Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C:18]3[S:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[N:20][C:19]=3[CH3:33])=[O:17])[CH2:11]2)=[CH:6][C:3]=1[C:4]#[N:5].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[N:20][C:19]=3[CH3:33])=[O:17])[CH2:11]2)=[CH:6][C:3]=1[C:4]1[NH:40][N:39]=[N:38][N:5]=1
Reactant: Cc1ccc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C#N
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1-c1nnn[nH]1
Yield: 46 %

Procedure:
(R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzonitrile (262 mg, 0.56 mmol) was dissolved in toluene (5 mL). Trimethyltin azide (230 mg, 1.12 mmol) was added and the mixture heated at reflux for 24 h. The mixture was diluted with diethyl ether (100 mL) and washed with 0.1 N HCl (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 7.5% methanol/chloroform (0.5% ammonium hydroxide modifier). The product fractions were combined and concentrated under reduced pressure. The resultant oil was taken up in 100 mL ethyl acetate and extracted with 0.1 N HCl (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 132 mg (46%) of the desired {3-[4-methyl-3-(1H-tetrazol-5-yl)-phenyl]-piperidin-1-yl}-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanone as a clear oil.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:12])([F:11])[CH2:9][OH:10].[N+]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=1)([O-])=O.[Cl-].[NH4+]>O1CCCC1>[F:7][C:8]([F:12])([F:11])[CH2:9][O:10][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc([N+](=O)[O-])ccn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc(OCC(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.9 %

Procedure:
To a solution of potassium tert-butoxide (0.45 g, 4.02 mmol) in tetrahydrofuran (8 mL) is added 2,2,2-trifluoroethanol (0.27 mL, 3.69 mmol), and the mixture is stirred at room temperature for 20 minutes. A solution of 4-nitropicolinonitrile (0.50 g, 3.35 mmol) in tetrahydrofuran (8 mL) is added dropwise the mixture, and the resulting mixture is stirred at room temperature for 20 minutes. The reaction mixture is poured into saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL). The organic layer is dried over sodium sulfate and concentrated in vacuo to give 0.71 g (>99% yield) of the title compound as yellow oil. This material is used for the next reaction (Step-2) without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH2:18][N:19]2C(=O)C4C(=CC=CC=4)C2=O)[CH2:10]3)=[CH:5][CH:4]=[N:3]1.CO.O1CCCC1.NN>>[NH2:19][CH2:18][C@@H:17]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)[C:12]1=[O:16])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc2c(c1)CN([C@H](CN)Cc1cccc(F)c1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
The product of Step D (0.72 g, 1.45 mmol) was dissolved in methanol (4 mL, 100 mmol) and tetrahydrofuran (4 mL, 50 mmol). To the resulting solution was added hydrazine (2 mL, 60 mmol). The solution was stirred at 50° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by combi-flash chromatography eluting with MeOH/EtOAc (20-60%). The product was further purified by prep.-LC/MS (pH=10). The purification afforded 345 mg (37.3% yield) of the final product as white solid. LC-MS found: 365.2 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.70 (d, J=3.6 Hz, 1H), 7.66 (s, 1H), 7.58 (dd, J1=7.8 Hz, J2=1.2 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.23 (dd, J1=7.8 Hz, J2=6.3 Hz, 1H), 7.03 (m, 2H), 6.93 (ddd, J1=8.7 Hz, J2=8.4 Hz, J3=2.4 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 4.46 (s, 2H), 4.40 (m, 1H), 3.86 (s, 3H), 3.04 (dd, J1=14.4 Hz, J2=5.1 Hz, 1H), 2.88 (dd, J1=14.40 Hz, J2=4.5 Hz, 1H), 2.82 (d, J=6.9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2.CO.C1(C)C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[O:12][CH:26]=[N:25][CH:24]=1)=[CH:5]2
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Product: Fc1ccc2[nH]c(-c3cnco3)cc2c1
Yield: 26 %

Procedure:
To a 100 mL round-bottom flask was added 5-fluoro-1H-indole-2-carbaldehyde 47 (0.627 g, 3.84 mmol), methanol (40 mL), p-toluene sulfonylmethyl isocyanide (0.826 g, 4.23 mmol), followed by potassium carbonate (0.68 g, 4.92 mmol). The reaction mixture was stirred at reflux for about 1.5 hour and followed by TLC. The solvent was then evaporated and saturated aq. NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (2×20 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. Crude product was further purified by silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 5-(5-fluoro-1H-indol-2-yl)oxazole 48 (0.202 g, 72% yield). MS (ES) m/z 203 (M+H+).
Reaction SMILES: [Na].[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:29])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:29])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:16]
Reactant: Oc1ccc(C2=CCCCC2)cc1
Reactant: CCCCCCCCC(Br)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)OCC

Procedure:
To a solution of 1.6g of sodium in 100 ml of absolute ethanol, 10 g of p-(1-cyclohexenyl)-phenol in a small amount of absolute ethanol are added at room temperature under anhydrous conditions and with stirring. 10 g of α-bromo-decanoic acid ethyl ester are then added dropwise and the reaction mixture is stirred up for 24 hours at 50° C. The ethanol is subsequently stripped off in vacuo and the residue is partitioned between water and ice-cold N-sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and concentrated in vacuo. The residue yields the crude α-[p-(1-cyclohexenyl)-phenoxy]-decanoic acid ethyl ester of the formula ##STR21## in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CS(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of p-nitrobenzoylchloride (0.925 g, 5.0 mmol) and methanesulfonamide (0.465 g, 4.9 mmol) in dry DCM (10 mL) was cooled to 0° C. To this was added triethylamine (1.48 g, 14.7 mmol) then the mixture was allowed to warm to r.t. and stirred for 12 h. Concentration in vacuo gave the crude title compound, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[C:28]#[N:29])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]=1[CH3:24])=[O:6].Br[C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>COCCOC.O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[C:28]#[N:29])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])=[CH:10][C:9]=1[CH3:24])=[O:6]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: C=C(c1cc(C)c(NC(=O)c2ccc(C#N)c(N)c2)c(C)c1)C(F)(F)F
Temperature: 130 °C
Yield: 81.3 %

Procedure:
3-Amino-4-cyano-N-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (6 g, 15.3 mmol) (Example I4) was dissolved in a mixture of 1,2-dimethoxyethane (22 ml) and tetrahydrofuran (22 ml) in a microwave vial. Then, at 0° C. under an argon atmosphere, 2-bromo-3,3,3-trifluoro-propene (3.20 ml, 30.6 mmol), bis(triphenylphosphine) palladium(II) dichloride (PdCl2(PPh3)2) (0.32 g, 0.46 mmol) and triphenylphosphine (0.6 g, 2.29 mmol) were added. Finally, an aqueous solution of sodium hydroxide (2M) (30 ml) was added at 0° C. under an argon atmosphere. The vial was sealed and heated to 130° C. for 10 minutes in a microwave oven. The reaction mixture was allowed to cool to ambient temperature and concentrated. The residue was suspended in ethyl acetate (500 ml) and filtered through a plug of Celite®. The filtrate was washed twice with water (500 ml). The aqueous phases were extracted with ethyl acetate (500 ml). The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give 3-amino-4-cyano-N-[2,6-dimethyl-4-(1-trifluoromethyl-vinyl)-phenyl]-benzamide (4.47 g, 81% yield) which was used without further purification. LC/MS (Method A): 360 (MH+); RT: 1.82.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14])([O-])=O.CO>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14]
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Nc1ccc2nc[nH]c(=O)c2c1

Procedure:
Hydrogenation of 6-nitro-3H-quinazolin-4-one (2 g) in EtOH (200 mL) was catalyzed by Pd/c (10%, 200 mg) under a H2 balloon for 1 h. MeOH (200 mL) was added to the mixture. The suspension was filtered through a layer of Celite® and the filtrate was concentrated in vacuum to give the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-])=O>C(O)C.[Pd]>[N:28]1([CH2:27][CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([C:12]3([CH2:11][NH:10][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[NH2:1])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:19][CH:20]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=[N+]([O-])c1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 36.8 %

Procedure:
A solution of (3-Nitro-pyridin-4-yl)-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine (200 mg, 0.45 mmol) in ethanol (˜5 mL) was hydrogenated for 4 hours at room temperature at 40 psi in the presence of 10% Pd/C (20 mg, 10% w/w). The reaction mixture was filtered over Arbocel® and rinsed with ethanol. The filtrate was concentrated in vacuo to give a brown oily residue. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (94:6:0.6, by volume) to provide the title compound (68 mg, 36%). HRMS ESI+ m/z 411.2750 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Reactant: CS(=O)(=O)Cl
Product: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1NS(C)(=O)=O

Procedure:
Obtained according to the same procedure as the compound of Example 207, by sulphonylation of (4-amino-3-methoxyphenyl)(1-methoxy-2-methylindolizin-3-yl)methanone with methanesulphonyl chloride. The product is purified by chromatography on a silica column, eluting with a toluene/ethyl acetate (7:3) mixture. A yellow powder is obtained.
Reaction SMILES: FC1C=CC([C:8]2([C:12]3C4C(=CC=C(OCCN)C=4)CC[N:13]=3)CCC2)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([C:37]3[C:46]4[C:41](=[CH:42][C:43]([OH:47])=[CH:44][CH:45]=4)[CH2:40][CH2:39][N:38]=3)[CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2([C:37]3[C:46]4[C:41](=[CH:42][C:43]([O:47][CH2:8][CH2:12][NH2:13])=[CH:44][CH:45]=4)[CH2:40][CH2:39][N:38]=3)[CH2:36][CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Oc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Reactant: NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Product: NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-yl}oxy)ethanamine was prepared analogously to 2-({1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine using 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-ol in place of 1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (cf. example 65).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])([OH:3])=O.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>CCCCCCC>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][C:1]2=[O:3]
Reactant: O=C(O)CCc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: O=S(Cl)Cl
Product: O=C1CCc2c(Cl)cccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
33.5 g (181 mmol) of the 1-(2-carboxyethyl)-2-chlorobenzene and 83.4 ml of thionyl chloride are placed in a reaction vessel and stirred at 80° C. for one hour. The excess thionyl chloride is subsequently taken off and the residue is admixed with 200 ml of heptane. The reaction mixture is stirred for 30 minutes and the solvent is subsequently removed in an oil pump vacuum. The residue is taken up in 536 ml of methylene chloride and, while cooling in ice, 48.4 g (363 mmol) of aluminum trichloride are added a little at a time over a period of 10 minutes. The resulting reaction solution is stirred at 0° C. for another 2 hours before the reaction mixture is poured onto 300 ml of ice water. After the aqueous phase has been separated off and extracted once with 60 ml of toluene, the combined organic phases are washed with 80 ml of water and with 100 ml of saturated NaCl solution. After drying over magnesium sulfate, the solvent is removed in an oil pump vacuum. 29 g (96%) of the desired product are isolated.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16](Cl)=[O:17])[CH:8]=1)[CH3:4]>C1COCC1>[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([NH:2][CH3:1])=[O:17])[CH:8]=1)[CH3:4]
Reactant: CCOC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)NC)cc([N+](=O)[O-])c1
Reaction time: 0.33 h

Procedure:
To a 2M solution of methylamine in THF (256 ml) at −20° C. was added a pre-cooled solution of 3-chlorocarbonyl-5-nitro-benzoic acid ethyl ester (60 g) in THF (500 ml) dropwise. This was stirred for 20 min and then filtered. The filtrate was concentrated in vacuum and the solid recrystallised from diethyl ether to give the title compound (22.5 g) as a solid. An oxalyl chloride solution in DCM (63 ml, 2M), was added with DMF (5 ml). The reaction was stirred for 2 h and then concentrated in vacuum. The residue was triturated with toluene and again concentrated in vacuum leaving the title compound (60 g). Rt=1.53 min (method D).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Na].Cl[CH:11]1[CH2:16][CH2:15][CH2:14][O:13][CH:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C>CCOCC.O>[C:17]1(/[CH:12]=[CH:11]/[CH2:16][CH2:15][CH2:14][OH:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClC1CCCOC1c1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1C
Product: OCCC/C=C/c1ccccc1
Yield: 29 %

Procedure:
Into a flask fitted with dropping funnel, mechanical stirrer and reflux condenser with nitrogen inlet was introduced 2 ml of dry xylene (a) and 69 g (3.0 g-atom) of sodium (b). The xylene was heated until the metal softened, the heating mantel removed, the flask briskly shaken to divide the sodium into sand-like particles and the flask allowed to cool. The xylene was removed and the sodium sand washed with dry ether (3×100 ml) and the finely divided metal residue covered with 1.2 liters of dry ether (c). To the rapidly stirred suspension was added 256 g (1.3 mole) of 3-chloro-2-phenyltetrahydropyran (e) in 20 ml of ether (f). The addition was dropwise until the reaction began, as evidenced by a blue color and the remainder of the halide was added over 90 minutes. The resulting gray slurry was stirred, refluxed after one hour of addition, with the color changing to cream color and the reaction vessel then cooled in an ice bath and with rapid stirred 40 ml of ethanol followed by 9 ml of water were added cautiously. After separation of the layers, the aqueous phase was extracted with ether (3×200 ml), the combined ethereal fractions washed with brine (200 ml) and dried over potassium carbonate. In vacuo removal of solvent left 219 g of a red liquid which was fractionally distilled and the fraction boiling at 94°-95°/0.18 mm Hg collected providing 61.5 g (29% yield).
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[CH:5]12[N:8]([C:9]([C:11]3[S:12][C:13]([Br:23])=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:1]([CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1C2CCC1COC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1nc(-c2ccc(Cl)cc2)c(Br)s1)N1C2CCC1COC2
Temperature: 52.5 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
To a stirred solution 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(4-(4-chlorophenyl)thiazol-2-yl)methanone (Step-2 of compound 68, 0.2 g, 0.60 mmol) in DMF (10 ml) at 0° C. was added N-bromosuccinimide (0.10 g, 0.60 mmol) in a portionwise manner. The resulting reaction mixture was stirred at 50-55° C. for 4 hrs. The progress of reaction was monitored by TLC. The reaction mixture was cooled to room temperature, water (40 ml) was added slowly and aqueous layer was extracted with ethyl acetate (2×50 ml). The organic layer was washed with water (1×30 ml). Combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.12 g, 48.6%). MS: m/z 414 (M+1).
Reaction SMILES: C([C:4](=[C:10]([NH2:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.[OH-].[NH4+]>>[NH2:18][C:10]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)C=C(N)C(F)(F)C(F)(F)F
Yield: 88.5 %

Procedure:
Preparation of Ethyl 2-Chloro-4-Pentafluoroethyl-5-Thiazolecarboxylate To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil; dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo -4-pentafluoroethyl-5-thiazole-carboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoro-ethyl-5-thiazolecarboxylate, nD25 =1 4460.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.Cl[C:31]1[C:32]2[N:39]=[CH:38][N:37]([CH2:40][CH3:41])[C:33]=2[N:34]=[N:35][CH:36]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:15])=[O:16])=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][C:5]([C:31]2[C:32]3[N:39]=[CH:38][N:37]([CH2:40][CH3:41])[C:33]=3[N:34]=[N:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: CCn1cnc2c(Cl)cnnc21
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)c(OC)c1
Product: CCn1cnc2c(-c3ccc(Cl)c(-c4ccc(S(=O)(=O)CC)cc4OC)c3)cnnc21
Yield: 19 %

Procedure:
Prepared according to the method described for Example 45 using 2-(6-chloro-4′-(ethylsulfonyl)-2′-methoxy-[1,1′-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 56) and 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8) to afford the title compound as an off white solid in 19% yield, 9.9 mg.