Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:2][CH3:3])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)ccc4F)cc23)CC1
Agent: CN
Solvent: O=C(O)C(F)(F)F
Product: CCCNCc1ccc(F)c(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 61.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting propylamine (44 μL, 0.524 mmol) for methanamine to afford 15.4 mg of the title compound (61.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[CH2:7][OH:8].[CH3:10][O:11][C:12]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:13]=1[NH2:14]>>[NH2:14][C:13]1[CH:15]=[CH:16][C:17]([C:2]2[CH:3]=[N:4][N:5]([CH3:9])[C:6]=2[CH2:7][OH:8])=[CH:18][C:12]=1[O:11][CH3:10]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: Cn1ncc(Br)c1CO
Product: COc1cc(-c2cnn(C)c2CO)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 158 using (4-bromo-1-methyl-1H-pyrazol-5-yl)methanol (Preparation 222) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. The residue was purified using Biotage silica gel column chromatography eluting with EtOAc followed by elution through an SCX-2 cartridge.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[O:15])=[C:12]([CH3:29])[O:11][N:10]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])=[C:12]([CH3:29])[O:11][N:10]=1
Reactant: COC(=O)CCC1CCCCC1NC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)N[C@@H]1CCCC[C@H]1CCC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl 3-(2-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)propanoate (0.127 g, 0.3 mmol) in THF (5 mL) was treated with a 0.5 M sol'n of LiOH in water (3 mL). The sol'n was stirred at r.t. for 5 hr. The reaction was diluted with water (3 mL) and washed with EtOAc (2×5 mL). The pH of the aqueous was adjusted to ˜3 with 0.1 M HCl and extracted with EtOAc (4×5 mL). The organic extractions were then washed with brine (2×5 mL), dried over sodium sulfate and the solvent removed to afford 0.095 g (80%) as a white solid. MS (ES+) m/z 409.0 (M+H)+, (ES−) m/z 407.0 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.Br[C:21]1[C:22](=[O:29])[N:23]([CH3:28])[CH:24]=[C:25]([Br:27])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[Br:27][C:25]1[CH:26]=[C:21]([NH:1][C:2]2[N:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]3)=[CH:4][CH:3]=2)[C:22](=[O:29])[N:23]([CH3:28])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)nc2)C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Yield: 89.9 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 206c (950 mg, 3.6 mmol), XantPhos (125 mg, 0.29 mmol), Pd2dba3 (260 mg, 0.29 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.03 g, 3.9 mmol), Cs2CO3 (1.8 g, 7.2 mmol), and 1,4-dioxane (20 mL). The system was evacuated and refilled with N2. It was then heated at reflux for 2 h. After the completion of the reaction, the mixture was filtered off and washed with methanol (100 mL). The combined filtrate was evaporated in vacuo and the residue was purified on reverse-phase Combiflash to afford 206d (1.46 g, 90%). MS-ESI: [M+H]+ 451.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:32][O:33][C:34]([CH:36]1[CH:41](OS(C(F)(F)F)(=O)=O)[CH2:40][CH2:39][N:38]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:37]1)=[O:35].C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:32][O:33][C:34]([C:36]1[CH2:37][N:38]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:39][CH2:40][C:41]=1[C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)=[O:35]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1=C(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 91.2 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.20 g, 0.49 mmol), 4-trifluoromethanesulphonyloxy-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.29 g, 0.75 mmol), potassium acetate (0.12 g, 1.22 mmol), Pd(dppf)2Cl2.DCM (0.04 g, 0.05 mmol), DME:IMS:water 7:2:1 (5 mL), were sealed in a microwave vial and heated by microwave irradiation at 120° C. for 10 min. The reaction mixture was cooled to RT, water and DCM were added, the organic layer separated, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (239 mg, 91%). 1H NMR 300 MHz (CDCl3) δ: 8.49 (1 H, d, J=8.30 Hz), 7.87 (1 H, d, J=0.64 Hz), 7.64 (1 H, s), 6.92 (1 H, dd, J=8.31, 1.80 Hz), 6.84 (1 H, d, J=1.77 Hz), 6.00 (1 H, m), 4.49-4.47 (4 H, m), 4.27 (2 H, s), 3.62 (2 H, t, J=5.69 Hz), 3.57 (2 H, s), 2.50 (3 H, s), 1.59 (6 H, d, J=6.63 Hz), 1.51 (9 H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=O)[O:10][N:9]=2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].CN(C)C=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2noc(=O)[nH]2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(Cl)n2)cc1[N+](=O)[O-]

Procedure:
To a solution of 3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one (106) (12 g, 54.26 mmol) in POCl3 (120 mL) was added N,N-dimethylformamide (12 mL). The resulted solution was heated to reflux for 72 hours then concentrated under vacuum. The residue was dissolved in water (250 mL) and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine (3×250 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (PE/EA=10:1) to afford 5-chloro-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (107) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.64 (dd, J=1.5, 8.4 Hz, 1H), 8.18 (dd, J=1.5, 7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 2.70 (s, 3H). MS m/z 240.7 (M+1)+.
Reaction SMILES: C([O:8][P:9]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]([CH3:83])([CH3:82])[C:26]([O:28][C:29]1[C:33]([O:34][C:35](=[O:63])[C:36]([CH3:62])([CH3:61])[CH2:37][O:38][CH2:39][CH2:40][CH2:41][O:42][P:43]([O:53]CC2C=CC=CC=2)([O:45]CC2C=CC=CC=2)=[O:44])=[C:32]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[N:31]([C:69]2[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=2)[C:30]=1[C:77](=[O:81])[N:78]([CH3:80])[CH3:79])=[O:27])([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH3:83][C:25]([CH3:82])([CH2:24][O:23][CH2:22][CH2:21][CH2:20][O:19][P:9]([OH:10])([OH:11])=[O:8])[C:26]([O:28][C:29]1[C:33]([O:34][C:35](=[O:63])[C:36]([CH3:61])([CH3:62])[CH2:37][O:38][CH2:39][CH2:40][CH2:41][O:42][P:43]([OH:45])([OH:53])=[O:44])=[C:32]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[N:31]([C:69]2[CH:70]=[CH:71][C:72]([O:75][CH3:76])=[CH:73][CH:74]=2)[C:30]=1[C:77](=[O:81])[N:78]([CH3:79])[CH3:80])=[O:27]
Reactant: CCOC(=O)c1c(OC(=O)C(C)(C)COCCCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(OC(=O)C(C)(C)COCCCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(OC(=O)C(C)(C)COCCCOP(=O)(O)O)c(OC(=O)C(C)(C)COCCCOP(=O)(O)O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Yield: 101 %

Procedure:
A solution of 2-(dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl bis(3-(3-((bis(benzyloxy)phosphoryl)oxy)propoxy)-2,2-dimethylpropanoate) (56) (37 mg, 0.03 mmol) in MeOH (4 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 40° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford 2-(dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl bis(2,2-dimethyl-3-(3-(phosphonooxy)propoxy)propanoate) (UL1-118) (25 mg, 95%) as a white gum: m/z 825 (M+H)+ (ES+); 823 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 7.24-7.16 (m, 2H), 6.98-6.91 (m, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.90-3.81 (m, 4H), 3.79 (s, 3H), 3.51-3.43 (m, 8H), 2.82 (s, 3H), 2.70 (s, 3H), 1.86-1.73 (m, 4H), 1.25 (s, 6H), 1.19 (s, 6H), 1.01 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(P(C1CCCCC1)C1CCCCC1)C.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C:18](=[O:24])[CH2:17]2>CO.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@H:18]([OH:24])[CH2:17]2
Reactant: O=C1CN2CCC1CC2
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: CCP(C1CCCCC1)C1CCCCC1
Solvent: C1=CCCC=CCC1
Solvent: CO
Product: O[C@@H]1CN2CCC1CC2
Reaction time: 22 h
Yield: 66.8 %

Procedure:
In an autoclave (160 ml), a solution of 200 mg (0.41 mmol) of bis(1,5-cyclooctadiene)dirhodium(I) dichloride and 480 mg (0.81 mmol) of (R)-1-[(S)-2-diphenylphosphino)ferrocenyl]ethyl-dicyclohexylphosphine (IIIb, corresponding to an educt/catalyst molar ratio of 50) in 70 ml of degassed methanol was added to 5.00 g (40 mmol) of 3-quinuclidinone under argon. The mixture was hydrogenated for 22 hours at 75° C. and 50 bar of H2. After evaporation of the reaction solution, the pH was adjusted to 1 with 1N hydrochloric acid and the mixture was extracted three times with 50 ml of dichloromethane. The aqueous phase was adjusted to pH 14 with sodium hydroxide solution (30 percent) and evaporated to dryness. The residue was extracted four times with 100 ml of dichloromethane and the combined organic extracts were dried over MgSO4 and evaporated to give 3.40 g (67 percent) of (S)-3-quinuclidinol in the form of a white crystalline solid. Recrystallization from ethyl acetate gave 2.65 g (52 percent) of (S)-3-quinuclidinol with 7 percent ee. Other data concerning the product was: ##EQU7##
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]([N:9]1[C:13]([OH:14])=[C:12]([C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:17]=2[CH3:34])[CH:11]=[N:10]1)([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:8][C:6]([N:9]1[C:13]([O:14][C:1](=[O:3])[CH3:2])=[C:12]([C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:17]=2[CH3:34])[CH:11]=[N:10]1)([CH3:5])[CH3:7]
Reactant: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3O)c2C)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3OC(C)=O)c2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.25 mL of acetyl chloride in 3 mL of dry dichloromethane was added slowly under nitrogen at 0° C. with stirring to a solution of 1.5 g (3.4 mmol) of 1-(1,1-dimethylethyl)-5-hydroxy-4-(2-methyl-4-methylsulfonyl-3-(4-methoxyphenyl)benzoyl)pyrazole and 0.52 mL of triethylamine in about 20 mL of dry dichloromethane. The mixture was allowed to warm to ambient temperature and stir for 2 hours and was then diluted with dichloromethane. The resulting solution was extracted with saturated aqueous sodium bicarbonate solution and with water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residual yellow oil was chromatographed on silica gel eluting with a 50:50 mixture of ethyl acetate and hexane. The product fractions were combined and concentrated by evaporation under reduced pressure to obtain 1.03 g (62 percent of theory) of the title compound as a white powder melting at 160-163° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:33])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:32].[Li+].[OH-].Cl>C1COCC1.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10](=[O:33])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH3:31])[C:27]([OH:29])=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:32]
Reactant: COC(=O)C(C)NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(C(=O)NC(C)C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A mixture of Methyl 2-(3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxamido)propanoate (Example 101) (1.0 equiv.) and LiOH (3.0 equiv.) in 25 ml of 4:1 THF/water was stirred at room temperature for 15 min. The mixture was slightly acidified to pH <7 by adding 2N HCl and then the solvent was evaporated. The solid was suspended in water and filtered, given water washings and air-dried. The resulting solid was triturated with acetone and methanol and collected by filtration. This yielded the title compound as a white solid (43%) after drying in vacuo; 1H NMR (300 MHz, DMSO-d6) δ: 1.38-1.40 (d, J=7.2 Hz, 3H), 2.32 (s, 3H), 4.38-4.43 (m, 1H), 7.12-7.18 (m, 2H), 7.27-7.32 (m, 1H), 7.60 (S, 1H), 7.67-7.70 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 8.05-8.08 (d, J=8.7 Hz, 1H), 832 (s, 1H), 8.65 (s, 1H), 9.18-9.21 (d, J=7.2 Hz, 1H), 12.76 (brs, 1H); ms (ESI) m/z 445.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH2:20][CH3:21])[CH:8]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.Cl[C:32]1[C:37]([CH3:38])=[C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:35]=[CH:34][N:33]=1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH2:20][CH3:21])[CH:8]=1)[C:32]1[C:37]([CH3:38])=[C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:35]=[CH:34][N:33]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(-c2ncnc(Cl)c2C)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(CC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(CC)c1)c1ncnc(-c2ccc(C)cc2)c1C
Temperature: 100 °C
Yield: 18.6 %

Procedure:
A mixture of ethyl {4-[(butylamino)methyl]-2-ethylphenoxy}acetate (0.23 g, 0.78 mmol), N,N-diisopropylethylamine (0.18 mL, 1.05 mmol) and 4-chloro-5-methyl-6-(4-methylphenyl)pyrimidine (0.114 g, 0.52 mmol) were heated at 100° C. in a sealed reactivial for 18 h. After this time the reactivial was allowed to cool to room temperature and the residue dissolved in CH2Cl2 (50 mL) and washed with water (10 mL) and brine (10 mL). The organic extract was separated by hydrophobic frit and evaporated. Purification by Biotage™ chromatography (Silica, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (46 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([CH2:35][CH3:36])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:34])=[C:13]([CH:33]=1)[C:14]([NH:16][C:17]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20])=[O:15])[CH3:4].CS(O)(=O)=O>O1CCOCC1>[CH2:35]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:34])=[C:13]([CH:33]=1)[C:14]([NH:16][C:17]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:18]=1[C:19]([OH:21])=[O:20])=[O:15])[CH3:36]
Reactant: CCN(CC)CCOc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(CC)CCOc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Dioxane (3.0 mL) and a 4 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to the obtained methyl 2-(5-(2-(diethylamino)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate (0.087 g), followed by stirring at room temperature for 2 hours and 30 minutes and then at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature and adjusted to a pH of 6.9 with methanesulfonic acid, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.079 g of 2-(5-(2-(diethylamino)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoic acid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][C:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]34[O:29][CH2:28][C:25]([CH3:30])([CH2:26][O:27]3)[CH2:24][O:23]4)=[C:16]([CH3:31])[CH:15]=2)=[C:9]([CH3:11])[CH:10]=1)CCC.[F:40][C:41]1[CH:48]=[C:47](Br)[CH:46]=[CH:45][C:42]=1[C:43]#[N:44].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCCC1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[F:40][C:41]1[CH:48]=[C:47]([C:6]2[S:7][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]45[O:23][CH2:24][C:25]([CH3:30])([CH2:26][O:27]4)[CH2:28][O:29]5)=[C:16]([CH3:31])[CH:15]=3)=[C:9]([CH3:11])[CH:10]=2)[CH:46]=[CH:45][C:42]=1[C:43]#[N:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)c(CCc2ccc(OCC34OCC(C)(CO3)CO4)c(C)c2)s1
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: Cc1cc(CCc2sc(-c3ccc(C#N)c(F)c3)cc2C)ccc1OCC12OCC(C)(CO1)CO2

Procedure:
A mixture of tributyl[4-methyl-5-(2-{3-methyl-4-[(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methoxy]phenyl}ethyl)thien-2-yl]stannane (intermediate 100, 0.037 g) and 2-fluoro-4-bromobenzonitrile (0.011 g) in tetrahydrofuran (2 ml) was treated with palladium bis(dibenzylideneacetone) (0.0035 g) and trifuranyl phosphine (0.0013 g) and the resulting mixture stirred at reflux for 3 hours. The solvent was removed and the residue purified by Biotage® chromatography using a mixture of petroleum ether:ethyl acetate (4:1) as eluent to give the title compound.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7]Br)[C:3]([NH2:5])=[O:4].[H-].[Na+].[F:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:2]3[CH2:6][CH2:7][NH:5][C:3]3=[O:4])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: NC(=O)C(Br)CCBr
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCC1Oc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Typical Procedure 2 was followed. Reaction of 2,4-dibromo-butyramide with NaH and 4-(4-fluoro-phenoxy)-phenol provided the title compound. MS ESI+: m/z=288 [M+H]+.
Reaction SMILES: [Mg].[Si:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[C:17]1([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN([CH:27]=[O:28])C>BrC(Br)C.O>[Si:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:27]=[O:28])=[CH:12][C:11]=1[C:17]1([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC1(c2cc(Br)ccc2O[Si](C)(C)C(C)(C)C)CCCCC1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: O
Product: CC1(c2cc(C=O)ccc2O[Si](C)(C)C(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.54 g of magnesium are placed in a 500 ml three-necked round-bottomed flask and then a solution containing 22.09 g (57.7 mmol) of 4-tert-butyldimethylsilyloxy-3-(1-methylcyclohexyl)bromobenzene is added through a dropping funnel. The reaction is activated by a few drops of dibromoethane. 4.45 ml (57 mmol) of DMF are then added and the mixture is left stirring for 30 min at room temperature. The reaction medium is poured into water and then extracted with ethyl acetate. After rinsing the organic phase with water, drying over magnesium sulphate, evaporation and chromatography on silica in the dichloromethane/hexane eluent (50/50), 16 g (84%) of the expected derivative are isolated.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[OH:27][C:7]1[C:8]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:18][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:11][C:6]=1[C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5]
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A mixture of 7-hydroxy-2,4-diphenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (45 mg, 0.12 mmol) and glycine (179 mg, 2.38 mmol) in 0.5 M sodium methoxide/methanol (4.5 mL) was refluxed for four days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3 mL). The suspension was extracted with ethyl acetate (2×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (47 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.46 (t, 1H), 8.68 (m, 2H), 8.22 (m, 2H), 7.65 (m, 6H), 4.09 (m, 2H); MS: (+) m/z 406.0 (M+1)