Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1.[Na].[CH:14]([OH:17])([CH3:16])[CH3:15]>>[CH:14]([O:17][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1)([CH3:16])[CH3:15]
Reactant: CC(C)O
Reactant: Clc1cc(-n2cccn2)ncn1
Agent: [Na]
Product: CC(C)Oc1cc(-n2cccn2)ncn1

Procedure:
Following the procedure of Example 15, 180 mg of 6-chloro-4-(1-pyrazolyl)pyrimidine was reacted with 23 mg of sodium metal and 3 ml of anhydrous isopropylalcohol to yield 127 mg of an oily substance, 6-isopropoxy-4-(1-pyrazolyl)pyrimidine,
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[N:16]([CH3:20])[N:17]=[N:18][CH:19]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(O)C>CCCCCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[N:16]([CH3:20])[N:17]=[N:18][CH:19]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1cnnn1C
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cnnn1C
Yield: 45.4 %

Procedure:
Racemic compound 73.5 (3.28 g, 12 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 30% i-PrOH in hexane as eluant. Eluant containing the peak with less retention time was concentrated and compound 73.6 (1.5 g, 5.45 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 276.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-])=O)=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:4][CH2:3]1.O.NN>C1COCC1.CCO.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:18])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c3cccnc23)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c3cccnc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 8-(4-methyl-1-piperazinyl)-5-nitroquinoline (0.379 g, 1.39 mmol) in THF:EtOH 1:4 solvent system was added Raney-Ni (1.0 mL suspension in EtOH) followed by hydrazine hydrate (0.348 g, 6.95 mmol). The mixture was stirred vigorously at room temperature for 16 hours and then filtered through celite pretreated with water. The filtrate was concentrated, and the residue was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 0.337 g of 8-(4-methyl-1-piperazinyl)-5-quinolinylamine. The amine was dissolved in CH2Cl2 (6.0 mL) and pyridine (0.785 mL, 9.73 mmol) and benzenesulfonyl chloride (0.178 mL, 1.39 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then washed with saturated aqueous NaHCO3. The organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 0.130 g of the free base which was converted to its HCl-salt: 1H NMR (DMSO-d6) δ; 11.09 (br s, 1H), 10.32 (s, 1H), 8.94–8.89 (m, 1H), 8.55–8.48 (m, 1H), 7.68–7.65 (m, 2H), 7.64–7.57 (m, 2H), 7.54–7.49 (m, 2H), 7.27–7.22 (m, 1H), 7.12–7.08 (m, 1H), 3.95–3.84 (m, 2H), 3.55–3.49 (m, 2H), 3.45–3.35 (m, 2H), 3.26–3.16 (m, 2H), 2.85–2.82 (m, 3); MS (posESI) m/z 383 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]#[N:20])=[CH:6][CH:5]=1)(O)=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl>O1CCCC1.O1CCCC1.O>[OH:2][CH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]#[N:20])=[CH:6][CH:5]=1
Reactant: N#Cc1cc2ccccc2n1-c1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cc2ccccc2n1-c1ccc(CO)cc1
Reaction time: 0.33 h
Yield: 56.1 %

Procedure:
2.8 g (0.0107 mol) of 1-(4-carboxyphenyl)-2-cyanoindole was dissolved in 100 ml tetrahydrofuran and cooled in an ice-bath. 1.5 ml (0.01 mol) of triethylamine was added, followed by the dropwise addition of 1.1 ml (0.01 mol) ethyl chloroformate. After stirring for 20 minutes the precipitate was removed by filtration and a solution of 1.2 g (0.1 mol) sodium borohydride in 60 ml tetrahydrofuran-water 3:1 was added dropwise to the filtrate. After stirring an additional 20 minutes, 5 ml of 10% hydrochloric acid was added, and the mixture extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to an oil. The oily material was chromatographed on silica gel, eluting with ethyl acetate-hexane 7:3 to give 1.5 g (0.006 mole) of 1-[4-(hydroxymethyl)phenyl]-2-cyanoindole as an oil.
Reaction SMILES: C[N:2](C)C=O.[CH3:6][O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=1)=[O:9].C([O-])=O.[NH4+].C(OCC)(=O)C>O>[NH2:2][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:11][CH:12]=1)=[CH:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dimethylformamide (123 l), 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (24.5 kg) and ammonium formate (21.0 kg) were charged in 2000-liter reactor at room temperature and heated, and a reaction was carried out at the inner temperature of 100 to 105° C. for 5 hours. After completion of the reaction, the mixture was cooled down to room temperature, ethyl acetate (613 l) and water (613 l) were added, the mixture was stirred, and an ethyl acetate layer was separated, and then washed with 10% sodium chloride solution (613 l) and with 20% sodium chloride solution (613 l). The ethyl acetate layer was concentrated in vacuo to 125 l and then diluted with n-heptane (625 l) at the inner temperature of 40 to 45° C. to separate crystals of 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene. The cyrstals were filtered at room temperature and washed with a mixture of n-heptane (104 l) and ethyl acetate (21 l). The crystals were dried overnight in vacuo and purified by suspending in a 70% aqueous acetone (158 l) to give 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (14.3 kg).
Reaction SMILES: [F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N+:23]([O-])=[CH:22][CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[C-]#N.[CH3:30][N:31](C)C(Cl)=O>C(#N)C>[F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:30]#[N:31])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: [O-][n+]1ccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)cc1
Reactant: CN(C)C(=O)Cl
Agent: [C-]#N
Solvent: CC#N
Product: N#Cc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Reaction time: 14 h

Procedure:
100 mg (0.26 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(N-oxido-4-pyridyl)-2-pyrimidineamine, 90 μl (0.72 mmol) or trimethylsiyl cyanide and 66 μl (0.72 mmol of N,N-dimethyl-carbamoyl chloride are dissolved in 5 ml of acetonitrile and stirred at 60° for 14 h. Concentration under reduced pressure and recrystalisation from tetrahydrofuran/diethyl ether give N-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamine; FAB-MS: 390 (M+ +H), Rf =0.7 (hexane:ethyl acetate=1:1).
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.OCCCCCCCCCCCC(O)=O.[CH:41]1([N:47]=[C:48]=[N:49][CH:50]2[CH2:55][CH2:54][CH2:53]CC2)CCCCC1>O1CCCC1>[CH3:1][N:47]([C:48]1[CH:53]=[CH:54][CH:55]=[CH:50][N:49]=1)[CH3:41]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)CCCCCCCCCCCO
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 365 mg of radicicol, 1.8 g of 12-hydroxydodecanoic acid, 20 ml of dry tetrahydrofuran, 1 g of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 485 mg of the title compound were obtained.
Reaction SMILES: C([S:4][C@H:5]1[N:8]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:22])[C@@H:6]1[Br:23])(=O)C.[N+]([O-])([O-])=O.[Ag+:28].C(N(CC)CC)C>CO>[Br:23][C@@H:6]1[C@@H:5]([S-:4])[N:8]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:11])[C:7]1=[O:22].[Ag+:28]
Reactant: COc1ccc(COC(=O)CN2C(=O)[C@H](Br)[C@H]2SC(C)=O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(COC(=O)CN2C(=O)[C@H](Br)[C@H]2[S-])cc1
Reaction time: 1 h

Procedure:
A solution of p-methoxybenzyl [(3S, 4R)-4-acetylthio-3-bromo-2-oxoazetidin-1-yl]acetate (4.13 g, 0.01 mol) in methanol (90 ml) was added with stirring in subdued light to a solution of silver nitrate (2.27 g, 0.0133 mol) in methanol (90 ml). Triethylamine (1.87 ml, 0.0133 mol) was then added with ice cooling, and stirring continued for 1 hr. at 5-10° C. followed by 30 min. at room temperature. The mixture was re-cooled (ice bath) and the precipitated solid filtered and washed twice with ice cold methanol then hexane to give the title compound, yield, 4.6 g (96%).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using [1,1′-biphenyl]-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cscn2)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.076 g, 0.21 mmol), EtOH (3.6 mL) and DMF (0.49 mL), 4-(morpholinomethyl)benzaldehyde (0.047 g, 0.23 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.64 mL, 0.64 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.045 g, 42%); 1H-NMR (500 Mz, DMSO-d6): δ 2.38 (m, 4H), 2.68 (m, 4H), 3.53 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.71 (m, 4H), 3.76 (s, 2H, NCH2), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.10 (s, 1H, pyridine 6-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.44 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=1.85 min—510/512 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 510.1866, calculated for C25H29ClN7OS (M+H)+: 510.1843.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][N:17]=[C:16]([N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH3:21])[CH:15]=1)[CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:39]([O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([N:20]([C:16]2[CH:15]=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:19]=[CH:18][N:17]=2)[CH3:21])[CH2:23][CH2:24]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)Cl
Reactant: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(N(C)c2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
7d was dissolved in DCM (1 mL) and triethylamine (0.1 mL, 14 eq) was added. Isopropyl chloroformate (0.1 mL of a 1 M solution in toluene, 2 eq) was added and the reaction mixture was stirred at room temperature for 17 h. The solution was evaporated and purified by preparative HPLC to give 7-1; LC-MS 474.0 (MH+), tR=5.21 (Method 5). EC50: 69 nM.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:6]=1.[Cl-].[NH4+].C(O)C.O>O1CCCC1.[Fe]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:6]=1
Reactant: Nc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(SCc2csc(N)n2)cc1
Yield: 78.8 %

Procedure:
To a mixture of 2-amino-4-(4-nitrophenylthiomethyl)thiazole (15 g) and ammonium chloride (2 g) in a mixture of tetrahydrofuran (100 ml), ethanol (150 ml) and water was added portionwise added the iron powder (15 g) at 80° C. with stirring. The mixture was refluxed for 2 hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure. The residue was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was triturated with chloroform. The precipitates were collected by filtration, washed with ether and dried in vacuo to give 2-amino-4-(4-aminophenylthiomethyl)thiazole (10.50 g, yield: 73.0%). mp: 130°-132° C.
Reaction SMILES: [OH:1][C:2]1C=CC2[C:4](=CC=C([N+]([O-])=O)C=2)[C:3]=1C=O.C[N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](C)(C)[C:19]1=[CH2:29]>C(O)C>[O:1]1[CH:2]=[CH:3][CH:4]=[CH:29][C:19]21[CH2:20][C:21]1[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:18]2
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: O=Cc1c(O)ccc2cc([N+](=O)[O-])ccc12
Solvent: CCO
Product: C1=COC2(C=C1)Cc1ccccc1N2
Temperature: 0 °C

Procedure:
A solution is prepared of 2.17 g. (0.0295 mole) of 2-hydroxy-6-nitro-1-naphthaldehyde in 80 cm3 of hot ethanol, to this is added 1.73 g. (0.0295 mole) of 1,3,3-trimethyl-2-methyleneindoline and the mixture is heated for two hours at boiling temperature under reflux. The mixture is then cooled to 0° C. and a precipitate of indolinespiropyran is obtained. This is filtered and dried. The composition has a melting point of 234° C. The product is recrystallized twice from benzene and the melting point is increased to 240°-241° C. The purified product weight is 1.34 g. which represents a recovery of 36%.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:14][C:15]([N:17]1C[CH2:23][CH2:22][C@@H:18]1C(O)=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:4][C:2]([C@H:1]1[CH2:23][CH2:22][CH2:18][N:17]1[C:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
A mixture composed of 40 mL of toluene and 40 mL of oxalyl chloride was added—in 30 minutes at room temperature—to a solution of 100 g of 1-[(benzyloxy)carbonyl]-D-proline in 200 mL of toluene and 0.5 mL of DMF. After stirring for 2 hours at 20-25° C. the HPLC showed complete conversion and the reaction mixture was concentrated with oil at about 40° C. under vacuum, redissolved to toluene and reconcentrated obtaining 122.1 g of residue. At 20-25° C. the residue was dissolved in 100.00 mL of THF and this solution was used in example 2.
Reaction SMILES: [O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].Cl[CH2:37][C:38](=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:37][C:38](=[O:40])[CH3:39])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCOc1c(OCC(C)=O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of trans-2-[3-(2- oxopropylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]5- (3,4,5-trimethoxyphenyl)tetrahydrofuran (51 mg, 0.1 mmol), chloroacetone(16 uL, 0.2 mmol) and potassium carbonate (28 mg, 0.2 mmol) in DMF (1 mL) was stirred at room temperature for 40 h. The reaction mixture was diluted with ethyl ether and washed with water and brine. The organic extracts were dried (MgSO4), filtered, and evaporated to a residue (58 mg), which was purified by preparative TLC (hexane ethyl acetate; 3:2. v/v). The title compound was isolated as a colorless foam: Rf 0.38; MS, m/z 564M+.; NMR (CDCl3) δ 1.08(t, CH2CH2CH3), 2.33 & 2.38 (2 s, OCH2COCH3 & SO2CH2COCH3), 4.48 (s, SO2CH2), 4.68 (s, OCH2CO), 5.20 (m, H-2 & H-5), 6.62 (s, 2 H, C5ArH), 7.20 & 7.52 (2 d, 2 H, C2ArH)
Reaction SMILES: O=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([C:9]([OH:11])=[O:10])[CH2:3]1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[OH-].[Na+]>O.CN(C)C=O>[O:8]=[C:6]1[CH2:5][CH:4]([C:9]([OH:11])=[O:10])[CH2:3][C:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)=[CH:7]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CC(=O)CC(C(=O)O)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC(C(=O)O)C1
Temperature: 25 °C

Procedure:
A mixture of 3,5-dioxocyclohexanecarboxylic acid (1.00 g, 6.41 mmol), 3-(trifluoromethyl)aniline (880 μL, 1.14 g, 4.05 mmol), Ytterbium(III) trifluormethanesulfonate (20 mg, 32 μmol, 0.5 mol %) and N,N-dimethylformamide (3 mL) is stirred at room temperature over night. Water and aqueous sodium hydroxide are added and the mixture is washed with diethyl ether. The organic layer is discarded, and the aqueous layer is acidified with aqueous hydrogen chloride and extracted with diethyl ether. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 1.30 g; ESI mass spectrum [M+H]+=300, Retention time HPLC: 1.08 min (V001—006).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][CH:46]([N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 66.7 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (139 mg, 0.30 mmol), 2-(methyloxy)-4-[4-(4-morpholinyl)-1-piperidinyl]aniline (79 mg, 0.27 mmol) and p-toluenesulfonic acid (137 mg, 0.71 mmol) in iPrOH was heated in the microwave at 180° C. for 13.5 min. The mixture was dissolved in DCM and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 129 mg (60%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.38 (br s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.46-7.35 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 6.96 (t, J=6.8 Hz, 1H), 6.65 (m, 1H), 6.48-6.43 (m, 2H), 3.77 (s, 3H), 3.71 (d, J=12.4 Hz, 2H), 3.56-3.54 (M, 4H), 2.67-2.62 (m, 2H), 2.49-2.46 (m under DMSO peak, 4H), 2.27-2.22 (m, 1H), 1.86-1.83 (m, 2H), 1.52-1.44 (m, 2H). MS (ESI) m/z=717 [M+H]+.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14].C([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](OC(F)(F)F)[CH:26]=2)[N:21]([CH2:33][C:34]([OH:36])=[O:35])[CH:20]=1)(=O)C>>[CH3:10][O:11][CH2:12][C:13]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:33][C:34]([OH:36])=[O:35])[CH:20]=1)=[O:14]
Reactant: COCC(=O)Cl
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Agent: c1ccc2[nH]ccc2c1
Product: COCC(=O)c1cn(CC(=O)O)c2ccccc12

Procedure:
was prepared from 1H-indole in a similar manner as described in Scheme A13 (in step A, 2-methoxyacetyl chloride was used instead of acetyl chloride) for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 248.0 [M+H]+; tR (HPLC conditions c): 3.42 min.
Reaction SMILES: CCO.[O:4]=[C:5]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=2)[NH:9][C@@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[O:6]1>C1COCC1.Cl[Pd]Cl>[C:19]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[OH:18])[CH2:11][C@@H:10]([C:5]([OH:6])=[O:4])[NH2:9])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)ccc1O
Agent: Cl[Pd]Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C[C@H](N)C(=O)O)ccc1O
Reaction time: 18 h
Yield: 105.9 %

Procedure:
To a 300 mL Parr bottle were added 0.73 g of PdCl2 and 20 mL of 1:1 THF:EtOH. To this was added a solution of 2.43 g of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-tert-butyl-4-hydroxybenzyl)morpholine in 80 mL of 1:1 THF:EtOH. The mixture was deoxygenated by bubbling nitrogen through for 10 min and was hydrogenated at 45 psi for 18 h. The vessel was purged with nitrogen, catalyst removed by filtration, and the filtrate concentrated in vacuo. The residue was partitioned between water and hexane. The aqueous solution was washed with four additional 50 mL portions of hexane, subjected to brief rotary evaporation to remove residual hexane, frozen and lyophilized to afford 1.47 g (92%) of 3-tert-butyl-L-tyrosine.HCl as a tan hygroscopic solid.