Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1.C(N(CC)CC)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>O1CCCC1>[CH3:1][O:2][C:3]([C@H:4]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:33](=[O:34])[NH:13][C:8]=2[CH:7]=1)=[O:25]
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(N)c1)NC(=O)OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)[nH]c2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a dilute solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester (600 mg, 1.44 mmol) in tetrahydrofuran (125 mL) was added triethylamine (320 mg, 3.17 mmol) followed by 1,1′-carbonyldiimidazole (280 mg, 1.73 mmol). The reaction mixture was stirred at room temperature for 16 h and then filtered to remove solid. The filtrate was evaporated and subjected to flash column chromatography (1:12 methanol/methylene chloride) to give the title compound (313 mg, 59% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[N:10]=[C:6]2[C:5]([Br:15])=[N:4][CH:3]=1.C[Si](C)(C)[NH:18][C:19]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1[F:29].CS(C)=O>C(#N)C>[F:29][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[C:19]=1[NH:18][S:11]([C:9]1[N:10]=[C:6]2[C:5]([Br:15])=[N:4][CH:3]=[C:2]([Br:1])[N:7]2[N:8]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1nc2c(Br)ncc(Br)n2n1
Reactant: COC(=O)c1cccc(F)c1N[Si](C)(C)C
Solvent: CC#N
Solvent: CS(C)=O
Product: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(Br)ncc(Br)n2n1
Reaction time: 1 h

Procedure:
A solution of 0.75 g (20 mmol) of 5,8-dibromo-2-chlorosulfonyl[1,2,4]triazolo[1,5-a]pyrazine in 8 mL of dry acetonitrile was placed in a flask equipped with a drying tube and was treated sequentially with 6.0 mL (6.0 mmol) of a 1M solution of N-trimethylsilyl-2-fluoro-6-methoxycarbonylaniline in acetonitrile and 25 μL (0.35 mmol) of dimethyl sulfoxide at room temperature with stirring. The reaction became progressively darker and after 1 hour, the volatiles were removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by flash column chromatography on silica gel using a 0.5 to 4 percent ethanol/dichloromethane gradient as eluent to obtain 715 mg (70 percent of theory) of the desired product as an orange glassy solid melting at 190°-195° C.; Mass Spectrum, m/e 510 (M+1).
Reaction SMILES: [ClH:1].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(N[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[NH:20])=[CH:14][CH:13]=1)=O)(C)C.NC1C=CC([C:41]([NH:43][NH:44][C:45]([NH:47][C:48]2[CH:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51]([OH:58])=[C:50]([C:59]([CH3:62])([CH3:61])[CH3:60])[CH:49]=2)=[O:46])=[O:42])=CC=1.CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NC1C=CC(N)=CC=1)=O)(C)C>>[ClH:1].[CH3:57][C:54]([C:52]1[CH:53]=[C:48]([NH:47][C:45]([NH:44][NH:43][C:41]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[NH:20])=[CH:14][CH:13]=2)=[O:42])=[O:46])[CH:49]=[C:50]([C:59]([CH3:60])([CH3:61])[CH3:62])[C:51]=1[OH:58])([CH3:55])[CH3:56]
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc(NC(=N)c3cccs3)cc2)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc(N)cc2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C(=O)Nc2ccc(N)cc2)cc(C(C)(C)C)c1O
Agent: Cl
Product: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc(NC(=N)c3cccs3)cc2)cc(C(C)(C)C)c1O
Yield: 58 %

Procedure:
The experimental protocol used is the same as that described for compound 1, with N-[(4-aminophenyl) carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxy phenyl]-urea replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. The free base is purified on a silica column (eluant: heptane/ethyl acetate: 1/1). The pure fractions are collected and concentrated under reduced pressure. The evaporation residue is diluted in 15 ml of acetone and salified with a molar solution of HCl in anhydrous ether, as described previously. 0.40 g (58%) of a yellow powder is obtained. Melting point: 254-255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](S)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][N:10]=1
Reactant: Sc1ncc(-c2ccc(Cl)cc2)o1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1ccc(-c2cnc(Cl)o2)cc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
2-amino-1-(4-chlorophenyl)ethanone hydrochloride (0.80 g, 3.88 mmol) and carbon disulfide (0.47 mL, 0.59 g, 7.76 mmol) was suspended in ethanol (10 mL). To this was slowly added a solution of sodium carbonate (0.44 g, 4.08 mmol) in water (4 mL) at ambient temperature. After heating to 80° C. ext. temp. for 18 h the cold mixture was filtered. The filtrate was diluted with acetic acid (40 mL) and stirred for 15 min. at room temperature. Evaporation of the solvents in vacuo gave 1.42 g of a crude 5-(4-chlorophenyl)oxazole-2-thiol which was of ca. 61% purity (HPLC-MS) and used as is in the next step. The crude oxazole-2-thiol compound (1.42 g, max. 3.88 mmol) was suspended in phosphorous oxychloride (5 mL). To this was added dropwise triethyl amine (1.15 mL, 0.84 mg, 8.27 mmol) and the mixture heated to 105° C. ext. temperature for 4 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with aq. sat. bicarbonate (100 mL) and water (50 mL). Drying (sodium sulfate) and concentration in vacuo yielded crude product (615 mg), which was purified by column chromatography (SiO2, 5-40% ethyl acetate in heptanes) to give pure 2-chloro-5-(4-chlorophenyl)oxazole (105 mg, 0.49 mmol, 13%, purity 96% HPLC-MS).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[N:8][C:7]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[CH2:25][NH:26]C(=O)OC(C)(C)C)=[N:6][C:5]=2[CH2:4][NH:3]1.Cl>CC(O)=O>[NH2:26][CH2:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][N:19]1[C:7]1[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[C:10]2[C:2](=[O:1])[NH:3][CH2:4][C:5]=2[N:6]=1
Reactant: Cc1cccc(Nc2nc(N3CCCCC3CNC(=O)OC(C)(C)C)nc3c2C(=O)NC3)c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cccc(Nc2nc(N3CCCCC3CN)nc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of tert-butyl (1-(5-oxo-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperidin-2-yl)methylcarbamate (207.1 mg, 0.458 mmol) in HOAc (3 mL) was added HCl (1 mL, 32.9 mmol). The mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (50 mL) and was extracted with EtOAc-THF (1/1, 2×40 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure and the residue was washed with EtOH to give the title compound as a pale yellow solid (27.4 mg, 17%). 1H-NMR (DMSO-d6) δ ppm 1.32-1.70 (m, 7H), 1.89-1.92 (m, 1H), 2.31 (s, 3H), 2.74-2.87 (m, 1H), 2.81-2.85 (m, 1H), 2.94 (br s, 1H), 4.17 (s, 2H), 4.68-4.79 (m, 2H), 6.88 (d, 1H, J=7.5 Hz), 7.22-7.25 (m, 1H), 7.49-7.50 (m, 1H), 7.60 (s, 1H), 8.06 (s, 1H), 8.58 (s, 1H). [M+H] calc'd for C19H25N6O, 353; found, 353.5.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]([CH3:15])[CH3:14])=O)(C)(C)C.[C:16]1(=O)[NH:20][C:19](=O)[CH:18]=[CH:17]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(O)C.O.O1CCCC1>[CH:13]([CH:12]1[CH:18]2[CH:17]([CH2:16][NH:20][CH2:19]2)[CH:9]([NH:8][CH3:6])[CH:10]=[CH:11]1)([CH3:15])[CH3:14]
Reactant: CC(C)C=CC=CNC(=O)OC(C)(C)C
Reactant: O=C1C=CC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CNC1C=CC(C(C)C)C2CNCC12
Yield: 18.7 %

Procedure:
50 g (0.24 mol) of 1-(tert.-butyloxycarbonylamino)-5-methyl-1,3-hexadiene are stirred together with 23 g (0.24 mol) of maleimide in 75 ml of ethanol and 75 ml of water under reflux for 24 hours. After cooling, the solid is filtered off with suction and rinsed with water to give, after drying, 56.3 g (76% of theory) of a solid of melting point 192°-195° C. 15 g (0.049 mol) are stirred together with 11 g (0.29 mol) of lithium aluminium hydride in 300 ml of tetrahydrofuran under reflux for 10 hours. After cooling, the mixture is hydrolysed with 10 ml of water, 10 ml of 10 per cent strength sodium hydroxide solution and finally 30 ml of water. The precipitate is filtered off with suction and rinsed with tetrahydrofuran and the combined filtrates are concentrated to dryness. 8.7 g of a solid are obtained and are purified by crystallisation (petroleum ether-ethyl acetate=1:5).
Reaction SMILES: [CH2:1]([O:7][C:8]([NH:10][C@@H:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH:76]=[CH2:77])=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([C@@:65]3([O:74][CH3:75])[CH2:69][NH:68][C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=1>C(Cl)Cl>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH:76]=[CH2:77])=[C:57]([C:59]2[CH:64]=[CH:63][C:62]([C@@:65]3([O:74][CH3:75])[CH2:69][N:68]([C:12](=[O:14])[C@@H:11]([NH:10][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:9])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)=[CH:61][CH:60]=2)[CH:58]=1
Reactant: C=Cc1ccc(Cl)cc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3cc(Cl)ccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
(S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (186 mg, 0.723 mmol), DIEA (0.303 mL, 1.735 mmol) and HATU (242 mg, 0.636 mmol) were added to a solution of (2S,4R)-methyl 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (215 mg, 0.578 mmol) in DCM (7 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified on the Biotage (10-50% EtOAc:Hex) to give (2S,4R)-methyl 4-(5′-chloro-2′-vinylbiphenyl-4-yl)-1-((S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxypyrrolidine-2-carboxylate (13 mg, 0.201 mmol, 35% yield) as a colorless oil. LCMS: rt=2.58 min. [M+H]+=612; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5](=O)[CH:6]([CH3:8])[CH3:7].[C:10]([CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:14])#[N:11].N12CCN(CC1)CC2.COCCOCCO>C(OCC)(=O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:5]([CH:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=[C:12]([C:10]#[N:11])[C:13]2=[O:14])=[CH:21][CH:20]=1
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Reactant: CO/C=C/C(=O)C(C)C
Agent: C1CN2CCN1CC2
Solvent: COCCOCCO
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 59.5 %

Procedure:
A mixture of (1E)-1-methoxy-4-methylpenta-1-en-3-one (508 mg, 3.96 mmol), 2-cyano-N-(4-fluorophenyl)acetamide (847 mg, 4.75 mmol), 1,4-diazabicyclo[2.2.2]octane (444 mg, 3.96 mmol) and 2-(2-methoxyethoxy)ethanol (10 mL) was stirred at 130° C. for 6 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, water (×2) and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→60/40) and silica gel column chromatography (NH silica gel, ethyl acetate/hexane=0/100→60/40) to give the title compound (604 mg, 59%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=O)[NH:6][CH:7]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:19])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-bromo-3-nitropyridin-2(1H)-one (4.62 g, 21.10 mmol) in POCl3 (46.2 ml) was added DMF (4.62 ml, 59.7 mmol) at room temperature. The mixture was refluxed for 2 hours, and then cooled to room temperature and concentrated in vacuo. The residue was treated with saturated aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give 5-bromo-2-chloro-3-nitropyridine (4.24 g, 85%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 8.37 (1H, d, J=2.4 Hz), 8.70 (1H, d, J=2.0 Hz).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH2:22])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C(N(CC)CC)C.CP(C)C.[F:44][CH:45]1[C:50](=O)[CH2:49][CH2:48][N:47]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:46]1.[B][B][B][B][B][B][B][B][B][B].C([O-])(O)=O.[Na+]>C1COCC1.CO>[C:55]([O:54][C:52]([N:47]1[CH2:48][CH2:49][CH:50]([NH:22][C:20]2[N:21]=[C:14]3[C:13]([C:5]4[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=4)=[CH:18][CH:17]=[CH:16][N:15]3[N:19]=2)[CH:45]([F:44])[CH2:46]1)=[O:53])([CH3:58])([CH3:56])[CH3:57]
Reactant: Nc1nc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccn2n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: CP(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cccn3n2)C(F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 8-(3,5-bis(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-c) (80 mg, 231 μmol) and hexachloroethane (65.6 mg, 277 μmol) under argon in dry THF (4 mL) was added triethylamine (70.1 mg, 96.6 μL, 693 mmol) followed by trimethylphosphine (1 M in THF, 277 μL, 277 μmol). The reaction mixture was stirred at room temperature for 0.5 hours, then tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (example 238b, 60.2 mg, 277 μmol) was added and the mixture heated to 150° C. for 30 minutes in the microwave. A solution of decaborane (28.2 mg, 30.0 μL, 231 μmol) in dry methanol (1 mL) was added to the reaction mixture and stirred at room temperature for 3 hours. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as off-white foam (107 mg, 85%) as a mixture of cis- and trans-isomers.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[O:13][CH3:14])=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]([NH2:32])=[S:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>C(OCC)C>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[C:3]1[N:32]=[C:30]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([O:16][CH3:15])[CH:18]=2)[S:31][CH:2]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Solvent: CCOCC
Product: COc1ccc(OC)c(-c2csc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 88 mg (0.33 mmol) 2-bromo-2′,5′-dimethoxyacetophenon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude reaction was diluted with diethyl ether and stirred for 15 minutes at room temperature. The product was filtered off and dried to yield 124 mg (98%) [4-(2,5-dimethoxy-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light green solid. MS ISP (m/e): 423.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.68 (s, 1H), 9.28 (s, 1H), 7.99 (s, 1H), 7.72 (s, 1H), 7.69 (d, 1H), 7.54 (s, 1H), 7.52 (d, 1H), 7.28 (d, 1H), 7.07 (d, 1H), 6.89 (dd, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.75 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH2:26])=[N:22][N+:23]([O-:25])=[O:24])=[CH:16][CH:15]=1)[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[Na+]>CO>[C:10]([O:9][C:7]([NH:6][CH2:5][CH:4]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH2:26])=[N:22][N+:23]([O-:25])=[O:24])=[CH:18][CH:19]=1)[C:3]([OH:27])=[O:2])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(NC(N)=N[N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccc(NC(N)=N[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
A mixture of the compound (0.42 g) obtained in Example 220, 2 N aqueous sodium hydroxide solution (0.6 ml) and methanol (10 ml) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and a 5% aqueous citric acid solution and ethyl acetate were added to the residue. The organic layer was washed with water, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methanol:methylene chloride=5:95) to give 0.34 g of the titled compound (yield, 84%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[OH-].Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)C1(c2ccc3[nH]ccc3c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2ccc3[nH]ccc3c2)CC1
Temperature: 45 °C
Yield: 87 %

Procedure:
To a solution of methyl 1-(1H-indol-5-yl)cyclopropanecarboxylate (1.74 g, 8 mmol) in CH3OH (50 mL) and water (20 mL) was added LiOH (1.7 g, 0.04 mol). The mixture was heated at 45° C. for 3 hr. Water was added and the mixture was acidified with concentrated HCl to pH 3 before being extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated to give 1-(1H-indol-5-yl)cyclopropanecarboxylic acid (1.4 g, 87%). 1H NMR (300 MHz, DMSO-d6) 7.43 (s, 1H), 7.30-7.26 (m, 2H), 7.04 (dd, J=1.5, 8.4 Hz, 1H), 6.35 (s, 1H), 1.45-1.41 (m, 2H), 1.14-1.10 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Cl:9]Cl>>[CH3:1][NH:2][C:3](=[O:8])[CH:4]([Cl:9])[C:5]([CH3:7])=[O:6]
Reactant: CNC(=O)CC(C)=O
Reactant: ClCl
Product: CNC(=O)C(Cl)C(C)=O
Yield: 97.4 %

Procedure:
Altogether, the aqueous phase was subjected to chlorination five times. A total of 492 parts by weight of N-methylacetoacetamide (MMAA) of 99.5% strength, and 283.5 parts by weight of chlorine were used, and altogether 588.6 parts by weight of 97.4% N-methyl-α-chloracetoacetamide (MMCAA) were obtained, that is, 96.8% of the theoretical yield, calculated on reacted MMAA.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([OH:16])=[CH:9][C:8]=1[F:17])[CH3:2].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[S:27][CH:28]=1.C(C1C=CC(C(N)=S)=CC=1)(C)C.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[S:27][CH:28]=2)=[CH:9][C:8]=1[F:17])[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(OCC)c(O)cc1F)OCC
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: CC(C)c1ccc(C(N)=S)cc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)C(Cc1cc(OCC)c(OCc2csc(-c3ccc(C(C)C)cc3)n2)cc1F)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(5-ethoxy-2-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole (prepared from 4-isopropyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in acetonitrile in the presence of cesium carbonate to yield [rac]-2-ethoxy-3-{5-ethoxy-2-fluoro-4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-{5-ethoxy-2-fluoro-4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid as light yellow solid.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].[C:7]1([CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>C(O)C.[OH-].[Na+]>[C:7]1([CH:13]([CH2:14][OH:15])[CH2:19][OH:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(CO)c1ccccc1
Temperature: 6 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
Sodium dihydrogen phosphate (58.3 g) was added to a solution of 50 g of diethyl phenylmalonate in 350 ml of ethanol. The mixture was cooled to 5-7° C. and a solution of 16.7 g of sodium borohydride in 38 ml of 0.2% NaOH was gradually added. The mixture was stirred for additional 2 hours and the Ethanol was distilled out. The reaction was quenched by adding 132 ml of water followed by heating to 50° C.-60° C. for 2 hours. The solution was then basified with 50% NaOH and extracted with ethyl acetate. The organic layer was washed with water and evaporated to dryness. The precipitate was crystallized from toluene. 20 g of 2-phenyl-1,3-propanediol was obtained with a yield of 63%.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:21][CH:20]=[C:19]([C:22]#[N:23])[C:18]=1[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[C:18]1[C:19]([C:22]#[N:23])=[CH:20][S:21][C:17]=1[NH:16][C:13](=[O:15])[CH2:12][N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1]
Reactant: O=C(O)Cn1c(=O)ccc2ncccc21
Reactant: N#Cc1csc(N)c1-c1nc2ccccc2s1
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3ncccc32)c1-c1nc2ccccc2s1

Procedure:
The title compound was prepared from 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (0.040 g, 0.19 mmol) and 5-amino-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile (0.073 g, 0.28 mmol) according to protocol A. The crude product was purified by prep HPLC. LCMS retention time (min)=5.122, method [12], MS (ESI) 446.1 (M+H). 1H NMR (CDCl3) δ 13.38 (s, 1H), 8.32 (d, J=5.6 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.47-7.42 (m, 1H), 7.35-7.30 (m, 1H), 4.95 (s, 2H), 3.33-3.28 (m, 2H), 2.99-2.94 (m, 2H).