Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35]([O:37][CH2:38][CH:39]([CH2:44][O:45][C:46](=[O:62])[C@H:47]([CH:59]([CH3:61])[CH3:60])[NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH2:40][C:41](O)=[O:42])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.COCCOC>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:41](=[O:42])[CH2:40][CH:39]([CH2:44][O:45][C:46](=[O:62])[C@H:47]([CH:59]([CH3:61])[CH3:60])[NH:48][C:49]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[CH2:38][O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:34])[CH3:33])[NH:30][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: COCCOC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2′,3′-dideoxy-3′-fluoroguanosine (1.35 g, 5 mmole), 3,3-bis (N-CBZ-L-valyloxymethyl)-propionic acid (3.6 g, 6 mmole), DMAP (0.061 g, 0.5 mmole) and HOBT (0.81 g, 6 mmole) was coevaporated two times with DME and reduced to about 120 ml. DCC (1.24 g, 6 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:35])=[CH:26][CH:27]=1)[CH3:21]
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)cc1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(4-ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=486.1.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH2:11][C:12]1[CH2:13][CH2:14][N:15]([C:18](=[S:20])[OH:19])[CH2:16][CH:17]=1)(=[O:10])=[O:9].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[N:29]2[CH2:32][C:31](=[O:33])[CH2:30]2)=[CH:24][CH:23]=1>O1CCCC1.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[N:29]2[CH2:30][C:31]([CH2:7][S:8]([CH2:11][C:12]3[CH2:17][CH2:16][N:15]([C:18](=[S:20])[OH:19])[CH2:14][CH:13]=3)(=[O:9])=[O:10])([OH:33])[CH2:32]2)=[CH:24][CH:23]=1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CS(=O)(=O)CC1=CCN(C(O)=S)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(CC1=CCN(C(O)=S)CC1)CC1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
The phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid is prepared in the following manner: 0.52 g of potassium tert-butoxide is added to a mixture of 0.72 g of the phenolic ester of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-carbothioic acid and 0.708 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 15 cm3 of dry tetrahydrofuran cooled under an inert atmosphere to −78° C. The reaction mixture is stirred at −78° C. for 4 hours and then 0.354 g of 1-[bis(4-chlorophenyl)-methyl]azetidin-3-one are added. After two hours at −78° C., the temperature is allowed to return to 20° C. The reaction mixture is diluted in 100 cm3 of water and then the tetrahydrofuran is evaporated off under 2.7 kPa at 40° C. The aqueous phase is extracted with twice 100 cm3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, concentrated under 2.7 kPa at 40° C. The residue obtained is chromatographed on silica (200 g of silica, Amicon, 20-45 μm, porosity 60Angstroem, column 5 cm in diameter), eluting with a cyclohexane:ethyl acetate (6:4 by volume) mixture. The fractions with an Rf={fraction (11/64)} (cyclohexane:ethyl acetate 6:4, silica plate, Merck reference 1.05719, Merck KGaA, 64721 Darmstatd, Germany) are combined and concentrated under 2.7 kPa at 40° C. to give 240 mg of the phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[N+:8]([O-])[CH:9]=[CH:10][CH:11]=1.C[Si]([C:20]#[N:21])(C)C.C(N(CC)CC)C>C(#N)C>[C:20]([C:7]1[C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(Oc2cccc(F)c2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1Oc1cccc(F)c1

Procedure:
A mixture of 33.44 g of 3-(3-fluorophenoxy)pyridine N-oxide, 64.6 ml of trimethylsilyl cyanide and 45.9 ml of triethylamine in 180 ml of acetonitrile was refluxed for 4 hours. After the reaction mixture was concentrated, 200 ml of methylene chloride and 100 ml of 2M aqueous potassium carbonate was added to the residue and the mixture was stirred for a few minutes. The organic layer separated was washed with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated. The solid obtained was washed with isopropyl ether to yield 28.30 g of pale brown crystals, which were recrystallized from ethyl acetate to give slightly brown crystals, mp 92°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N+:11]([O-])=O.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH2:11]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(F)cc1C
Yield: 99.7 %

Procedure:
1-Fluoro-4-methoxy-5-methyl-2-nitro-benzene (1.18 g, 6.4 mmol) was dissolved in 40 ml of methanol at room temperature. 10% Palladium on Carbon (200 mg) was added and the mixture was stirred under a balloon of hydrogen overnight. The mixture was filtered through celite. The filtrate was concentrated in vacuo to give 2-fluoro-5-methoxy-4-methyl-phenylamine (990 mg, quantitative) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16]C)=[C:4]([NH2:15])[C:5](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]([OH:8])=[O:7].Cl.B(Br)(Br)Br.C(Cl)Cl>C(OCC)C>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([NH2:15])[C:5](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1c(Cl)cc(C(F)(F)F)c(C(=O)O)c1N
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1c(O)c(Cl)cc(C(F)(F)F)c1C(=O)O
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
4-Chloro-3-methoxy-6-trifluoromethylanthranilic acid (5 mg, 0.019 mmol) was dissolved in diethyl ether (1 mL) and HCl (2M, 20 L) was added. The solution was evaporated and co-evaporated with toluene. The residue was dissolved in CH2Cl2 (2 mL), cooled to -60 C., and BBr3 (9 L, 0.092 mmol) was added followed by stirring at -60 C. for 3 min, 0 C. for 3 h and room temperature for 6 h. Additional BBr3 (4 L, 0.04 mmol) was added at -35 C. and the stirring was continued at room temperature for 2 h. The reaction mixture was cooled to -20 C. and added to ice-cold NaHCO3 (2 mL, sat.) followed by stirring for 1 h at room temperature. Methylene chloride (2 mL) was added and pH was adjusted to 5. The phases were separated and the H2O phase was washed with EtOAc (3). The combined organic layers were dried (Na2SO4), filtered and evaporated. The crude product was purified on a silica gel coloumn (EtOAc EtOAc-HOAc 100:1) and the title compound was isolated (3 mg). 1H NMR (CD3OD): 6.97 (s, 1H). MS (EI, 70 eV): m/z (rel. int.) 257/255 (M+, 0.16/0.54)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)=[CH:5][CH:4]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[C:31]3[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]3=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(OC)cc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc(OC)cc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.75 g of ethyl 2-(3-p-methoxyphenylureido)thiazol-4-ylglyoxylate, 0.95 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[C:14](F)[C:15]([F:17])=[CH:16][C:9]3=[CH:8][C:7]=2[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[C:14]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([C:26]5[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=5)[CH2:35]4)[C:15]([F:17])=[CH:16][C:9]3=[CH:8][C:7]=2[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: Fc1cccc(C2CNCCN2)c1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5cccc(F)c5)C4)cc3nc21
Yield: 87.3 %

Procedure:
Working under the conditions of Example 16, but starting with 1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.5 g) and (RS)-2-(3-fluorophenyl)piperazine (1.98 g), (RS)-1-ethyl-7-fluoro-8-[3-(3-fluorophenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (2 g) is obtained in the form of a yellow solid, m.p. 284° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16][CH:13]1[CH2:14][CH2:15]1)=[O:6]
Reactant: COc1cccc(C(=O)O)c1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: COc1cccc(C(=O)NCC(CC2CC2)c2ccc(C(F)(F)F)nc2)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=413.1, tR (minutes, Method G)=2.84. [α]D20=+20.9 (c=0.86 mg/mL,CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:21][C:20]([CH3:22])=[CH2:19])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: C=C(C)CBr
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(Cl)cc1C(C)=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A suspension of 5′-chloro-2′-hydroxyacetophenone (0.86 g, 5.0 mmol), potassium carbonate (1.4 g, 10 mmol) and 3-bromo-2-methylpropene (0.56 mL, 5.5 mmol) in anhydrous N,N-dimethylformamide (20 mL) was stirred at 60° C. for 4 hours. After cooling, the reaction mixture was diluted with water (100 mL), and the whole was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title reference compound (1.1 g) as orange oil (Yield 96%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH2:45][CH2:46]Br)C>>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23](/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH2:45][CH2:46][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:48])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1/C=C/CCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCC/C=C/c2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Starting with 0.242 g (1.17 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.604 g (1.17 mmol) of (E)-2-(6-bromo-1-hexenyl)-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound was obtained (97 mg; 15.8% overall yield) as a white solid, mp 105°-109° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:3]=1.Br[CH:13]([CH:16]=O)[CH:14]=[O:15].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:13]([CH:14]=[O:15])=[CH:16][N:11]=2)[CH:3]=1
Reactant: Cc1ccnc(NC(N)=S)c1
Reactant: O=CC(Br)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccnc(Nc2ncc(C=O)s2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A mixture of (4-methylpyridin-2-yl)-thiourea (334 mg, 2 mmol), 2-bromomalonaldehyde (302 mg, 2 mmol) and sodium acetate (250 mg, 3.0 mmol) in acetic acid (5 mL) was stirred at 100° C. for 3 h. The mixture was cooled to RT and diluted with water and the precipitate formed was collected, washed with water and dried to afford 2-(4-methylpyridin-2-ylamino)-thiazole-5-carbaldehyde (350 mg, 80%). MS m/z 220 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1cccc(Cl)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-chloro-phenyl)-butan-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O>C(Cl)Cl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=3[C:7](=[O:9])[C:14]=2[CH:15]=1
Reactant: O=C(O)c1cc(Br)ccc1COc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2cc(Br)ccc2COc2ccc(Br)cc21
Temperature: 0 °C
Yield: 47 %

Procedure:
A solution of 5-bromo-2-(4-bromophenoxymethyl)benzoic acid (100 g, 0.26 mole), and trifluoroacetic anhydride (160 mL) in one liter of methylene chloride containing 20 drops of boron trifluoride-ether complex was refluxed for three hours. The mixture was poured into ice water and then extracted with diethyl ether. Concentration of ether solution under reduced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep 500) with hexane/ethyl acetate (9:1) gave the ketone (45 g) mp 193°-194° C. pmr (DMSO-d6) δ: 8.12 (d, J=2.7 Hz, 1H, H4) , 7.27-7.91 (m, 4H, aromatic H) , 7.10 (d, J=8.8 Hz, 1H, H4), 5.32 (s, 2H, ArCH2O).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>CN(C=O)C>[NH2:22][S:21]([N:2]([CH2:3][C:4]1[N:5]2[CH:11]=[N:10][CH:9]=[C:6]2[S:7][CH:8]=1)[CH3:1])(=[O:24])=[O:23]
Reactant: CNCc1csc2cncn12
Reactant: NS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1csc2cncn12)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 47 mg potion of 3-(N-methylamino)methylimidazo[5,1-b]thiazole was dissolved in 1 ml of DMF, and 0.305 ml of N,N-diisopropylethylamine and 100 mg of sulfamoyl chloride were further added at -45° C., followed by stirring for 8 hours, while the solution was heated up to room temperature. Then, the reaction solution was concentrated under reduced pressure, and 10 ml of water and an aqueous sodium hydrogencarbonate solution were then added to adjust the solution to pH 9.0. Afterward, extraction was carried out four times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 37.4 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:26][C:24]2[N:25]=[C:21]([CH3:20])[S:22][CH:23]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc(C=O)cs1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1csc(C)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-methylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 346.85 g/mol.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH2:35])=[N:34][C:29]2=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:35][C:33]3[S:32][C:30]4[C:29]([N:34]=3)=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[N:31]=4)=[O:16])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: COc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 42.1 %

Procedure:
The compound of example A80 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.5 g,1.32 mmol), 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.286 g, 1.59 mmol), HOBt (0.267 g, 1.98 mmol), and EDCI (0.378 g,1.98 mmol), N-methyl morpholine (0.4 g, 3.97 mmol) in DMF (10 mL) to provide the title compound (0.280 g).
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:54]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:55][C:56]([O-])=[O:57].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:31][N:32]=[N:33][N:34]=3)=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:56](=[O:57])[CH2:55][C:54]([O:60][CH2:61][CH3:62])=[O:59])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c21
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2C1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Ethyl 2-ethyl-3-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate (1.94 g), monoethyl malonate (0.74 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.80 g), and triethylamine (1.40 g) are dissolved in dichloromethane (20 ml). The mixture is stirred overnight at room temperature. The reaction mixture is washed with water, dried over sodium sulfate, and then evaporated to remove the solvent. The residue is dissolved in ethanol (30 ml) and thereto is added fumaric acid (2.00 g). The mixture is refluxed for three hours and evaporated to remove the solvent. The resulting residue is treated with a saturated sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is dried and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.07 g) as foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH3:17][CH2:18][O:19][CH2:20][CH:21](Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6]1([CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH2:7][C:8]2=[O:11]
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CCOCC(Cl)Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: O=C1CC2(CCOCC2)c2ccc(Br)cc21
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-1-indanone (0.50 g, 2.35 mmol) in anhydrous THF (40 mL) under N2 atmosphere at −78° C. was added a solution of NHMDS (1 M in THF, 2.5 mL, 2.5 mmol) within 30 min, followed by TMSCl (0.281 g, 0.327 mL 2.59 mmol) after stirred 30 min. To this reaction mixture was added NHMDS (1 M in THF, 6.0 mL, 6.0 mmol) within 30 min at this temperature. The temperature was allowed to warm to −30 to −20° C., after stirred another 30 min, 2,2-dichlorodiethyl ether (336 mg, 0.275 mL, 2.35 mmol) was added. Then the reaction temperature was allowed to warm to room temperature without removing cooling bath, and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl, and extracted with EA two times. The combined organic phases were washed with 1 M HCl, H2O, brine successively, and dried over anhydrous Na2SO4, and filtered, and concentrated to give black oil. It was purified by flash chromatography on silica gel yield 103 mg of the desired product. MS ESI+ve m/z 281 (M+H)30.