10 mL) was added Et3N (0.68 mL, 4.9 mmol) followed by diethyl cyanophosphonate (0.44 mL, 2.9 mmol). The mixture was stirred at ambient temperature for 2 hours then concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (0.26 g, 0.62 mmol, 32% yield). MS (DCI/NH3) m/z 423 (M+H)+.
Reaction SMILES: [OH-].[Na+].FC(F)(F)C([O-])=O.[S:10]1[C:14]2[C:15]3([CH2:23][CH2:22][NH2+:21][CH2:20][CH2:19]3)[O:16][CH2:17][CH2:18][C:13]=2[CH:12]=[CH:11]1>ClCCl>[S:10]1[C:14]2[C:15]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:16][CH2:17][CH2:18][C:13]=2[CH:12]=[CH:11]1
Reactant: c1cc2c(s1)C1(CC[NH2+]CC1)OCC2
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1cc2c(s1)C1(CCNCC1)OCC2
Temperature: 0 °C
Yield: 86 %

Procedure:
3-Thiopheneethanol (123.03 mL, 1.11 mol) is added to a solution of N-tert-butoxycarbonyl-4-piperidone (185 g, 928.48 mmol) in dichloromethane (1300 mL) and stirred at room temperature. Then trifluoroacetic acid (280.82 mL, 3.71 moles) is added dropwise (5 min) while cooling with an ice/water bath (internal temperature=14° C.-30° C., caution: CO2 evolution). The reaction mixture is gradually warmed to ambient temperature and stirred at that temperature for 20 hr. The solvent is evaporated to provide a beige crystalline solid upon cooling in vacuo. The solid is slurried in methyl t-butyl ether (200 mL), filtered, washed with methyl t-butyl ether (2×1000 mL) and dried under vacuum to afford 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-ium trifluoroacetate as a white solid in 95% yield. MS=(m/z): 210 (M+1). 10 M sodium hydroxide (220.36 mL, 2.20 mol) is added to a stirred suspension of 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-ium trifluoroacetate (285 g, 881.44 mmol) in dichloromethane (1 L) with cooling (ice/water bath) and the resulting mixture is stirred till a biphasic mixture is obtained. The phases are separated and the aqueous layer is extracted with dichloromethane (2×200 mL). Combined organics are concentrated under vacuum to obtain a thick oil which is triturated with water to obtain a light yellow precipitate. The precipitate is filtered, washed with water (300 mL) and hexane (200 mL) and dried under vacuum at 35° C. for 20 hr. to yield the title compound as a light yellow solid in 86% yield. MS (m/z): 210 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[C:6](=[C:7]([CH2:12][O:13]C3CCCCO3)[CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:4](=[O:28])[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[OH:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:4](=[O:28])[CH2:3][C:2]2([CH3:29])[CH3:1]
Reactant: CC1(C)CC(=O)N(COCC[Si](C)(C)C)c2c(COC3CCCCO3)cccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC1(C)CC(=O)N(COCC[Si](C)(C)C)c2c(CO)cccc21

Procedure:
Analogously to Example 129c, 0.68 g of 4,4-dimethyl-8-(tetrahydropyran-2-yloxymethyl)-1-(2-trimethylsilanylethoxymethyl)-3,4-dihydro-1H-quinolin-2-one and 0.041 g of pyridinium p-toluenesulphonate are reacted. The title compound is obtained as a yellowish oil. Rf=0.55 (1:1 EtOAc-heptane); Rt=4.78.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10]C(C)=O>>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:10]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)=O
Product: CC(=O)c1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is acetone and the carboxylic acid is benzoic acid to yield acetophenone.