Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[NH2:3][C:4]1[C:9](Cl)=[C:8]([F:11])[N:7]=[C:6](Cl)[C:5]=1[F:13]>[C].[Pd].C(N(CC)CC)C>[NH2:3][C:4]1[C:5]([F:13])=[CH:6][N:7]=[C:8]([F:11])[CH:9]=1
Reactant: Nc1c(F)c(Cl)nc(F)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1cc(F)ncc1F
Reaction time: 288 h
Yield: 90.8 %

Procedure:
To 40 ml of methanol were added 4.5 g of 4-amino-2,5-dichloro-3,6-difluoropyridine and 4.5 g of triethylamine together with 0.40 g of 10% palladium carbon, and the mixture was hydrogenated at 50° C. for 12 days. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 100 ml of chloroform, and the mixture was washed with 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added 1.5 g of triethylamine, 0.35 g of 10% palladium on carbon, and 30 ml of methanol, and the mixture was hydrogenated at 50° C. for 41 hours. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 100 ml of chloroform, and the mixture was washed with 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2.67 g of the title compound as precipitate as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9]CC2C=CC=CC=2)=[CH:7][CH:6]=1.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[CH:17][CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To 0.72 g of ([4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene, were added 2 ml of ethyl acetate, 0.7 ml of ethanol and 36 mg of 10% palladium/carbon, and the mixture was stirred for 5 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, the filtrate was concentrated to obtain 0.48 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C(=O)O)c1ccc(N)cc1
Reaction time: 24 h

Procedure:
A mixture of 1 (6.7 g, 1 mmol) in THF (100 ml) and EtOH (100 ml) is slowly added 10% Pd/C (680 mg) at room temperature. The reaction mixture is hydrogenated for 24 h with H2 balloon at room temperature. The mixture is filtered through celite pad and washed with EtOH. The filtrate is concentrated in vacuo.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([I:1])=[C:10]([CH3:11])[CH:9]=3)[CH:5]=[N:6]2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc2[nH]ncc2cc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1I
Yield: 51.1 %

Procedure:
5-Iodo-6-methylindazole (1.3 g, 5.0 mmol), p-fluorobenzeneboronic acid (1.4 g, 10 mmol), anhydrous copper(II) acetate (1.4 g, 7.5 mmol) and pyridine (0.80 mL, 10 mmol) were stirred in dichloromethane (30 mL) overnight. Additional portions of p-fluorobenzeneboronic acid (0.47 g, 3.4 mmol), anhydrous copper(II) acetate (0.45 g, 2.5 mmol) and pyridine (0.27 mL, 3.4 mmol) were added. The mixture was filtered through celite after stirring for an additional night. The filtrate was concentrated and purified by column chromatography (SiO2, toluene) to give the subtitle compound (0.90 g, 51%) as a light orange powder.
Reaction SMILES: [CH2:1]([N:3]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[CH2:8][C@H:4]1[C:5]([OH:7])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][NH2:45].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH2:44][NH:45][C:5](=[O:7])[C@@H:4]1[CH2:8][C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:3]1[CH2:1][CH3:2]
Reactant: CCN1C(=O)C(C)(C)C[C@H]1C(=O)O
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)C[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
1-ethyl-4,4-dimethyl-5-oxoproline (0.130 g, 0.702 mmol, prepared as described below), 1-Hydroxybenzotriazole (0.161 g, 1.053 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.202 g, 1.053 mmol) were dissolved in dichloromethane (5 ml) and stirred for 15 minutes at room temperature. [(2-chloro-4-fluorophenyl)methyl]amine (0.134 g, 0.842 mmol) and diisopropylethylamine (0.184 ml, 1.053 mmol) were then added to the mixture and stirring continued overnight at room temperature. The mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water and extracted with ethyl acetate. The combined organic layers were washed sequentially with 3N citric acid, water, saturated aqueous sodium carbonate, water (×3), and then brine and dried over anhydrous sodium sulfate. Concentration gave a crude solid which was subsequently purified by mass-directed automated HPLC to give N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxoprolinamide (0.146 g) as a solid. LC/MS [M+H]+=327/329, retention time=2.35 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH3:12].[I:14]I>FC(F)(F)S([O-])(=O)=O.[Ag+].CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:14])[C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: II
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: COC(=O)c1cc(I)c(C)cc1OC
Yield: 88.7 %

Procedure:
A methanol solution (28 ml) of 2-methoxy-4-methylbenzoic acid methyl ester (1.2 g, 7.0 mmol) obtained in Step 1 above, silver trifluoromethanesulfonate (2.0 g, 7.8 mmol), and iodine (2.0 g, 7.8 mmol) was stirred at room temperature for 1.5 hour. The reaction solution was concentrated under reduced pressure. The resulting pale yellow solid was separated by filtration, and washed with ethyl acetate (300 ml). The washing solution was sequentially washed with 5% aqueous sodium thiosulfate solution (100 ml), and a saturated aqueous sodium chloride solution (100 ml). Then, the solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1) to yield 5-iodo-2-methoxy-4-methylbenzoic acid methyl ester (1.9 g) as a pale yellow solid material.
Reaction SMILES: [Mg].Cl[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].II.[CH:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18]>CCOCC>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[CH2:3][CH:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(O)Cc1ccc(Cl)cc1Cl
Yield: 23 %

Procedure:
To 7.5g (0.384 mole) of magnesium turnings in 150 ml of ether is added a 10.0g (0.051 mole) portion of α,2,4-trichlorotoluene and a few crystals of iodine. When the iodine color has dissipated, the reaction is warmed to reflux, and 58.0g (0.297 mole) of additional α,2,4-trichlorotoluene in 50 ml of ether is added at such a rate that the refluxing is maintained. When the addition is complete, the reaction is stirred at reflux for 2 hours and cooled. To this reaction mixture is added 17.0g (0.197 mole) of valeraldehyde, and the reaction is heated again at reflux for 2 hours. The reaction is cooled and poured into ice cold dilute hydrochloric acid, and the organic phase is separated. The aqueous solution is extracted with ether, and the extract is combined with the organic phase. After a water wash, the organic solution is dried over anhydrous magnesium sulfate and stripped of solvent to give 57.2g of crude product. A distillation provides 11.3g (23%) of the product. Purity is determined by glc.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:12]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)[OH:13])=[CH:4][CH:5]=1)#[N:10]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN(O)Cc2ccc(C#N)cc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 10.0 grams of alpha-bromo-p-cyanotoluene, 1.77 grams of hydroxylamine hydrochloride and 10.6 grams of anhydrous sodium carbonate in 50 ml of dry N,N-dimethylformamide (DMF) is allowed to stand overnight at room temperature. The DMF solvent is then removed under reduced pressure and the reidue is partitioned between methylene chloride and water. The organic layer is washed with water, dried over anhydrous sodium sulfate and then evaporated in vacuo to give a solid residue which upon trituration with ethanol yields the above-named compound as a white solid, melting at 172°-175° C.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])=[O:5].Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>CC(N(C)C)=O>[CH2:20]([O:19][C:17]([S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])=[O:5])=[O:18])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)COC(=O)Cl
Reactant: C[C@H](N)C(=O)NC(=O)c1ccccc1S
Solvent: CC(=O)N(C)C
Product: CC(C)COC(=O)Sc1ccccc1C(=O)NC(=O)[C@H](C)N
Reaction time: 8 h

Procedure:
To a solution of N-(2-mercaptobenzoyl)-L-alaninamide (0.22 g, 1.00 mmol) in DMA (5 ml) was added iso-butyl chloroformate (0.2 g, 1.50 mmol), and the mixture was stirred for 8 h. The solvent was evaporated to dryness, and the residue was triturated with ethyl ether (25 ml). The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield, 73%. The product was further purified by column chromatography on silica using chloroform-methanol (7:3 v/v) as eluent with 82% recovery. 1H NMR (DMSO-d6): 0.94(d, 6H, 2CH3), 1.34(d, 3H, CH3), 1.96(m, 1H, CH), 4.06(d, 2H, CH2), 4.44quintet, 1H, CH), 7.16(brs, 1H, NH2), 7.38(brs, 1H, NH2), 7.54-7.80(m, 4H, Ar—H), 8.42(d, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=O.[Cl-].[OH:21][NH3+:22].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[N:22][OH:21]
Reactant: O=C(c1ccc(Oc2ccccc2)cc1)C(F)(F)F
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(Oc2ccccc2)cc1)C(F)(F)F
Temperature: 80 °C
Yield: 84.3 %

Procedure:
122 g (0.46 mol) of 2,2,2-trifluoro-1-(4-phenoxyphenyl)-ethanone are dissolved in 370 ml of ethanol and heated at 80° C. To the solution are added 33.3 g (0.48 mol) of hydroxylammonium chloride and 63.7 g (0.78 mol) of sodium acetate dissolved in 190 ml of water. The reaction mixture is refluxed for 5.5 hours, and poured into water. A pale yellow solid is precipitated. The solid is isolated by filtration and rinsed with water, and added in hexane and heated at 60° C. for 20 min. After cooling, the solid is isolated and rinsed with hexane, yielding 109 g of 2,2,2-trifluoro-1-(4-phenoxyphenyl)-ethanone oxime as a white solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 7.00-7.10 (m, 4H), 7.18 (t, 1H), 7.39 (t, 2H), 7.55 (d, 2H), 9.35 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[CH3:16][Mg]Br>CCOCC>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:16])([OH:13])[C:7]([CH3:11])([CH3:12])[S:8](=[O:9])(=[O:10])[C:4]=2[CH:3]=1
Reactant: C[Mg]Br
Reactant: CC1(C)C(=O)c2ccc(Br)cc2S1(=O)=O
Solvent: CCOCC
Product: CC1(O)c2ccc(Br)cc2S(=O)(=O)C1(C)C
Temperature: 25 °C
Yield: 97 %

Procedure:
A cooled (0° C.) solution of 6-bromo-2,2-dimethyl-1-benzothiophen-3(2H)-one 1,1-dioxide (Intermediate 241; 750 mg; 2.59 mmol) in anhydrous Et2O (22.5 ml) was treated carefully with a 3 M solution of methylmagnesium bromide in Et2O (2.6 ml; 7.8 mmol). The white solution was stirred at RT for 1.5 before being quenched with a saturated solution of NH4Cl in water. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to dryness to afford the title compound as a white solid (767 mg, 97%).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH3:14])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:5])[F:4])[CH:8]=1)[CH3:14])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(OC(F)(F)C(F)F)c1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (0.92 g, colorless oil) from 1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone (0.79 g, 3.36 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[N:14]([N:23]=[CH:24][N:25]=3)[C:15]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)=[CH:16][N:17]=2)[CH:6]=1)[CH3:2].[OH:27][C:28]1[CH:35]=[CH:34]C(CN)=[CH:30][CH:29]=1>>[OH:27][C:28]1[CH:35]=[CH:34][C:2]([CH2:1][NH:3][C:4](=[O:26])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]3[C:13]4[N:14]([N:23]=[CH:24][N:25]=4)[C:15]([C:18]4[CH:19]=[N:20][NH:21][CH:22]=4)=[CH:16][N:17]=3)[CH:6]=2)=[CH:30][CH:29]=1
Reactant: NCc1ccc(O)cc1
Reactant: CCNC(=O)c1cccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)c1
Product: O=C(NCc1ccc(O)cc1)c1cccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)c1

Procedure:
This compound may be prepared using methods as described for Compound 129, using 4-hydroxybenzylamine in step 5. LCMS: Rt=0.98 min (100%), m/z (ESI) 427 (M+H)+.
Reaction SMILES: CO.[N:3](=[C:5]1[C:11]2[CH:12]=[N:13][CH:14]=[N:15][C:10]=2[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1)O>C(O)C.[Ni]>[NH2:3][CH:5]1[C:11]2[CH:12]=[N:13][CH:14]=[N:15][C:10]=2[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:6]1
Reactant: ON=c1nc(-c2ccccc2)c2ccccc2c2ncncc12
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: NC1N=C(c2ccccc2)c2ccccc2-c2ncncc21
Reaction time: 30 h

Procedure:
A solution of 150 ml of methanol containing 5 g of 5-oximino-7-phenyl-5H-pyrimido[5,4-d][2]-benzazepine is treated with a slurry of active Raney-Nickel catalyst1 in ethanol (10 g). The resulting suspension is hydrogenated on a Parr apparatus at 60 psi and 23° C. for about 30 hours. The catalyst is removed by filtration and the filtrate is concentrated to afford the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=1>ClCCl>[CH3:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([Cl:2])=[O:15])[N:12]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(C(=O)Cl)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.2 %

Procedure:
Phosphorus pentachloride (13.35 g) was added in small portions to a suspension of 2-methyl-4-thiazolecarboxylic acid (7.65 g) in dry dichloromethane over a period of 10 minutes. The resulting mixture was vigorously stirred for 1.5 hours at room temperature and then concentrated under reduced pressure. The residue was dissolved in dry benzene (40 ml) and the mixture was concentrated under reduced pressure to give yellow powders of 2-methyl-4-thiazolecarbonyl chloride (9.0 g).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1.[CH3:16]O>>[Cl:5][C:6]1[CH:14]=[C:10]([C:11]([O:13][CH3:16])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1O

Procedure:
To a cold solution of 100 ml methanol is slowly added 100 ml thionyl chloride followed by 30 g of 5-chlorosalicylic acid. This is then refluxed overnight, the solvent removed and the residue dissolved in ether. The ether is washed with a sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated to dryness to obtain methyl 5-chlorosalicylate which is used directly in the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:17]2[C:12]([N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH3:27])[C:16]2=[O:26])=[CH:11]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:17]2[C:12]([N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH3:27])[C:16]2=[O:26])=[CH:11]1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Reaction time: 2 h

Procedure:
{2-[5-(3-Chloro-phenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl]-ethyl}-carbamic acid tert-butyl ester (step 5) (429 mg, 0.991 mmol) was dissolved in DCM (10 ml). TFA (1.374 ml, 17.84 mmol) was charged in 2 portions and the reaction stirred under nitrogen. After 2 hrs, the pH of the mixture was adjusted to pH 11 with saturated K3CO3 solution (20 mL). The layers were separated and the aqueous extracted with DCM (4×20 mL). The combined organics were passed through a hydrophobic frit and evaporated under reduced pressure to afford a tan solid, which was dried under vacuum at 50° C. for 5 h to afford the title compound as a tan solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a yellow powder: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.45 (1H, t, J 8), 7.56 (1H, ddd, J 8, 8 and 1), 7.62-7.68 (3H, m), 7.70 (1H, ddd, J 8, 8 and 1), 7.85 (1H, dd, J 8 and 1), 8.10 (1H, s), 9.06 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CO.[C:28]1([CH2:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+]>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCC(=O)CC3)cnc2N)cc1F
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCC(NCc4ccccc4)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To methyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (300 mg, 0.874 mmol) was added MeOH (4 mL), phenylmethanamine (112 mg, 1.048 mmol) and last dry 4 Å molecular sieves. The reaction was stirred at room temperature for 16 h. Then NaBH4 (165 mg, 4.37 mmol) was added and stirred at room temperature for 2 h followed by LCMS. To the reaction was added 150 mL of ethyl acetate, washed with saturated sodium bicarbonate, water (2×), saturated salt solution, dried over sodium sulfate, filtered and concentrated to residue to give 352 mg of the desired product in 2:1 trans to cis ratio, used as is (93%). LCMS (m/z): 435.3 (MH+), 0.68 min and 0.72 min.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7](COCC[Si](C)(C)C)[CH:8]=1)#[N:3].[CH2:20]([O:22][C:23](=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([C:32]2[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH:33]=2)[N:26]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:17]([C:6]2[NH:5][C:4]([C:2]#[N:3])=[CH:8][N:7]=2)=[O:19])=[C:27]([C:32]2[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH:33]=2)[N:26]=1)[CH3:21]
Reactant: CCOC(=O)Cc1ccc(N)c(C2=CCC(C)(C)CC2)n1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)n1

Procedure:
The title compound was prepared by coupling 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) and [5-amino-6-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-2-yl]-acetic acid ethyl ester (as prepared in the previous step) according to the procedure in Example 34, step (c), followed by SEM deprotection according to the procedure in Example 34, step (d). Mass spectrum (ESI, m/z): Calcd. for C22H25ClN5O3, 408.2 (M+H). found 408.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:21])[C:15](=[N+]=[N-])[C:16](=[O:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][OH:23]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:21])[CH:15]([O:23][CH3:22])[C:16](=[O:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CO
Agent: [Rh]
Solvent: CC(=O)O
Product: COC(C(C)=O)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C

Procedure:
A solution of 532 mg (1.8 mmol) of 1-(tert-butoxycarbonyl)-4-(2-diazo-1,3-dioxo-but-1-yl)piperidine in 5 mL of MeOH was treated with 25 mg (0.056 mmol) of rhodium (II) acetate dimer. The reaction was slowly warmed to 65° C. over 2 hours. Upon cooling, volatiles were removed under reduced pressure. The residue was partitioned between 100 mL of EtOAc and 100 mL of H2O. After separating phases, the organic layer was washed with 100 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 19:1 v/v hexanes/acetone as the eluant to afford the title compound as a yellow oil: RF: 0.39 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.45, 1.47 (2s, 9H), 1.68–1.71 (m, 3H), 2.19, 2.22 (2s, 3H), 2.78–2.89 (m, 2H), 3.44, 3.58 (2s, 3H), 4.03–4.3 (m, 2H).