Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([C:29]2[S:30][C:31]3[CH2:37][CH2:36][CH2:35][CH2:34][C:32]=3[N:33]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:45][CH2:46]C>CN(C=O)C.O>[CH2:1]([O:2][C:3]1[CH:28]=[C:27]([C:29]2[S:30][C:31]3[CH2:37][CH2:36][CH2:35][CH2:34][C:32]=3[N:33]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)[CH2:45][CH3:46]
Reactant: CCCI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3OC)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
Ethyl ((1S)-5-{3-[2-hydroxy-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-phenoxy]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 165, 90 mg, 0.177 mmol) was dissolved in DMF (3 mL) after which Cs2CO3 (69.3 mg, 0.213 mmol) and water (3 drops) were added. Iodopropane (0.02 mL, 0.213 mmol) was added to the flask, and the reaction mixture was stirred at room temperature for 18 h. The mixture was then filtered and the filtrate purified by preparative HPLC giving the desired ester as a white solid (88.7 mg, 91%). 1H NMR (400 MHz, CD2Cl2): δ 7.47 (s, 1H), 7.37 (dd, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 6.79 (s, 1H), 6.71 (dd, 1H), 4.23 (t, 2H), 4.19-4.13 (m, 4H), 4.03 (t, 2H), 3.50 (m, 1H), 2.94-2.78 (m, 6H), 2.70 (dd, 1H), 2.44-2.25 (m, 4H), 1.92-1.70 (m, 7H), 1.28 (t, 3H), 1.07 (t, 3H).
Reaction SMILES: C1C2C3C(=CC=CC=3)C(C=O)=CC=2SC=1.[CH:16]([C:18]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:21]2[S:22][C:23](C(OC)=O)=[CH:24][C:20]=2[CH:19]=1)=[O:17]>C(Cl)Cl.CCCCCC>[S:22]1[CH:23]=[CH:24][C:20]2[CH:19]=[C:18]([CH:16]=[O:17])[C:34]3[C:29]([C:21]1=2)=[CH:30][CH:31]=[CH:32][CH:33]=3
Reactant: COC(=O)c1cc2cc(C=O)c3ccccc3c2s1
Agent: O=Cc1cc2sccc2c2ccccc12
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc2ccsc2c2ccccc12
Yield: 61.9 %

Procedure:
Using the procedure outlined in 7B, methyl naphtho[1,2-b]-thiophene-2-carboxylate (10A) gave a 61.9% yield of naphtho[1,2-b]thiophene-5-carbaldehyde, mp 96°-96.5°, (C,H,S), (CH2Cl2 /hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:23])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17]OS(C)(=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([CH2:27][NH2:28])[CH:25]=C.[CH3:29]C(N(C)C)=O>>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][N:28]([CH2:27][CH:24]=[CH2:25])[CH3:29])[CH2:11][CH2:10]1)[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCN
Reactant: CC(=O)N(C)C
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Product: C=CCN(C)CC#C[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 420 mg (1.22 mmol) of trans-Methanesulfonic acid 3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-prop-2-ynyl ester in 4 ml DMA was treated at 0° C. with 0.234 ml (2.43 mmol) of N-allylmethylamine and stirred at RT for 16 h. The solution was concentrated and the residual oil was extracted with aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution and dried over Na2SO4 to yield after flash column chromatography on silica gel with hexane/EtOAc (2:1) 355 mg (91%) trans-{4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-cyclohexyl}-methyl-carbamic acid tert-butyl ester, MS: 321 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]3[C:15]([NH:16][C@H:17]4[C@@H:21]([CH3:22])[CH2:20][NH:19][CH2:18]4)=[C:14]([C:23]([NH2:25])=[O:24])[CH:13]=[N:12][N:11]3[CH:26]=2)[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O.Br[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([N:19]2[CH2:20][C@H:21]([CH3:22])[C@H:17]([NH:16][C:15]3[C:10]4[N:11]([CH:26]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)[N:9]=4)[N:12]=[CH:13][C:14]=3[C:23]([NH2:25])=[O:24])[CH2:18]2)=[N:36][CH:37]=1)#[N:40]
Reactant: N#Cc1ccc(Br)nc1
Reactant: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CNC[C@@H]4C)c3n2)cn1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CN(c5ccc(C#N)cn5)C[C@@H]4C)c3n2)cn1
Yield: 63.8 %

Procedure:
A solution of 2-(1-ethyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, 2 TFA (0.020 g, 0.034 mmol), 6-bromonicotinonitrile (0.013 g, 0.069 mmol) and Hunig's Base (0.030 ml, 0.172 mmol) in DMF (0.3 ml) in a reaction vial was stirred at 100° C. for 5 h. The crude material was purified via preparative LC/MS (Method A). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound of Example 1 (10.0 mg, 0.022 mmol, 63.8% yield). 1H NMR (500 MHz, deuterated 1:1 methanol:chloroform) δ 8.53 (br. s., 1H), 8.51 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.84 (d, J=8.9 Hz, 1H), 6.69 (d, J=7.4 Hz, 1H), 6.32 (br. s., 1H), 4.43 (q, J=7.3 Hz, 3H), 4.19 (br. s., 1H), 4.12-3.91 (m, 2H), 3.70-3.57 (m, 1H), 3.06 (d, J=12.9 Hz, 1H), 1.72 (t, J=7.4 Hz, 3H), 1.43 (d, J=6.9 Hz, 3H). LC/MS (Method F): m/z 456.20 ([M+H]+), Rt. 1.310 min.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([Cl:16])[N:7]=1)C.[NH3:18].CO>>[Cl:16][C:8]1[N:7]=[C:6]([CH2:5][C:4]([NH2:18])=[O:3])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: N
Reactant: CCOC(=O)Cc1nc(Cl)cc2ccccc12
Solvent: CO
Product: NC(=O)Cc1nc(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(3-chloro-isoquinolin-1-yl)-acetic acid ethyl ester (2.5 g, 10 mmol) is dissolved in 4N NH3/MeOH (50 ml). The solution is transferred into an autoclave and kept at 120° C. for 48 hours. After cooling to RT the solvent is removed and the resulting crude product is purified on silica gel using methylene chloride (100%)→methylene chloride/methanol (95/5) as eluent, affording 2-(3-chloro-isoquinolin-1-yl)-acetamide as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:28])([CH3:27])[CH:20]([NH2:26])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[CH3:18][C:19]([CH3:28])([CH3:27])[CH:20]([NH:26][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:21]1[S:22][CH:23]=[CH:24][N:25]=1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: CC(C)(C)C(N)c1nccs1
Product: CC(C)(C)C(NC(=O)c1cc(OCC2CC2)c(C2CC2)cn1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 2,2-Dimethyl-1-thiazol-2-yl-propylamine (CAN 1247122-26-4) as starting materials and isolated (15 mg, 26%) as white solid; MS (ESI, m/z): 386.4 (M+H+).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[NH:8]([C:15]([C:18]1[N:19]([CH3:30])[C:20]([C:23]2[CH:28]=CC(O)=[CH:25][CH:24]=2)=[N:21][N:22]=1)([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:5]([O:4][C:1]1[CH:25]=[CH:24][C:23]([C:20]2[N:19]([CH3:30])[C:18]([C:15]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:17])[CH3:16])=[N:22][N:21]=2)=[CH:28][CH:2]=1)(=[O:7])[CH3:6]
Reactant: Cn1c(-c2ccc(O)cc2)nnc1C(C)(C)Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2nnc(C(C)(C)Nc3ccccc3)n2C)cc1
Reaction time: 3 h

Procedure:
Acetic anhydride (37 μl) was added to a pyridine solution (1 ml) of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenol (60 mg), followed by stirring for 3 hours. After most of acetic anhydride and pyridine was removed by evaporation under reduced pressure, the residue was purified by thin layer chromatography (chloroform:methanol=9:1) to obtain 40 mg of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenyl acetate (white crystals).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[S:15][C:16]3[C:22]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[C:19]([O:29][CH3:30])[C:17]=3[N:18]=2)=[O:12])=[CH:9][N:8]=1>O1CCOCC1>[CH2:1]([O:3][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[S:15][C:16]3[C:22]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=[C:19]([O:29][CH3:30])[C:17]=3[N:18]=2)=[O:12])=[CH:9][N:8]=1)[CH3:2]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1
Temperature: 50 °C
Yield: 53 %

Procedure:
To a stirred solution of 0.24 ml (4.94 mmol) ethanol in 5 ml dioxane at room temperature was added 270 mg (6.18 mmol) sodium hydride (55% dispersion in mineral oil) and the mixture heated at 50° C. for 30 min. 500 mg (1.23 mmol) 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide was then added and the mixture heated at 80° C. for 16 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) followed by trituration in ether afforded 270 mg (53%) 6-ethoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide as a white crystalline solid. ES-MS m/e (%): 437 (M+Na+, 26), 415 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Li]CCCC.CCCCCC.[N:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=1>C1COCC1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([C:32]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)([OH:34])[CH3:33])=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccncc1
Reactant: Fc1ccc(-c2cnc(Br)cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)cn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 27.1 %

Procedure:
2-bromo-5-(4-fluorophenyl)pyrazine (115 mg, 0.4 mmol) in THF (10 mL) was cooled to −78° C., 1.6 M n-BuLi in hexane (0.56 mL, 0.8 mmol) added slowly at −78° C., the reaction mixture was stirred for 10 min at −78° C., and 1-(pyridin-4-yl)ethanone (54 mg, 0.4 mmol) in THF (3 mL) was added. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to obtain crude product. The crude product was purified by preparative TLC (mobile phase: 60% ethyl acetate in hexane) to afford 1-(5-(4-fluorophenyl)pyrazin-2-yl)-1-(pyridin-4-yl)ethanol as off-white solid (32 mg, 24% yield) in 98.7% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 8.93 (s, 1H), 8.48 (d, 2H), 8.16-8.13 (m, 2H), 7.49 (d, 2H), 7.34 (t, 2H), 6.43 (s, 1H), 1.90 (s, 3H); LC-MS m/z calculated for [M+H]+ 296.11, found 296.1.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([NH:20][NH2:21])=[O:19])[C:13]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:12]1=2)[C:8](=[O:10])[CH3:9].Cl[C:37]([O:39][CH2:40][CH3:41])=O>CO.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[O:19][C:37]([O:39][CH2:40][CH3:41])=[N:21][N:20]=2)[C:13]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)NN)c2cc(Cl)ccc21
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1nnc(N2CCCC(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(C)=O)c3ccc(Cl)cc32)o1

Procedure:
To a stirring solution of N-(3,5-Bistrifluoromethyl-benzyl)-N-(8-chloro-1-hydrazinocarbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.13 mmol, 73 mg) in MeOH (1 mL) was added ethyl chloroformate (0.41 mmol, 45.0 μL) and the reaction mixture was refluxed for 12 h. After completion (by TLC), the mixture was cooled, diluted with EtOAc (20 mL), washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product as viscous oil. Purification by flash silica gel column chromatography gave the title compound as colorless foam; Rf 0.40 (EtOAc/Hexane, 1:1, v/v); MS (ES+): 599 (M+Na+).
Reaction SMILES: N1CCCCC1.CN(C=O)C.[NH:12](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:13]([C:35]([OH:37])=[O:36])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:34])[NH:19]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O.CC(N=C=NC(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:12][C@H:13]([C:35]([OH:37])=[O:36])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:34]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](N)C(=O)O

Procedure:
After removing the Fmoc groups of the DMBHA resin prepared in (1) with 20% piperidine/DMF, 2.5 eq of Fmoc-Arg(Mtr)-OH based on the DMBHA resin was added, and condensation reaction was carried out in DMF according to the DIPCDI-HOBt method.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1ncc(C=O)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CNc2ncc(C=O)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask, 2-amino-pyrimidine-5-carbaldehyde (31, 0.750 g, 6.09 mmol), 6-methoxy-pyridine-3-carbaldehyde (29, 1.67 g, 12.2 mmol), trifluoroacetic acid (2.5 mL, 32.0 mmol), and triethylsilane (5.00 mL, 31.3 mmol) were combined with 10 mL of acetonitrile. The reaction was stirred at room temperature overnight, then concentrated under vacuum and combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel flash column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:5]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:4]=1.[H-].[Na+].[CH3:33]I>O1CCCC1>[CH3:33][O:16][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:4][C:5]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:24])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CI
Reactant: CC(C)[Si](OCc1cc(C(F)(F)F)ccc1C1(O)CCCCCC1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CO[Si](C(C)C)(C(C)C)C(C)C)CCCCCC1
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)phenyl)cycloheptanol (284 mg; 0.639 mmol) in tetrahydrofuran (3.5 mL) at room temperature was added sodium hydride (40 mg; 1 mmol; 60% dispersion in mineral oil). After stirring at room temperature for 15 minutes methyl iodide (80 uL; 1.28 mmol) was added. Reaction stirred for 16 hours. More sodium hydride (20 mg; 0.5 mmol; 60% dispersion in mineral oil) was added. After 5 minutes methyl iodide (0.1 mL; 1.6 mmol) was added. The reaction was stirred for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (2×) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-15% ethyl acetate in heptanes) to yield 279 mg (95.2%) of the title compound as a colorless oil. MS-GC (El): Calc: 458.6 Found: 439 (M−F). 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (d, J=1.24 Hz, 1H), 7.44 (dd, J=8.30, 1.24 Hz, 1H), 7.34 (d, J=8.30 Hz, 1H), 5.11 (s, 2H), 2.95 (s, 3H), 2.16 (m, 2H), 2.01 (m, 2H), 2.0 (dd, J=14.94, 14.52 Hz, 1H), 1.97 (dd, J=14.94, 14.52 Hz, 1H), 1.83-1.58 (m, 6H), 1.3-1.16 (m, 2H), 1.13 (s, 12H), 1.11 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>CC(OC)(C)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 4-methyl-3-nitrophenol (10.0 g), butyl bromide (9.4 g), sodium carbonate (6.9 g) and DMF (50 mL) was heated at 80° C. for 7 hours. The cooled reaction solution was diluted with MTBE and washed twice each with water and sodium hydroxide solution. The organic phase was dried and concentrated. The product with the molecular weight of 209.25 (C11H15NO3) was obtained in this way; MS (ESI): 210 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH3:22])[CH:17]=[C:16]([O:23][CH2:24][CH3:25])[C:15]=2[F:26])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH2:27](O)[CH2:28][CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:27]([O:12][C:11](=[O:13])[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH3:22])[CH:17]=[C:16]([O:23][CH2:24][CH3:25])[C:15]=1[F:26])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCO
Reactant: CCOc1cc(OCC)c(F)c(C(Nc2ccc(C#N)cc2)C(=O)O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
The (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid (220 mg) described in example 2.15 was dissolved in THF (3.3 ml). n-Butanol (64 mg), triphenylphosphine (179 mg) and diethylazo dicarboxylate (122 mg) were added and the mixture was stirred for 3 h at room temperature. The mixture was concentrated and the product was purified by column chromatography to give 109 mg of (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid butyl ester as an off-white solid. MS: 414 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([OH:17])=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:36][C:29]=12)[NH2:23]>>[F:19][C:20]1[CH:21]=[C:22]([NH:23][C:15]([C:10]2[C:9](=[O:18])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[I:14])=[O:17])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:36][C:29]=12
Reactant: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1)c1c(I)ccn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared by procedure G using 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (141.25 mg; 0.39 mmol; 1.20 eq.) instead of 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid and using 3-fluoro-4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline (105.00 mg; 0.33 mmol; 1.00 eq.) instead of 4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline, and was obtained as a brown solid (106 mg, 49%). (HPLC (method F): 94%, RT: 4.43 min); MS (m/z) 662 [M+H]+, RT: 3.8 min.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][C:12]1[S:16][C:15]([NH2:17])=[N:14][CH:13]=1>CC(C)=O>[Br-:1].[NH2:17][C:15]1[S:16][C:12]([CH3:11])=[CH:13][N+:14]=1[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cnc(N)s1
Reactant: CCOC(=O)CC(=O)CBr
Solvent: CC(C)=O
Product: CCOC(=O)CC(=O)C[n+]1cc(C)sc1N
Product: [Br-]
Reaction time: 8 h
Yield: 82 %

Procedure:
Ethyl 4-bromo-3-oxobutanoate (92 g, 0.35 mol) was added to a solution of 5-methylthiazol-2-amine (40 g, 0.35 mol) in acetone (400 mL). The mixture was left to stand overnight and then evaporated to give 2-amino-3-(4-ethoxy-2,4-dioxobutyl)-5-methylthiazol-3-ium bromide in 82% yield, 101 g. 2-amino-3-(4-ethoxy-2,4-dioxobutyl)-5-methylthiazol-3-ium bromide (101 g, 0.28 mol) was then refluxed in ethanol (250 mL) for 2 hours. The solvent was then evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate hydrobromide as yellow crystals in 97% yield, 85 g. Solid K2CO3 was added to a solution of ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate hydrobromide (85 g, 0.28 mol) in water (300 mL) to pH ˜8. The product was extracted with chloroform (3×100 mL), and the combined extracts were dried over Na2SO4 and evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate in 84% yield 52 g. Ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate (52 g, 0.23 mol) was refluxed in 10% aqueous HCl (150 mL) for 2 hours. The solution was evaporated to dryness to give the title compound as brown crystals in 59% yield 32.3 g; m/z 197 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:30])([CH3:29])[C:14]([O:16][CH2:17][O:18][C:19](ON1C(=O)CCC1=O)=[O:20])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][C:13]([CH3:30])([CH3:29])[C:14]([O:16][CH2:17][O:18][C:19]([CH:10]([NH2:11])[C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:20])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)C(N)[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]methyl 2,2-dimethylpropanoate (547 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 6 (476 mg, 76% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 2H), 1.13 (s, 9H), 1.17-1.38 (br. m, 3H), 1.64-1.72 (br. m, 2H), 1.82-1.91 (br. m, 2H), 2.09 (tt, J=12.0, 3.6 Hz, 1H), 2.78-2.87 (br. m, 2H), 5.61 (s, 2H), 7.54 (t, J=5.6 Hz, 1H), 11.98 (br. s, 1H). MS (ESI) m/z 316.11 (M+H)+; 314.01 (M−H)−.